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Zhou Y, Li M, Lin S, Zhu Z, Zhuang Z, Cui S, Chen L, Zhang R, Wang X, Shen B, Chen C, Yang R. Mechanical sensing protein PIEZO1 controls osteoarthritis via glycolysis mediated mesenchymal stem cells-Th17 cells crosstalk. Cell Death Dis 2025; 16:231. [PMID: 40169556 PMCID: PMC11961634 DOI: 10.1038/s41419-025-07577-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 03/04/2025] [Accepted: 03/20/2025] [Indexed: 04/03/2025]
Abstract
Aberrant mechanical stimuli can cause tissue attrition and activate mechanosensitive intracellular signaling, impacting the progression of osteoarthritis (OA). However, the precise relationship between mechanical loading and bone metabolism remains unclear. Here, we present evidence that Piezo1 senses the mechanical stimuli to coordinate the crosstalk between mesenchymal stem cells (MSCs) and T helper 17 (Th17) cells, leading to the deterioration of bone and cartilage in osteoarthritis (OA). Mechanical loading impaired the property of MSCs by inhibiting their osteo-chondrogenic differentiation and promoting inflammatory signaling to enhance Th17 cells. Mechanistically, mechanical stimuli activated Piezo1, thereby facilitating Ca2+ influx which upregulated the activity of Hexokinase 2(HK2), the rate-limiting enzyme of glycolysis. The resultant increase in glycolytic activity enhanced communication between MSCs and T cells, thus promoting Th17 cell polarization in a macrophage migration inhibitory factor (MIF) dependent manner. Functionally, Wnt1cre; Piezo1fl/fl mice reduced bone and cartilage erosion in the temporomandibular joint condyle following mechanical loading compared to control groups. Additionally, we observed activated Piezo1 and HK2-mediated glycolysis in patients with temporomandibular joint OA, thereby confirming the clinical relevance of our findings. Overall, our results provide insights into how Piezo1 in MSCs coordinates with mechano-inflammatory signaling to regulate bone metabolism. The schema shows that mechanical sensing protein PIEZO1 in MSCs controls osteoarthritis via glycolysis mediated MSCs and Th17 cells crosstalk in a MIF dependent manner.
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Affiliation(s)
- Yikun Zhou
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials Beijing, Beijing, China
- Department of Orthodontics, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Mingzhao Li
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials Beijing, Beijing, China
| | - Shuai Lin
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials Beijing, Beijing, China
| | - Zilu Zhu
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials Beijing, Beijing, China
| | - Zimeng Zhuang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials Beijing, Beijing, China
| | - Shengjie Cui
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials Beijing, Beijing, China
| | - Liujing Chen
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials Beijing, Beijing, China
| | - Ran Zhang
- Department of Oral Pathology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Xuedong Wang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials Beijing, Beijing, China
| | - Bo Shen
- National Institute of Biological Sciences, Beijing, China, Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
| | - Chider Chen
- Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA
| | - Ruili Yang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials Beijing, Beijing, China.
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Wang Z, Wang K, Yu Y, Fu J, Zhang S, Li M, Yang J, Zhang X, Liu X, Lv F, Ma L, Cai H, Tian W, Liao L. Identification of human cranio-maxillofacial skeletal stem cells for mandibular development. SCIENCE ADVANCES 2025; 11:eado7852. [PMID: 39742474 PMCID: PMC11691644 DOI: 10.1126/sciadv.ado7852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 11/19/2024] [Indexed: 01/03/2025]
Abstract
Compared with long bone that arises from the mesoderm, the major portion of the maxillofacial bones and the front bone of the skull are derived from cranial neural crest cells and undergo intramembranous ossification. Human skeletal stem cells have been identified in embryonic and fetal long bones. Here, we describe a single-cell atlas of the human embryonic mandible and identify a population of cranio-maxillofacial skeletal stem cells (CMSSCs). These CMSSCs are marked by interferon-induced transmembrane protein 5 (IFITM5) and are specifically located around the periosteum of the jawbone and frontal bone. Additionally, these CMSSCs exhibit strong self-renewal and osteogenic differentiation capacities but lower chondrogenic differentiation potency, mediating intramembranous bone formation without cartilage formation. IFITM5+ cells are also observed in the adult jawbone and exhibit functions similar to those of embryonic CMSSCs. Thus, this study identifies CMSSCs that orchestrate the intramembranous ossification of cranio-maxillofacial bones, providing a deeper understanding of cranio-maxillofacial skeletal development and promising seed cells for bone repair.
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Affiliation(s)
- Zhuo Wang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Engineering Research Center of Oral Translational Medicine, Ministry of Education and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China
| | - Kun Wang
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Yejia Yu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Engineering Research Center of Oral Translational Medicine, Ministry of Education and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China
| | - Jing Fu
- Department of Reproductive Endocrinology, West China Second University Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, China
| | - Siyuan Zhang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Engineering Research Center of Oral Translational Medicine, Ministry of Education and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China
| | - Maojiao Li
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Engineering Research Center of Oral Translational Medicine, Ministry of Education and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China
| | - Jian Yang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Engineering Research Center of Oral Translational Medicine, Ministry of Education and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China
| | - Xuanhao Zhang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Engineering Research Center of Oral Translational Medicine, Ministry of Education and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China
| | - Xiaodong Liu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Engineering Research Center of Oral Translational Medicine, Ministry of Education and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China
| | - Fengqiong Lv
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, China
- Department of Operating Room Nursing, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Li Ma
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, China
- Department of Operating Room Nursing, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Haoyang Cai
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Weidong Tian
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Engineering Research Center of Oral Translational Medicine, Ministry of Education and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China
| | - Li Liao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Engineering Research Center of Oral Translational Medicine, Ministry of Education and National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China
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Liu L, Le PT, DeMambro VE, Feng T, Liu H, Ying W, Baron R, Rosen CJ. Calorie restriction induces mandible bone loss by regulating mitochondrial function. Bone 2025; 190:117326. [PMID: 39528064 PMCID: PMC11618829 DOI: 10.1016/j.bone.2024.117326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/04/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024]
Abstract
Caloric restriction (CR), commonly used as both a lifestyle choice and medical strategy, has been shown to adversely impact appendicular bone mass. However, its influence on alveolar bone health and the underlying mechanisms remain poorly understood. In this study, 8-week-old C57BL/6 J mice were fed with 30 % CR for 8 weeks. Micro-architecture, histologic parameters, and in vitro trajectories of osteoblast and adipocyte differentiation were examined. To further explore the underlying mechanisms, metabolic cages and in vitro bioenergetics were performed. Our results showed that 8 weeks of CR led to trabecular and cortical bone loss in the mandibles of female mice. CR in female mice decreased bone formation and bone resorption activities but induced adiposity in the mandibles. After CR, the adipogenesis in mesenchymal cells from orofacial bones (OMSCs) was greatly accelerated, whereas osteogenic differentiation was reduced in females. Undifferentiated CR OMSCs showed marked suppression in ATP production rates from mitochondria in female mice. ATP production rates decreased after osteogenesis but were upregulated during adipogenesis in female mice. Conversely, the generation of reactive oxygen species (ROS) was heightened during both osteoblastic and adipogenic differentiation in female CR groups. Collectively, our study indicated that CR could cause significant bone loss in the mandibles of female mice, almost certainly related to a reduced ATP supply and the unregulated generation of ROS.
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Affiliation(s)
- Linyi Liu
- MaineHealth Institute for Research, Scarborough, ME 04074, USA.
| | - Phuong T Le
- MaineHealth Institute for Research, Scarborough, ME 04074, USA.
| | | | - Tiange Feng
- MaineHealth Institute for Research, Scarborough, ME 04074, USA.
| | - Hanghang Liu
- West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - Wangyang Ying
- School of Computing and Augmented Intelligence, Arizona State University, Tempe, AZ 85281, USA.
| | - Roland Baron
- Division of Bone and Mineral Research, Dept of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
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Cui C, Lu C, Cai Y, Xiong Y, Duan Y, Lan K, Fan Y, Zhou X, Wei X. PTH1R Suppressed Apoptosis of Mesenchymal Progenitors in Mandibular Growth. Int J Mol Sci 2024; 25:12607. [PMID: 39684319 DOI: 10.3390/ijms252312607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/14/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Genetic abnormalities of the parathyroid hormone 1 receptor (PTH1R) lead to profound craniomaxillofacial bone and dentition defects on account of inappropriate tissue metabolism and cellular differentiation. The coordinated activity of differentiation and viability in bone cells is indispensable for bone metabolism. Recent research demonstrates mesenchymal progenitors are responsive to PTH1R signaling for osteogenic differentiation, whereas the effect of PTH1R on cellular survival remains incompletely understood. Here, we report that mice with deletion of PTH1R in Prx1-positive mesenchymal cells (Prx1Cre;PTH1Rfl/fl) exhibit decreased alveolar bone mass due in part to apoptotic response activation. The exploration of oral bone-derived mesenchymal stem cells (OMSCs) with PTH1R deficiency suggests PTH1R signaling modulates OMSCs' apoptosis by interfering mitochondrial function and morphology. The underlying molecular mechanisms are studied by transcriptome sequencing analysis, finding that inositol trisphosphate receptor-3 (IP3R-3), an endoplasmic reticulum calcium channel protein, serves as a modulator of pro-apoptosis in OMSCs. Furthermore, we find PTH1R and its downstream protein kinase A (PKA) pathway dampen IP3R-3's expression. Of note, OMSCs with IP3R-3 overexpression recapitulate the PTH1R-deletion phenotypes, while IP3R-3 silence rescues mitochondrial dysfunction. Altogether, our study uncovers the anti-apoptotic function of PTH1R signaling in OMSCs and proves that excess apoptosis partly contributes to a weakening potential of osteogenic differentiation and aberrant mandibular development.
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Affiliation(s)
- Chen Cui
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Chuang Lu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Yanling Cai
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Yuhua Xiong
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Yihong Duan
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Kaiwen Lan
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Yi Fan
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Xi Wei
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
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5
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Lin C, Yang YS, Ma H, Chen Z, Chen D, John AA, Xie J, Gao G, Shim JH. Engineering a targeted and safe bone anabolic gene therapy to treat osteoporosis in alveolar bone loss. Mol Ther 2024; 32:3080-3100. [PMID: 38937970 PMCID: PMC11403231 DOI: 10.1016/j.ymthe.2024.06.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 06/04/2024] [Accepted: 06/24/2024] [Indexed: 06/29/2024] Open
Abstract
Alveolar bone loss in elderly populations is highly prevalent and increases the risk of tooth loss, gum disease susceptibility, and facial deformity. Unfortunately, there are very limited treatment options available. Here, we developed a bone-targeted gene therapy that reverses alveolar bone loss in patients with osteoporosis by targeting the adaptor protein Schnurri-3 (SHN3). SHN3 is a promising therapeutic target for alveolar bone regeneration, because SHN3 expression is elevated in the mandible tissues of humans and mice with osteoporosis while deletion of SHN3 in mice greatly increases alveolar bone and tooth dentin mass. We used a bone-targeted recombinant adeno-associated virus (rAAV) carrying an artificial microRNA (miRNA) that silences SHN3 expression to restore alveolar bone loss in mouse models of both postmenopausal and senile osteoporosis by enhancing WNT signaling and osteoblast function. In addition, rAAV-mediated silencing of SHN3 enhanced bone formation and collagen production of human skeletal organoids in xenograft mice. Finally, rAAV expression in the mandible was tightly controlled via liver- and heart-specific miRNA-mediated repression or via a vibration-inducible mechanism. Collectively, our results demonstrate that AAV-based bone anabolic gene therapy is a promising strategy to treat alveolar bone loss in osteoporosis.
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Affiliation(s)
- Chujiao Lin
- Department of Medicine/Division of Rheumatology, UMass Chan Medical School, Worcester, MA 01655, USA
| | - Yeon-Suk Yang
- Department of Medicine/Division of Rheumatology, UMass Chan Medical School, Worcester, MA 01655, USA
| | - Hong Ma
- Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA 01655, USA; Horae Gene Therapy Center, Umass Chan Medical School, Worcester, MA 01655, USA; Viral Vector Core, UMass Chan Medical School, Worcester, MA 01655, USA
| | - Zhihao Chen
- Department of Medicine/Division of Rheumatology, UMass Chan Medical School, Worcester, MA 01655, USA
| | - Dong Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Implantology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Aijaz Ahmad John
- Department of Medicine/Division of Rheumatology, UMass Chan Medical School, Worcester, MA 01655, USA
| | - Jun Xie
- Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA 01655, USA; Horae Gene Therapy Center, Umass Chan Medical School, Worcester, MA 01655, USA; Viral Vector Core, UMass Chan Medical School, Worcester, MA 01655, USA
| | - Guangping Gao
- Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA 01655, USA; Horae Gene Therapy Center, Umass Chan Medical School, Worcester, MA 01655, USA; Viral Vector Core, UMass Chan Medical School, Worcester, MA 01655, USA; Li Weibo Institute for Rare Diseases Research, UMass Chan Medical School, Worcester, MA 01655, USA.
| | - Jae-Hyuck Shim
- Department of Medicine/Division of Rheumatology, UMass Chan Medical School, Worcester, MA 01655, USA; Horae Gene Therapy Center, Umass Chan Medical School, Worcester, MA 01655, USA; Li Weibo Institute for Rare Diseases Research, UMass Chan Medical School, Worcester, MA 01655, USA.
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Zakaria MF, Sonoda S, Kato H, Ma L, Uehara N, Kyumoto-Nakamura Y, Sharifa MM, Yu L, Dai L, Yamauchi-Tomoda E, Aijima R, Yamaza H, Nishimura F, Yamaza T. Erythropoietin receptor signal is crucial for periodontal ligament stem cell-based tissue reconstruction in periodontal disease. Sci Rep 2024; 14:6719. [PMID: 38509204 PMCID: PMC10954634 DOI: 10.1038/s41598-024-57361-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 03/18/2024] [Indexed: 03/22/2024] Open
Abstract
Alveolar bone loss caused by periodontal disease eventually leads to tooth loss. Periodontal ligament stem cells (PDLSCs) are the tissue-specific cells for maintaining and repairing the periodontal ligament, cementum, and alveolar bone. Here, we investigated the role of erythropoietin receptor (EPOR), which regulates the microenvironment-modulating function of mesenchymal stem cells, in PDLSC-based periodontal therapy. We isolated PDLSCs from patients with chronic periodontal disease and healthy donors, referred to as PD-PDLSCs and Cont-PDLSCs, respectively. PD-PDLSCs exhibited reduced potency of periodontal tissue regeneration and lower expression of EPOR compared to Cont-PDLSCs. EPOR-silencing suppressed the potency of Cont-PDLSCs mimicking PD-PDLSCs, whereas EPO-mediated EPOR activation rejuvenated the reduced potency of PD-PDLSCs. Furthermore, we locally transplanted EPOR-silenced and EPOR-activated PDLSCs into the gingiva around the teeth of ligament-induced periodontitis model mice and demonstrated that EPOR in PDLSCs participated in the regeneration of the periodontal ligament, cementum, and alveolar bone in the ligated teeth. The EPOR-mediated paracrine function of PDLSCs maintains periodontal immune suppression and bone metabolic balance via osteoclasts and osteoblasts in the periodontitis model mice. Taken together, these results suggest that EPOR signaling is crucial for PDLSC-based periodontal regeneration and paves the way for the development of novel options for periodontal therapy.
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Affiliation(s)
- Mhd Fouad Zakaria
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
- Department of Periodontology, Kyushu University Graduate School of Dental Science, Fukuoka, Japan
| | - Soichiro Sonoda
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Hiroki Kato
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Lan Ma
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
- Guangdong Provincial Key Laboratory of Stomatology, South China Center of Craniofacial Stem Cell Research, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Norihisa Uehara
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yukari Kyumoto-Nakamura
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - M Majd Sharifa
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Liting Yu
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Lisha Dai
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Erika Yamauchi-Tomoda
- Department of Oral and Maxillofacial Radiology, Kyushu University Graduate School of Dental Science, Fukuoka, Japan
| | - Reona Aijima
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Haruyoshi Yamaza
- Department of Pediatric Dentistry, Kyushu University Graduate School of Dental Science, Fukuoka, Japan
| | - Fusanori Nishimura
- Department of Periodontology, Kyushu University Graduate School of Dental Science, Fukuoka, Japan
| | - Takayoshi Yamaza
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
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7
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Wang Y, Li HY, Guan SY, Yu SH, Zhou YC, Zheng LW, Zhang J. Different Sources of Bone Marrow Mesenchymal Stem Cells: A Comparison of Subchondral, Mandibular, and Tibia Bone-derived Mesenchymal Stem Cells. Curr Stem Cell Res Ther 2024; 19:1029-1041. [PMID: 37937557 DOI: 10.2174/011574888x260686231023091127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 08/04/2023] [Accepted: 09/01/2023] [Indexed: 11/09/2023]
Abstract
BACKGROUND Stem cell properties vary considerably based on the source and tissue site of mesenchymal stem cells (MSCs). The mandibular condyle is a unique kind of craniofacial bone with a special structure and a relatively high remodeling rate. MSCs here may also be unique to address specific physical needs. OBJECTIVE The aim of this study was to compare the proliferation and multidirectional differentiation potential among MSCs derived from the tibia (TMSCs), mandibular ramus marrow (MMSCs), and condylar subchondral bone (SMSCs) of rats in vitro. METHODS Cell proliferation and migration were assessed by CCK-8, laser confocal, and cell scratch assays. Histochemical staining and real-time PCR were used to evaluate the multidirectional differentiation potential and DNA methylation and histone deacetylation levels. RESULTS The proliferation rate and self-renewal capacity of SMSCs were significantly higher than those of MMSCs and TMSCs. Moreover, SMSCs possessed significantly higher mineralization and osteogenic differentiation potential. Dnmt2, Dnmt3b, Hdac6, Hdac7, Hdac9, and Hdac10 may be instrumental in the osteogenesis of SMSCs. In addition, SMSCs are distinct from MMSCs and TMSCs with lower adipogenic differentiation and chondrogenic differentiation potential. The multidirectional differentiation capacities of TMSCs were exactly the opposite of those of SMSCs, and the results of MMSCs were intermediate. CONCLUSION This research offers a new paradigm in which SMSCs could be a useful source of stem cells for further application in stem cell-based medical therapies due to their strong cell renewal and osteogenic capacity.
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Affiliation(s)
- Yu Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Hong-Yu Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Shu-Yuan Guan
- Department of Stomatology, Medical College, Dalian University, Dalian, 116622, Liaoning, China
| | - Si-Han Yu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ya-Chuan Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Li-Wei Zheng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jun Zhang
- Yunnan Key Laboratory of Stomatology, Kunming Medical University School and Hospital of Stomatology, Kunming, China
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8
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Shao B, Zhou D, Wang J, Yang D, Gao J. A novel LncRNA SPIRE1/miR-181a-5p/PRLR axis in mandibular bone marrow-derived mesenchymal stem cells regulates the Th17/Treg immune balance through the JAK/STAT3 pathway in periodontitis. Aging (Albany NY) 2023; 15:7124-7145. [PMID: 37490712 PMCID: PMC10415575 DOI: 10.18632/aging.204895] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 07/06/2023] [Indexed: 07/27/2023]
Abstract
Periodontitis is a microbial-related chronic inflammatory disease associated with imbalanced differentiation of Th17 cells and Treg cells. Bone marrow-derived mesenchymal stem cells (BM-MSCs) possess wide immunoregulatory properties. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) contribute to the immunomodulation in the pathological mechanisms of inflammatory diseases. However, critical lncRNAs/miRNAs involved in immunomodulation of mandibular BM-MSCs largely remain to be identified. Here, we explored the molecular mechanisms behind the defective immunomodulatory ability of mandibular BM-MSCs under the periodontitis settings. We found that mandibular BM-MSCs from P. gingivalis-induced periodontitis mice had significantly reduced expression of LncRNA SPIRE1 than that from normal control mice. LncRNA SPIRE1 knockdown in normal BM-MSCs caused Th17/Treg cell differentiation imbalance during the coculturing of BM-MSCs and CD4 T cells. In addition, LncRNA SPIRE1 was identified as a competitive endogenous RNA that sponges miR-181a-5p in BM-MSCs. Moreover, miR-181a-5p inhibition attenuated the impact of LncRNA SPIRE1 knockdown on the ability of BM-MSCs in modulating Th17/Treg balance. Prolactin receptor (PRLR) was validated as a downstream target of miR-181a-5p. Notably, targeted knockdown of LncRNA SPIRE1 or PRLR or transfection of miR-181a-5p mimics activated the JAK/STAT3 signaling in normal BM-MSCs, while treatment with STAT3 inhibitor C188-9 restored the immunomodulatory properties of periodontitis-associated BM-MSCs. Furthermore, BM-MSCs with miR-181a-5p inhibition or PRLR-overexpression showed enhanced in vivo immunosuppressive properties in the periodontitis mouse model. Our results indicate that the JAK/STAT3 pathway is involved in the immunoregulation of BM-MSCs, and provide critical insights into the development of novel targeted therapies against periodontitis.
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Affiliation(s)
- Bingyi Shao
- Northern Department of Endodontics, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Duo Zhou
- Northern Department of Endodontics, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Jie Wang
- Northern Department of Endodontics, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Deqin Yang
- Northern Department of Endodontics, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
| | - Jing Gao
- Northern Department of Endodontics, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
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9
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Zheng Y, Deng J, Wang G, Zhang X, Wang L, Ma X, Dai Y, E L, Liu X, Zhang R, Zhang Y, Liu H. P53 negatively regulates the osteogenic differentiation in jaw bone marrow MSCs derived from diabetic osteoporosis. Heliyon 2023; 9:e15188. [PMID: 37096002 PMCID: PMC10121411 DOI: 10.1016/j.heliyon.2023.e15188] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 03/27/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
Patients with diabetic osteoporosis (DOP) often suffer from poor osseointegration of artificial implants, which is a challenge that affects implant outcomes. The osteogenic differentiation ability of human jaw bone marrow mesenchymal stem cells (JBMMSCs) is the key to implant osseointegration. Studies have shown that the microenvironment of hyperglycemia affects the osteogenic differentiation of mesenchymal stem cells (MSC), but the mechanism is still unclear. Therefore, the aim of this study was to isolate and culture JBMMSCs from surgically derived bone fragments from DOP patients and control patients to investigate the differences in their osteogenic differentiation ability and to elucidate its mechanisms. The results showed that the osteogenic ability of hJBMMSCs was significantly decreased in the DOP environment. Mechanism study showed that the expression of senescence marker gene P53 was significantly increased in DOP hJBMMSCs compared to control hJBMMSCs according to RNA-sequencing result. Further, DOP hJBMMSCs were found to display significant senescence using β-galactosidase staining, mitochondrial membrane potential and ROS assay, qRT-PCR and WB analysis. Overexpression of P53 in hJBMMSCs, knockdown of P53 in DOP hJBMMSCs, and knockdown followed by overexpression of P53 significantly affected the osteogenic differentiation ability of hJBMMSCs. These results suggest that MSC senescence is an important reason for decreasing osteogenic capacity in DOP patients. P53 is a key target in regulating hJBMMSCs aging, and knocking down P53 can effectively restore the osteogenic differentiation ability of DOP hJBMMSCs and promote osteosynthesis in DOP dental implants. It provided a new idea to elucidate the pathogenesis and treatment of diabetic bone metabolic diseases.
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Affiliation(s)
- Ying Zheng
- Medical School of Chinese PLA, Beijing 100853, China
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Junhao Deng
- Senior Department of Orthopedics, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China
| | - Gang Wang
- Medical School of Chinese PLA, Beijing 100853, China
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Xiaru Zhang
- Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing 100085, China
| | - Lin Wang
- Medical School of Chinese PLA, Beijing 100853, China
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Xiaocao Ma
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Yawen Dai
- Medical School of Chinese PLA, Beijing 100853, China
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Lingling E
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Xiangwei Liu
- Medical School of Chinese PLA, Beijing 100853, China
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Rong Zhang
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Yi Zhang
- Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Beijing 100085, China
- Corresponding author.
| | - Hongchen Liu
- Medical School of Chinese PLA, Beijing 100853, China
- Institute of Stomatology & Oral Maxilla Facial Key Laboratory, Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
- Corresponding author. Medical School of Chinese PLA, Beijing 100853, China.
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10
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Jeyaraman M, Verma T, Jeyaraman N, Patro BP, Nallakumarasamy A, Khanna M. Is mandible derived mesenchymal stromal cells superior in proliferation and regeneration to long bone-derived mesenchymal stromal cells? World J Methodol 2023; 13:10-17. [PMID: 37035028 PMCID: PMC10080497 DOI: 10.5662/wjm.v13.i2.10] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/01/2023] [Accepted: 02/10/2023] [Indexed: 03/15/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are cells with the characteristic ability of self-renewal along with the ability to exhibit multilineage differentiation. Bone marrow (BM) is the first tissue in which MSCs were identified and BM-MSCs are most commonly used among various MSCs in clinical settings. MSCs can stimulate and promote osseous regeneration. Due to the difference in the development of long bones and craniofacial bones, the mandibular-derived MSCs (M-MSCs) have distinct differentiation characteristics as compared to that of long bones. Both mandibular and long bone-derived MSCs are positive for MSC-associated markers such as CD-73, -105, and -106, stage-specific embryonic antigen 4 and Octamer-4, and negative for hematopoietic markers such as CD-14, -34, and -45. As the M-MSCs are derived from neural crest cells, they have embryogenic cells which promote bone repair and high osteogenic potential. In vitro and in vivo animal-based studies demonstrate a higher rate of proliferation and high osteogenic potential for M-MSCs as compared to long-bones MSCs, but in vivo studies in human subjects are lacking. The BM-MSCs have their advantages and limitations. M-MSCs may be utilized as an alternative source of MSCs which can be utilized for tissue engineering and promoting the regeneration of bone. M-MSCs may have potential advantages in the repair of craniofacial or orofacial defects. Considering the utility of M-MSCs in the field of orthopaedics, we have discussed various unresolved questions, which need to be explored for their better utility in clinical practice.
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Affiliation(s)
- Madhan Jeyaraman
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600056, Tamil Nadu, India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Department of Regenerative Medicine, Indian Stem Cell Study Group Association, Lucknow 226010, Uttar Pradesh, India
| | - Tushar Verma
- Department of Orthopaedic Rheumatology, Fellow in Indian Orthopaedic Rheumatology Association, Lucknow 226010, Uttar Pradesh, India
| | - Naveen Jeyaraman
- Department of Regenerative Medicine, Indian Stem Cell Study Group Association, Lucknow 226010, Uttar Pradesh, India
- Department of Orthopaedic Rheumatology, Fellow in Indian Orthopaedic Rheumatology Association, Lucknow 226010, Uttar Pradesh, India
- Department of Orthopaedics, Rathimed Speciality Hospital, Chennai 600040, Tamil Nadu, India
| | - Bishnu Prasad Patro
- Department of Regenerative Medicine, Indian Stem Cell Study Group Association, Lucknow 226010, Uttar Pradesh, India
- Department of Orthopaedics, All India Institute of Medical Sciences, Bhubaneswar 751019, Odisha, India
| | - Arulkumar Nallakumarasamy
- Department of Regenerative Medicine, Indian Stem Cell Study Group Association, Lucknow 226010, Uttar Pradesh, India
- Department of Orthopaedic Rheumatology, Fellow in Indian Orthopaedic Rheumatology Association, Lucknow 226010, Uttar Pradesh, India
- Department of Orthopaedics, All India Institute of Medical Sciences, Bhubaneswar 751019, Odisha, India
| | - Manish Khanna
- Department of Regenerative Medicine, Indian Stem Cell Study Group Association, Lucknow 226010, Uttar Pradesh, India
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11
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Soares AP, Fischer H, Aydin S, Steffen C, Schmidt-Bleek K, Rendenbach C. Uncovering the unique characteristics of the mandible to improve clinical approaches to mandibular regeneration. Front Physiol 2023; 14:1152301. [PMID: 37008011 PMCID: PMC10063818 DOI: 10.3389/fphys.2023.1152301] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 03/07/2023] [Indexed: 03/19/2023] Open
Abstract
The mandible (lower jaw) bone is aesthetically responsible for shaping the lower face, physiologically in charge of the masticatory movements, and phonetically accountable for the articulation of different phonemes. Thus, pathologies that result in great damage to the mandible severely impact the lives of patients. Mandibular reconstruction techniques are mainly based on the use of flaps, most notably free vascularized fibula flaps. However, the mandible is a craniofacial bone with unique characteristics. Its morphogenesis, morphology, physiology, biomechanics, genetic profile, and osteoimmune environment are different from any other non-craniofacial bone. This fact is especially important to consider during mandibular reconstruction, as all these differences result in unique clinical traits of the mandible that can impact the results of jaw reconstructions. Furthermore, overall changes in the mandible and the flap post-reconstruction may be dissimilar, and the replacement process of the bone graft tissue during healing can take years, which in some cases can result in postsurgical complications. Therefore, the present review highlights the uniqueness of the jaw and how this factor can influence the outcome of its reconstruction while using an exemplary clinical case of pseudoarthrosis in a free vascularized fibula flap.
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Affiliation(s)
- Ana Prates Soares
- Department of Oral and Maxillofacial Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Berlin Institute of Health at Charité—Universitätsmedizin Berlin, Berlin, Germany
- *Correspondence: Ana Prates Soares,
| | - Heilwig Fischer
- Department of Oral and Maxillofacial Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- Centrum für Muskuloskeletale Chirurgie, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité—Universitätsmedizin Berlin, Berlin, Germany
| | - Sabrin Aydin
- Department of Oral and Maxillofacial Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Claudius Steffen
- Department of Oral and Maxillofacial Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Katharina Schmidt-Bleek
- Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Berlin Institute of Health at Charité—Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health Centre for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité—Universitätsmedizin Berlin, Berlin, Germany
| | - Carsten Rendenbach
- Department of Oral and Maxillofacial Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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12
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Ji X, Chen H, Liu B, Zhuang H, Bu S. Chk2 deletion rescues Bmi1 deficiency-induced mandibular osteoporosis by blocking DNA damage response pathway. Am J Transl Res 2023; 15:2220-2232. [PMID: 37056849 PMCID: PMC10086904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 03/15/2023] [Indexed: 04/15/2023]
Abstract
OBJECTIVES Bmi1 deficiency has been proved to be able to cause mandibular osteoporosis through suppressing oxidative stress. However, the role of DNA damage response pathway in this pathogenesis had not been well understood. In this study, we investigate whether mandibular osteoporosis induced by Bmi1 deficiency could be rescued by blocked DNA damage response pathway. METHODS The protein expression levels of antioxidant enzymes and DNA damage and damage response pathway molecules in mandibular tissue were examined using Western blots. Double knockout mice that lacked both Bmi1 and Chk2 were generated and their mandibular phenotypes were compared at 6 weeks old to wild-type, Chk2-/-, and Bmi1-/- mice using radiograph, micro-CT, histopathology, cellular and molecular techniques. RESULTS Bmi1 deficiency induces oxidative stress and DNA damage and activates DNA damage response pathways in mouse mandibles. Chk2 deletion rescued mandibular osteoporosis through promoting formation of osteoblastic bone as well as decreasing osteoclastic bone resorption. Mechanistically, Chk2 deletion suppressed oxidative stress, DNA damage, as well as cell senescence. In addition, it boosted proliferation of bone marrow mesenchymal stem cells (BM-MSCs) that derived from mandible through blocking the DNA damage response pathway. CONCLUSION Abolish the expression of Chk2 could rescue Bmi1 deficiency-related mandibular osteoporosis through promoting BM-MSC proliferation and osteoblastic bone formation, reducing osteoclastic bone resorption, decreasing oxidative stress, inhibiting damage of DNA and associated response pathways, suppressing cell senescence as well as senescence-associated secretory phenotype (SASP). These findings offer a theoretical basis for using Chk2 or p53 inhibitors to prevent and treat age-related mandibular osteoporosis.
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Affiliation(s)
- Xiaolei Ji
- Department of Stomatology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
- Department of Stomatology, The Affiliated BenQ Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Haiyun Chen
- Department of Plastic Surgery, Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Boyang Liu
- The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Hai Zhuang
- Department of Stomatology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Shoushan Bu
- Department of Stomatology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
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13
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Fan Y, Lyu P, Bi R, Cui C, Xu R, Rosen CJ, Yuan Q, Zhou C. Creating an atlas of the bone microenvironment during oral inflammatory-related bone disease using single-cell profiling. eLife 2023; 12:82537. [PMID: 36722472 PMCID: PMC9925051 DOI: 10.7554/elife.82537] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 01/30/2023] [Indexed: 02/02/2023] Open
Abstract
Oral inflammatory diseases such as apical periodontitis are common bacterial infectious diseases that may affect the periapical alveolar bone tissues. A protective process occurs simultaneously with the inflammatory tissue destruction, in which mesenchymal stem cells (MSCs) play a primary role. However, a systematic and precise description of the cellular and molecular composition of the microenvironment of bone affected by inflammation is lacking. In this study, we created a single-cell atlas of cell populations that compose alveolar bone in healthy and inflammatory disease states. We investigated changes in expression frequency and patterns related to apical periodontitis, as well as the interactions between MSCs and immunocytes. Our results highlight an enhanced self-supporting network and osteogenic potential within MSCs during apical periodontitis-associated inflammation. MSCs not only differentiated toward osteoblast lineage cells but also expressed higher levels of osteogenic-related markers, including Sparc and Col1a1. This was confirmed by lineage tracing in transgenic mouse models and human samples from oral inflammatory-related alveolar bone lesions. In summary, the current study provides an in-depth description of the microenvironment of MSCs and immunocytes in both healthy and disease states. We also identified key apical periodontitis-associated MSC subclusters and their biomarkers, which could further our understanding of the protective process and the underlying mechanisms of oral inflammatory-related bone disease. Taken together, these results enhance our understanding of heterogeneity and cellular interactions of alveolar bone cells under pathogenic and inflammatory conditions. We provide these data as a tool for investigators not only to better appreciate the repertoire of progenitors that are stress responsive but importantly to help design new therapeutic targets to restore bone lesions caused by apical periodontitis and other inflammatory-related bone diseases.
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Affiliation(s)
- Yi Fan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan UniversityChengduChina
| | - Ping Lyu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan UniversityChengduChina
| | - Ruiye Bi
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthognathic and TMJ Surgery, West China Hospital of Stomatology, Sichuan UniversityChengduChina
| | - Chen Cui
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of StomatologyGuangzhouChina
| | - Ruoshi Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan UniversityChengduChina
| | | | - Quan Yuan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Implantology, West China Hospital of Stomatology, Sichuan UniversityChengduChina
| | - Chenchen Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan UniversityChengduChina
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14
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Zhang X, Xiong Q, Lin W, Wang Q, Zhang D, Xu R, Zhou X, Zhang S, Peng L, Yuan Q. Schwann Cells Contribute to Alveolar Bone Regeneration by Promoting Cell Proliferation. J Bone Miner Res 2023; 38:119-130. [PMID: 36331097 DOI: 10.1002/jbmr.4735] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 10/27/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022]
Abstract
The plasticity of Schwann cells (SCs) following nerve injury is a critical feature in the regeneration of peripheral nerves as well as surrounding tissues. Here, we show a pivotal role of Schwann cell-derived cells in alveolar bone regeneration through the specific ablation of proteolipid protein 1 (Plp)-expressing cells and the transplantation of teased nerve fibers and associated cells. With inducible Plp specific genetic tracing, we observe that Plp+ cells migrate into wounded alveolar defect and dedifferentiate into repair SCs. Notably, these cells barely transdifferentiate into osteogenic cell lineage in both SCs tracing model and transplant model, but secret factors to enhance the proliferation of alveolar skeletal stem cells (aSSCs). As to the mechanism, this effect is associated with the upregulation of extracellular matrix (ECM) receptors and receptor tyrosine kinases (RTKs) signaling and the downstream extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase-protein kinase B (PI3K-Akt) pathway. Collectively, our data demonstrate that SCs dedifferentiate after neighboring alveolar bone injury and contribute to bone regeneration mainly by a paracrine function. © 2022 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Xiaohan Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Qiuchan Xiong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Weimin Lin
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Qian Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Danting Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ruoshi Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xinyi Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Shiwen Zhang
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lin Peng
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Quan Yuan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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15
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Lyu P, Song Y, Bi R, Li Z, Wei Y, Huang Q, Cui C, Song D, Zhou X, Fan Y. Protective Actions in Apical Periodontitis: The Regenerative Bioactivities Led by Mesenchymal Stem Cells. Biomolecules 2022; 12:1737. [PMID: 36551165 PMCID: PMC9776067 DOI: 10.3390/biom12121737] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/18/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022] Open
Abstract
Resulting from bacterial infection, apical periodontitis (AP) is a common inflammatory disease of the periapical region of the tooth. The regeneration of the destroyed periapical alveolar bone and the surrounding periodontium tissues has long been a difficult task in clinical practice. These lesions are closely related to pathogen invasion and an overreactive immune response. It is worth noting that the protective healing process occurs simultaneously, in which mesenchymal stem cells (MSCs) have a crucial function in mediating the immune system and promoting regeneration. Here, we review the recent studies related to AP, with a focus on the regulatory network of MSCs. We also discuss the potential therapeutic approaches of MSCs in inflammatory diseases to provide a basis for promoting tissue regeneration and modulating inflammation in AP. A deeper understanding of the protective action of MSCs and the regulatory networks will help to delineate the underlying mechanisms of AP and pave the way for stem-cell-based regenerative medicine in the future.
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Affiliation(s)
- Ping Lyu
- National Clinical Research Center for Oral Diseases, State Key Laboratory of Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yiming Song
- National Clinical Research Center for Oral Diseases, State Key Laboratory of Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Ruiye Bi
- National Clinical Research Center for Oral Diseases, State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Zucen Li
- National Clinical Research Center for Oral Diseases, State Key Laboratory of Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yali Wei
- National Clinical Research Center for Oral Diseases, State Key Laboratory of Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Qin Huang
- National Clinical Research Center for Oral Diseases, State Key Laboratory of Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Chen Cui
- Guangdong Province Key Laboratory of Stomatology, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou 510055, China
| | - Dongzhe Song
- National Clinical Research Center for Oral Diseases, State Key Laboratory of Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Xuedong Zhou
- National Clinical Research Center for Oral Diseases, State Key Laboratory of Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yi Fan
- National Clinical Research Center for Oral Diseases, State Key Laboratory of Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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Zhai M, Cui S, Li L, Cheng C, Zhang Z, Liu J, Wei F. Mechanical Force Modulates Alveolar Bone Marrow Mesenchymal Cells Characteristics for Bone Remodeling during Orthodontic Tooth Movement through Lactate Production. Cells 2022; 11:cells11233724. [PMID: 36496983 PMCID: PMC9738738 DOI: 10.3390/cells11233724] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 11/16/2022] [Accepted: 11/18/2022] [Indexed: 11/24/2022] Open
Abstract
Orthodontic tooth movement (OTM) relies on mechanical force-induced bone remodeling. As a metabolic intermediate of glycolysis, lactate has recently been discovered to participate in bone remodeling by serving as a signaling molecule. However, whether lactate could respond to mechanical stimulus during OTM, as well as whether lactate has an impact on the alveolar bone remodeling during orthodontics, remain to be further elucidated. In the current study, we observed physiologically elevated production of lactate along with increased osteogenic differentiation, proliferation, and migration of alveolar bone marrow mesenchymal cells (ABMMCs) under mechanical force. Inhibition of lactate, induced by cyclic mechanical stretch by GNE-140, remarkably suppressed the osteogenic differentiation, proliferation, and migration, yet enhanced apoptosis of ABMMCs. Mechanistically, these regulatory effects of lactate were mediated by histone lactylation. Taken together, our results suggest that force-induced lactate is involved in controlling bone remodeling-related cellular activities in ABMMCs and plays a vital role in the alveolar bone remodeling during OTM. Our findings indicate that lactate might be a critical modulator for alveolar bone remodeling during OTM, providing a novel therapeutic target for the purpose of more effectively controlling tooth movement and improving the stability of orthodontic results.
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17
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Song W, Bo X, Ma X, Hou K, Li D, Geng W, Zeng J. Craniomaxillofacial derived bone marrow mesenchymal stem/stromal cells (BMSCs) for craniomaxillofacial bone tissue engineering: A literature review. JOURNAL OF STOMATOLOGY, ORAL AND MAXILLOFACIAL SURGERY 2022; 123:e650-e659. [PMID: 35691558 DOI: 10.1016/j.jormas.2022.06.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/06/2022] [Accepted: 06/07/2022] [Indexed: 11/20/2022]
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Liu J, Watanabe K, Dabdoub SM, Lee BS, Kim DG. Site-specific characteristics of bone and progenitor cells in control and ovariectomized rats. Bone 2022; 163:116501. [PMID: 35872108 DOI: 10.1016/j.bone.2022.116501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 07/11/2022] [Accepted: 07/18/2022] [Indexed: 11/25/2022]
Abstract
One-third of postmenopausal women experience at least one osteoporotic bone fracture in their lifetime that occurs spontaneously or from low-impact events. However, osteoporosis-associated jaw bone fractures are extremely rare. It was also observed that jaw bone marrow stem cells (BMSCs) have a higher capacity to form mineralized tissues than limb BMSCs. At present, the underlying causes and mechanisms of variations between jaw bone and limb bone during postmenopause are largely unknown. Thus, the objective of the current study was to examine the site-specific effects of estrogen deficiency using comprehensive analysis of bone quantity and quality, and its association with characterization of cellular components of bone. Nine rats (female, 6 months old) for each bilateral sham and ovariectomy (OVX) surgery were obtained and maintained for 2 months after surgery. A hemi-mandible and a femur from each rat were characterized for parameters of volume, mineral density, cortical and trabecular morphology, and static and dynamic mechanical analysis. Another set of 5 rats (female, 9 months old) was obtained for assays of BMSCs. Following cytometry to identify BMSCs, bioassays for proliferation, and osteogenic, adipogenic, chondrogenic differentiation, and cell mitochondrial stress tests were performed. In addition, mRNA expression of BMSCs was analyzed. OVX decreased bone quantity and quality (mineral content, morphology, and energy dissipation) of femur while those of mandible were not influenced. Cellular assays demonstrated that mandible BMSCs showed greater differentiation than femur BMSCs. Gene ontology pathway analysis indicated that the mandibular BMSCs showed most significant differential expression of genes in the regulatory pathways of osteoblast differentiation, SMAD signaling, cartilage development, and glucose transmembrane transporter activity. These findings suggested that active mandibular BMSCs maintain bone formation and mineralization by balancing the rapid bone resorption caused by estrogen deficiency. These characteristics likely help reduce the risk of osteoporotic fracture in postmenopausal jawbone.
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Affiliation(s)
- Jie Liu
- Division of Orthodontics, College of Dentistry, The Ohio State University, Columbus, OH 43210, USA
| | - Keiichiro Watanabe
- Division of Orthodontics, College of Dentistry, The Ohio State University, Columbus, OH 43210, USA
| | - Shareef M Dabdoub
- Division of Biostatistics and Computational Biology, Department of Periodontics, College of Dentistry and Dental Clinics, The University of Iowa, Iowa City, IA 52242, USA.
| | - Beth S Lee
- Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Do-Gyoon Kim
- Division of Orthodontics, College of Dentistry, The Ohio State University, Columbus, OH 43210, USA.
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Yang J, Xu Y, Xue X, Zhang M, Wang S, Qi K. MicroRNA-26b regulates BMSC osteogenic differentiation of TMJ subchondral bone through β-catenin in osteoarthritis. Bone 2022; 162:116448. [PMID: 35618240 DOI: 10.1016/j.bone.2022.116448] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 05/13/2022] [Accepted: 05/17/2022] [Indexed: 01/22/2023]
Abstract
Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative disease of the joint. The early manifestations of TMJ-OA are abnormal remodeling of condylar subchondral bone. In bone tissue, bone marrow mesenchymal stem cells (BMSCs) and osteoblasts play important roles in the differentiation and maturation of most hematopoietic cells. MicroRNA-26b (miR-26b) is upregulated during the osteogenesis of BMSCs, and miR-26b overexpression leads to the activation of β-catenin and the enhancement of osteogenesis and cartilage formation. However, the pathologic mechanism remains unclear. In the present study, we used a rat model with OA-like changes in the TMJ induced by experimental unilateral anterior crossbite (UAC) and found that the level of miR-26b was markedly lower in BMSCs from the subchondral bones of UAC rats than in those from sham control rats. MiR-26b overexpression by agomiR-26b increased condylar subchondral bone osteogenesis in UAC rats. Notably, although agomiR-26b primarily affected miR-26b levels in the subchondral bone (but not in cartilage or the synovium), the overexpression of miR-26b in BMSCs in UAC rats largely rescued OA-like cartilage degradation, while the inhibition of miR-26b in BMSCs exacerbated cartilage degradation in UAC rats. We measured the expression levels of β-catenin and related osteogenic and osteoclastic factors after using miR-26b mimics and inhibitors in vivo. Moreover, BMSCs were treated with the β-catenin blocker Wnt-C59 and then transfected with miR-26b mimics or inhibitors. Then, we examined the expression of β-catenin as the direct target of miR-26b. The results of the present study indicate that miR-26b may modulate subchondral bone loss induced by abnormal occlusion and influence the osteogenic differentiation of subchondral BMSCs through β-catenin in the context of TMJ-OA progression.
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Affiliation(s)
- Jinlu Yang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research & Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, Department of Orthodontics, Stomatological Hospital, Xi'an Jiaotong University, Xi'an, PR China
| | - Yifei Xu
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Disease & Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi'an, PR China
| | - Xin Xue
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research & Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, Department of Orthodontics, Stomatological Hospital, Xi'an Jiaotong University, Xi'an, PR China
| | - Mian Zhang
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Disease & Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, Xi'an, PR China
| | - Shuang Wang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research & Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, Department of Orthodontics, Stomatological Hospital, Xi'an Jiaotong University, Xi'an, PR China.
| | - Kun Qi
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research & Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, Department of Orthodontics, Stomatological Hospital, Xi'an Jiaotong University, Xi'an, PR China.
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20
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Cheng Y, Du Y, Zhang X, Zhang P, Liu Y. Conditional knockout of Cdc20 attenuates osteogenesis in craniofacial bones. Tissue Cell 2022; 77:101829. [DOI: 10.1016/j.tice.2022.101829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/17/2022] [Accepted: 05/18/2022] [Indexed: 10/18/2022]
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21
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Li S, Gao L, Zhang W, Yu Y, Zheng J, Liang X, Xin S, Ren W, Zhi K. MiR-152-5p suppresses osteogenic differentiation of mandible mesenchymal stem cells by regulating ATG14-mediated autophagy. Stem Cell Res Ther 2022; 13:359. [PMID: 35883156 PMCID: PMC9327198 DOI: 10.1186/s13287-022-03018-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 04/17/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Osteoporosis affects the mandible resulting in bone loss. Though impairments are not life threatening, they affect a person's quality-of-life particularly vulnerable elderly. MicroRNAs (miRNAs) are novel regulatory factors that play an important role in regulating bone metabolism. Autophagy is evolutionarily conserved intracellular self-degradation process and is vital in the maintenance of both miRNA and bone homeostasis. However, the role of autophagy in the pathogenesis of miRNA regulating osteoporosis remains unclear. METHODS In the study, we established a rat osteoporosis model induced by ovariectomy (OVX) and isolated mesenchymal stem cells from mandible (MMSCs-M). Several miRNAs were identified to regulate osteoporosis in some studies. qRT-PCR was applied to examine the expression of miRNA, autophagy and osteogenic differentiation-related genes. Western blotting assays were performed to detect the expression of autophagy and osteogenic differentiation proteins. Immunofluorescence and transmission electron microscope were used to verify the autophagy activity. Transfecting technology was used to enhance or suppress the expression of miR-152-5p which enable us to observe the relationship between miR-152-5p, autophagy and osteogenic differentiation. Additionally, the measurement of reactive oxygen species was used to investigate the mechanism of autophagy affecting osteogenic differentiation. RESULTS We found an upregulated expression of miR-152-5p in MMSCs-M in OVX group. Downregulated autophagy-related gene, proteins and autophagosome were detected in vitro of OVX group compared with sham group. Moreover, downregulation of miR-152-5p promoted osteogenic differentiation of MMSCs-M as well as enhanced autophagy-related proteins in OVX group. Conversely, overexpression of miR-152-5p showed opposite effect in sham group. Meanwhile, we found Atg14 (autophagy-related protein homolog 14) was identified to be a direct target of miR-152-5p theoretically and functionally. In other words, we confirmed inhibition of miR-152-5p promoted the osteogenic differentiation via promoting ATG14-mediated autophagy. Furthermore, miR-152-5p/ATG14-mediated autophagy regulated osteogenic differentiation by reducing the endogenous ROS accumulation and maintaining cellular redox homeostasis. CONCLUSION Our data suggest that miR-152-5p is the first identified to regulate osteogenic differentiation by directly targeting autophagy-related protein ATG14 and regulating oxidative stress and therapeutic inhibition of miR-152-5p may be an efficient anabolic strategy for osteoporosis.
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Affiliation(s)
- Shaoming Li
- grid.412521.10000 0004 1769 1119Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao district, Qingdao, 266555 Shandong China ,grid.410645.20000 0001 0455 0905School of Stomatology, Qingdao University, Qingdao, 266003 China
| | - Ling Gao
- grid.412521.10000 0004 1769 1119Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao district, Qingdao, 266555 Shandong China ,grid.412521.10000 0004 1769 1119Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266555 China
| | - Weidong Zhang
- grid.412521.10000 0004 1769 1119Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao district, Qingdao, 266555 Shandong China ,grid.410645.20000 0001 0455 0905School of Stomatology, Qingdao University, Qingdao, 266003 China
| | - Yanbin Yu
- grid.412508.a0000 0004 1799 3811College of Safety and Environmental Engineering, Shandong University of Science and Technology, Qingdao, 266590 China
| | - Jingjing Zheng
- grid.412521.10000 0004 1769 1119Department of Endodontics, The Affiliated Hospital of Qingdao University, Qingdao, 266003 China
| | - Xiao Liang
- grid.412008.f0000 0000 9753 1393Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway
| | - Shanshan Xin
- grid.412521.10000 0004 1769 1119Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao district, Qingdao, 266555 Shandong China ,grid.410645.20000 0001 0455 0905School of Stomatology, Qingdao University, Qingdao, 266003 China
| | - Wenhao Ren
- grid.412521.10000 0004 1769 1119Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao district, Qingdao, 266555 Shandong China
| | - Keqian Zhi
- grid.412521.10000 0004 1769 1119Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao district, Qingdao, 266555 Shandong China ,grid.412521.10000 0004 1769 1119Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266555 China
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22
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Dekker H, Schulten EA, Lichters I, van Ruijven L, van Essen HW, Blom GJ, Bloemena E, ten Bruggenkate CM, Kullaa AM, Bravenboer N. Osteocyte Apoptosis, Bone Marrow Adiposity, and Fibrosis in the Irradiated Human Mandible. Adv Radiat Oncol 2022; 7:100951. [PMID: 35662809 PMCID: PMC9156996 DOI: 10.1016/j.adro.2022.100951] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 03/21/2022] [Indexed: 11/30/2022] Open
Abstract
Purpose To assess the effect of radiation therapy on osteocyte apoptosis, osteocyte death, and bone marrow adipocytes in the human mandible and its contribution to the pathophysiology of radiation damage to the mandibular bone. Methods and Materials Mandibular cancellous bone biopsies were taken from irradiated patients and nonirradiated controls. Immunohistochemical detection of cleaved caspase-3 was performed to visualize apoptotic osteocytes. The number of apoptotic osteocytes per bone area and per total amount of osteocytes, osteocytes per bone area, and empty lacunae per bone area were counted manually. The percentage fibrotic tissue and adipose tissue per bone marrow area, the percentage bone marrow of total area, and the mean adipocyte diameter (μm) was determined digitally from adjacent Goldner stained sections. Results Biopsies of 15 irradiated patients (12 men and 3 women) and 7 nonirradiated controls (5 men and 2 women) were assessed. In the study group a significant increase was seen in the number of empty lacunae, the percentage of adipose tissue of bone marrow area, and the adipocyte diameter. There was no significant difference in bone marrow fibrosis nor apoptotic osteocytes between the irradiated group and the controls. Conclusions Irradiation alone does not seem to induce excessive bone marrow fibrosis. The damage to bone mesenchymal stem cells leads to increased marrow adipogenesis and decreased osteoblastogenic potential. Early osteocyte death resulting in avital persisting bone matrix with severely impaired regenerative potential may contribute to the vulnerability of irradiated bone to infection and necrosis.
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Affiliation(s)
- Hannah Dekker
- Department of Oral and Maxillofacial Surgery/Oral Pathology, Amsterdam University Medical Centers and Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Engelbert A.J.M. Schulten
- Department of Oral and Maxillofacial Surgery/Oral Pathology, Amsterdam University Medical Centers and Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Inez Lichters
- Department of Oral and Maxillofacial Surgery/Oral Pathology, Amsterdam University Medical Centers and Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Leo van Ruijven
- Department of Functional Anatomy, Academic Centre for Dentistry Amsterdam (ACTA), Amsterdam, The Netherlands
| | - Huib W. van Essen
- Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Gerrit-Jan Blom
- Department of Radiotherapy, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Elisabeth Bloemena
- Department of Oral and Maxillofacial Surgery/Oral Pathology, Amsterdam University Medical Centers and Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Chris M. ten Bruggenkate
- Department of Oral and Maxillofacial Surgery/Oral Pathology, Amsterdam University Medical Centers and Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Department of Oral and Maxillofacial Surgery, Alrijne Hospital, Leiderdorp, The Netherlands
| | - Arja M. Kullaa
- Institute of Dentistry, Kuopio Campus, University of Eastern Finland, Kuopio, Finland
- Educational Dental Clinic, Kuopio University Hospital, Kuopio, Finland
| | - Nathalie Bravenboer
- Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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23
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Kamei H, Ishii T, Nishii Y. Semaphorin 3A regulates alveolar bone remodeling on orthodontic tooth movement. Sci Rep 2022; 12:9243. [PMID: 35654941 PMCID: PMC9163121 DOI: 10.1038/s41598-022-13217-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 05/23/2022] [Indexed: 11/21/2022] Open
Abstract
Semaphorin 3A (Sema3A) promotes osteoblast differentiation and inhibits osteoclast differentiation. In the present study, we observed the regulation of alveolar bone remodeling by Sema3A during orthodontic tooth movement (OTM). Four inflammatory cytokines (IL-1β, IL-6, TNFα, and INF-γ) involved in OTM were applied to osteoblasts in vitro, and Sema3A expression was determined by reverse-transcription quantitative polymerase chain reaction (RT-qPCR). In vivo, springs were attached to the maxillary first molars of C56BL/6J mice (OTM model) and the localization of Sema3A was confirmed by immunofluorescent. Recombinant Sema3A (rSema3A) was locally injected into the OTM model. Inflammatory cytokine localization in the OTM model was confirmed by immunohistochemistry. In vivo, more Sema3A was observed on the tension side in the OTM group. Injection of rSema3A into the OTM model increased mineralization on the tension side and decreased the number of osteoclasts on the compression side. In vitro, IL-1β significantly increased Sema3A mRNA levels. Immunohistochemistry for IL-1β in vivo showed more concentrated staining in the periodontal ligament on the tension side than on the compression side. In summary, our findings revealed the distribution of Sema3A in the periodontal ligament and demonstrated that rSema3A administration promotes bone formation and inhibits bone resorption during OTM.
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Affiliation(s)
- Hirokazu Kamei
- Department of Orthodontics, Tokyo Dental College, Tokyo, Japan
| | - Takenobu Ishii
- Department of Orthodontics, Tokyo Dental College, Tokyo, Japan.
| | - Yasushi Nishii
- Department of Orthodontics, Tokyo Dental College, Tokyo, Japan
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24
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Deng P, Chang I, Wang J, Badreldin AA, Li X, Yu B, Wang CY. Loss of KDM4B impairs osteogenic differentiation of OMSCs and promotes oral bone aging. Int J Oral Sci 2022; 14:24. [PMID: 35525910 PMCID: PMC9079076 DOI: 10.1038/s41368-022-00175-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/25/2022] [Accepted: 04/06/2022] [Indexed: 01/19/2023] Open
Abstract
Aging of craniofacial skeleton significantly impairs the repair and regeneration of trauma-induced bony defects, and complicates dental treatment outcomes. Age-related alveolar bone loss could be attributed to decreased progenitor pool through senescence, imbalance in bone metabolism and bone-fat ratio. Mesenchymal stem cells isolated from oral bones (OMSCs) have distinct lineage propensities and characteristics compared to MSCs from long bones, and are more suited for craniofacial regeneration. However, the effect of epigenetic modifications regulating OMSC differentiation and senescence in aging has not yet been investigated. In this study, we found that the histone demethylase KDM4B plays an essential role in regulating the osteogenesis of OMSCs and oral bone aging. Loss of KDM4B in OMSCs leads to inhibition of osteogenesis. Moreover, KDM4B loss promoted adipogenesis and OMSC senescence which further impairs bone-fat balance in the mandible. Together, our data suggest that KDM4B may underpin the molecular mechanisms of OMSC fate determination and alveolar bone homeostasis in skeletal aging, and present as a promising therapeutic target for addressing craniofacial skeletal defects associated with age-related deteriorations.
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Affiliation(s)
- Peng Deng
- Laboratory of Molecular Signaling, Division of Oral and Systemic Health Sciences, School of Dentistry, UCLA, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
| | - Insoon Chang
- Laboratory of Molecular Signaling, Division of Oral and Systemic Health Sciences, School of Dentistry, UCLA, Los Angeles, CA, USA
- Section of Endodontics, Division of Regenerative and Reconstructive Sciences, School of Dentistry, UCLA, Los Angeles, CA, USA
| | - Jiongke Wang
- Division of Preventive and Restorative Sciences, School of Dentistry, UCLA, Los Angeles, CA, USA
| | - Amr A Badreldin
- Laboratory of Molecular Signaling, Division of Oral and Systemic Health Sciences, School of Dentistry, UCLA, Los Angeles, CA, USA
| | - Xiyao Li
- Laboratory of Molecular Signaling, Division of Oral and Systemic Health Sciences, School of Dentistry, UCLA, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
- Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, UCLA, Los Angeles, CA, USA
| | - Bo Yu
- Division of Preventive and Restorative Sciences, School of Dentistry, UCLA, Los Angeles, CA, USA
| | - Cun-Yu Wang
- Laboratory of Molecular Signaling, Division of Oral and Systemic Health Sciences, School of Dentistry, UCLA, Los Angeles, CA, USA.
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.
- Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, UCLA, Los Angeles, CA, USA.
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25
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Ding Y, Mo C, Geng J, Li J, Sun Y. Identification of Periosteal Osteogenic Progenitors in Jawbone. J Dent Res 2022; 101:1101-1109. [PMID: 35319300 DOI: 10.1177/00220345221084200] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Unlike long bones, jawbone development is mainly accomplished by intramembranous ossification resulting from the differentiation of periosteal progenitor cells. However, the spatiotemporal ontogeny of periosteal progenitor cells during jawbone development and repair remains elusive. In this study, we mapped the transcriptional landscape of the human jawbone periosteum at single-cell resolution and identified a cathepsin K (Ctsk)+ periosteal subset. Lineage tracing analysis indicated that Ctsk-Cre-labeled periosteal cells could make contributions to jawbone development. However, different from the periosteal-specific location of Ctsk+ cells in long bone, we also identified Ctsk+ stromal cells in jawbone marrow and implied the heterogeneity of jawbone Ctsk+ hierarchy. In further analysis of the periosteal progenitor cell subset of heterogeneous Ctsk+ hierarchy, we identified a unique Ctsk+Ly6a+ subset of cells. The additional marker Ly6a helped to further confine the progenitor subset to the jawbone periosteum and was nearly undetectable in the bone marrow. Defects in the jawbone could activate the migration and osteogenic differentiation of Ctsk+Ly6a+ cells. Local ablation of Ctsk+ cells by diphtheria reduced the number of Ctsk+Ly6a+ cells and delayed the repair of the bone defect. Taken together, we identify a novel periosteal osteogenic progenitor subset that is active in jawbone osteogenesis and healing.
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Affiliation(s)
- Y Ding
- Department of Implantology, School & Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji University, Shanghai, China
| | - C Mo
- Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - J Geng
- Department of Implantology, School & Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji University, Shanghai, China
| | - J Li
- Department of Implantology, School & Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji University, Shanghai, China
| | - Y Sun
- Department of Implantology, School & Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji University, Shanghai, China
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26
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Clinical, Histological, and Scintigraphic Comparative Study of the Use of Mandibular Bone Marrow and Peripheral Blood in Bone Neoformation. Int J Dent 2022; 2021:4867574. [PMID: 35003261 PMCID: PMC8741402 DOI: 10.1155/2021/4867574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 11/08/2021] [Accepted: 12/13/2021] [Indexed: 11/25/2022] Open
Abstract
Materials and Methods The study included 16 patients with maxillary atresia. The region was grafted with xenograft blocks associated with the following treatments: G1, the patient's peripheral blood during surgery, and G2, dripping of mandibular bone marrow blood until the xenograft was completely wet. After 7 and 14 days, scintigraphic images of the regions of interest (ROI) were taken to quantify pixels, which indicate osteogenic activity. Additionally, trephined samples obtained at the time of implant placement were stained in H&E, and newly formed bone tissue was quantified. The data were tabulated and statistically analyzed at a significance level of 5%. Results Scintigraphic data showed greater osteogenic activity with mandibular bone marrow blood (G2) at all times evaluated (p < 0.05). As for the histomorphometric analysis, a greater amount of bone tissue was observed in samples treated with mandibular bone marrow blood (G2) compared to peripheral blood (G1) (p < 0.05). Conclusions The appositional bone reconstruction technique in the block associated with mandibular bone marrow blood increased bone neoformation and osteogenic activity compared to conventional graft treatment with peripheral blood.
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27
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Lyu P, Li B, Li P, Bi R, Cui C, Zhao Z, Zhou X, Fan Y. Parathyroid Hormone 1 Receptor Signaling in Dental Mesenchymal Stem Cells: Basic and Clinical Implications. Front Cell Dev Biol 2021; 9:654715. [PMID: 34760881 PMCID: PMC8573197 DOI: 10.3389/fcell.2021.654715] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 09/28/2021] [Indexed: 02/05/2023] Open
Abstract
Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) are two peptides that regulate mineral ion homeostasis, skeletal development, and bone turnover by activating parathyroid hormone 1 receptor (PTH1R). PTH1R signaling is of profound clinical interest for its potential to stimulate bone formation and regeneration. Recent pre-clinical animal studies and clinical trials have investigated the effects of PTH and PTHrP analogs in the orofacial region. Dental mesenchymal stem cells (MSCs) are targets of PTH1R signaling and have long been known as major factors in tissue repair and regeneration. Previous studies have begun to reveal important roles for PTH1R signaling in modulating the proliferation and differentiation of MSCs in the orofacial region. A better understanding of the molecular networks and underlying mechanisms for modulating MSCs in dental diseases will pave the way for the therapeutic applications of PTH and PTHrP in the future. Here we review recent studies involving dental MSCs, focusing on relationships with PTH1R. We also summarize recent basic and clinical observations of PTH and PTHrP treatment to help understand their use in MSCs-based dental and bone regeneration.
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Affiliation(s)
- Ping Lyu
- State Key Laboratory of Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China
| | - Bo Li
- State Key Laboratory of Oral Diseases, Department of Orthodontics, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Peiran Li
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ruiye Bi
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chen Cui
- Guangdong Province Key Laboratory of Stomatology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong, China
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases, Department of Orthodontics, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China
| | - Yi Fan
- State Key Laboratory of Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China
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De Paz D, Aviña AE, Cardona E, Lee CM, Lin CH, Lin CH, Wei FC, Wang AYL. The Mandible Ameliorates Facial Allograft Rejection and Is Associated with the Development of Regulatory T Cells and Mixed Chimerism. Int J Mol Sci 2021; 22:11104. [PMID: 34681764 PMCID: PMC8537927 DOI: 10.3390/ijms222011104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/07/2021] [Accepted: 10/11/2021] [Indexed: 11/16/2022] Open
Abstract
Vascularized composite allografts contain various tissue components and possess relative antigenicity, eliciting different degrees of alloimmune responses. To investigate the strategies for achieving facial allograft tolerance, we established a mouse hemiface transplant model, including the skin, muscle, mandible, mucosa, and vessels. However, the immunomodulatory effects of the mandible on facial allografts remain unclear. To understand the effects of the mandible on facial allograft survival, we compared the diversities of different facial allograft-elicited alloimmunity between a facial osteomyocutaneous allograft (OMC), including skin, muscle, oral mucosa, and vessels, and especially the mandible, and a myocutaneous allograft (MC) including the skin, muscle, oral mucosa, and vessels, but not the mandible. The different facial allografts of a BALB/c donor were transplanted into a heterotopic neck defect on fully major histocompatibility complex-mismatched C57BL/6 mice. The allogeneic OMC (Allo-OMC) group exhibited significant prolongation of facial allograft survival compared to the allogeneic MC group, both in the presence and absence of FK506 immunosuppressive drugs. With the use of FK506 monotherapy (2 mg/kg) for 21 days, the allo-OMC group, including the mandible, showed prolongation of facial allograft survival of up to 65 days, whereas the myocutaneous allograft, without the mandible, only survived for 34 days. The Allo-OMC group also displayed decreased lymphocyte infiltration into the facial allograft. Both groups showed similar percentages of B cells, T cells, natural killer cells, macrophages, and dendritic cells in the blood, spleen, and lymph nodes. However, a decrease in pro-inflammatory T helper 1 cells and an increase in anti-inflammatory regulatory T cells were observed in the blood and lymph nodes of the Allo-OMC group. Significantly increased percentages of donor immune cells were also observed in three lymphoid organs of the Allo-OMC group, suggesting mixed chimerism induction. These results indicated that the mandible has the potential to induce anti-inflammatory effects and mixed chimerism for prolonging facial allograft survival. The immunomodulatory understanding of the mandible could contribute to reducing the use of immunosuppressive regimens in clinical face allotransplantation including the mandible.
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Affiliation(s)
- Dante De Paz
- Department of Plastic Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (D.D.P.); (A.E.A.); (C.-H.L.); (F.-C.W.)
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-M.L.); (C.-H.L.)
- Department of Head and Neck Surgery, National Police Hospital, Lima 15072, Peru
| | - Ana Elena Aviña
- Department of Plastic Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (D.D.P.); (A.E.A.); (C.-H.L.); (F.-C.W.)
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-M.L.); (C.-H.L.)
| | - Esteban Cardona
- Department of Plastic Surgery, Clínica IPS Universitaria León XIII, University of Antioquia, Medellín 050010, Colombia;
| | - Chin-Ming Lee
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-M.L.); (C.-H.L.)
| | - Chia-Hsien Lin
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-M.L.); (C.-H.L.)
| | - Cheng-Hung Lin
- Department of Plastic Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (D.D.P.); (A.E.A.); (C.-H.L.); (F.-C.W.)
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-M.L.); (C.-H.L.)
| | - Fu-Chan Wei
- Department of Plastic Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (D.D.P.); (A.E.A.); (C.-H.L.); (F.-C.W.)
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-M.L.); (C.-H.L.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Aline Yen Ling Wang
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-M.L.); (C.-H.L.)
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Kwack KH, Lamb NA, Bard JE, Kramer ED, Zhang L, Abrams SI, Kirkwood KL. Discovering Myeloid Cell Heterogeneity in Mandibular Bone - Cell by Cell Analysis. Front Physiol 2021; 12:731549. [PMID: 34658914 PMCID: PMC8514701 DOI: 10.3389/fphys.2021.731549] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 09/06/2021] [Indexed: 01/28/2023] Open
Abstract
The myeloid-derived bone marrow progenitor populations from different anatomical locations are known to have diverse osteoclastogenesis potential. Specifically, myeloid progenitors from the tibia and femur have increased osteoclast differentiation potential compared to myeloid progenitors from the alveolar process. In this study, we explored the differences in the myeloid lineage progenitor cell populations in alveolar (mandibular) bone versus long (femur) bone using flow cytometry and high-throughput single cell RNA sequencing (scRNA-seq) to provide a comprehensive transcriptional landscape. Results indicate that mandibular bone marrow-derived cells exhibit consistent deficits in myeloid differentiation, including significantly fewer myeloid-derived suppressor cell (MDSC)-like populations (CD11b+Ly6C+, CD11b+Ly6G+), as well as macrophages (CD11b+F4/80+). Although significantly fewer in number, MDSCs from mandibular bone exhibited increased immunosuppressive activity compared to MDSCs isolated from long bone. Using flow cytometry panels specific for bone marrow progenitors, analysis of hematopoietic stem cells showed no defects in mandibular bone marrow in LSK (Lin-Sca1+cKit+) cell and LK (Lin-Sca1-cKit+) cell populations. While there was no significant difference in granulocyte progenitors, the granulocyte-monocyte progenitors and monocyte progenitor population were significantly decreased in the mandibular bone marrow. T-lymphocyte subsets were not significantly different between mandibular and femoral bone, except for CD4+CD25+Foxp3+ regulatory T lymphocytes, which were significantly increased in the mandible. In addition, B lymphocytes were significantly increased in mandible. Single cell RNA sequencing from mandible and femur BM revealed distinct differences in transcriptomic profiles in myeloid populations establishing previously unappreciated aspects of mandibular bone marrow populations. These analyses reveal site-specific differences in the myeloid progenitor cellular composition and transcriptional programs providing a deeper appreciation of the complex differences in myeloid cell heterogeneity from different anatomical bone marrow sites.
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Affiliation(s)
- Kyu Hwan Kwack
- Department of Oral Biology, University at Buffalo, The State University of New York, Buffalo, NY, United States
| | - Natalie A. Lamb
- Genomics and Bioinformatics Core, New York State Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States
| | - Jonathan E. Bard
- Genomics and Bioinformatics Core, New York State Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
| | - Elliot D. Kramer
- Department of Medicine, University at Buffalo, Buffalo, NY, United States
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Lixia Zhang
- Department of Oral Biology, University at Buffalo, The State University of New York, Buffalo, NY, United States
| | - Scott I. Abrams
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Keith L. Kirkwood
- Department of Oral Biology, University at Buffalo, The State University of New York, Buffalo, NY, United States
- Department of Head and Neck, Plastic and Reconstructive Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
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Guo S, Gu J, Ma J, Xu R, Wu Q, Meng L, Liu H, Li L, Xu Y. GATA4-driven miR-206-3p signatures control orofacial bone development by regulating osteogenic and osteoclastic activity. Theranostics 2021; 11:8379-8395. [PMID: 34373748 PMCID: PMC8344011 DOI: 10.7150/thno.58052] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 06/28/2021] [Indexed: 12/14/2022] Open
Abstract
Growth disorders in the orofacial bone development process may lead to orofacial deformities. The balance between bone matrix formation by mesenchymal lineage osteoblasts and bone resorption by osteoclasts is vital for orofacial bone development. Although the mechanisms of orofacial mesenchymal stem cells (OMSCs) in orofacial bone development have been studied intensively, the communication between OMSCs and osteoclasts remains largely unclear. Methods: We used a neural crest cell-specific knockout mouse model to investigate orofacial bone development in GATA-binding protein 4 (GATA4) morphants. We investigated the underlying mechanisms of OMSCs-derived exosomes (OMExos) on osteoclastogenesis and bone resorption activity in vitro. miRNAs were extracted from OMExos, and differences in miRNA abundances were determined using an Affymetrix miRNA array. Luciferase reporter assays were used to validate the binding between GATA4 and miR-206-3p in OMSCs and to confirm the putative binding of miR-206-3p and its target genes in OMSCs and osteoclasts. The regulatory mechanism of the GATA4-miR-206-3p axis in OMSC osteogenic differentiation and osteoclastogenesis was examined in vitro and in vivo. Results: Wnt1-Cre;Gata4fl/fl mice (cKO) not only presented inhibited bone formation but also showed active bone resorption. Osteoclasts cocultured in vitro with cKO OMSCs presented an increased capacity for osteoclastogenesis, which was exosome-dependent. Affymetrix miRNA array analysis showed that miR-206-3p was downregulated in exosomes from shGATA4 OMSCs. Moreover, the transcriptional activity of miR-206-3p was directly regulated by GATA4 in OMSCs. We further demonstrated that miR-206-3p played a key role in the regulation of orofacial bone development by directly targeting bone morphogenetic protein-3 (Bmp3) and nuclear factor of activated T -cells, cytoplasmic 1 (NFATc1). OMExos and agomiR-206-3p enhanced bone mass in Wnt1-cre;Gata4fl/fl mice by augmenting trabecular bone structure and decreasing osteoclast numbers. Conclusion: Our findings confirm that miR-206-3p is an important downstream factor of GATA4 that regulates the functions of OMSCs and osteoclasts. These results demonstrate the efficiency of OMExos and microRNA agomirs in promoting bone regeneration, which provide an ideal therapeutic tool for orofacial bone deformities in the future.
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Sonoda S, Murata S, Kato H, Zakaria F, Kyumoto-Nakamura Y, Uehara N, Yamaza H, Kukita T, Yamaza T. Targeting of Deciduous Tooth Pulp Stem Cell-Derived Extracellular Vesicles on Telomerase-Mediated Stem Cell Niche and Immune Regulation in Systemic Lupus Erythematosus. THE JOURNAL OF IMMUNOLOGY 2021; 206:3053-3063. [PMID: 34078710 DOI: 10.4049/jimmunol.2001312] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 04/05/2021] [Indexed: 01/09/2023]
Abstract
Systemic transplantation of stem cells from human exfoliated deciduous teeth (SHED) is used to treat systemic lupus erythematosus (SLE)-like disorders in MRL/lpr mice. However, the mechanisms underlying the SHED-based therapy remain unclear. In this study, we hypothesized that trophic factors within SHED-releasing extracellular vesicles (SHED-EVs) ameliorate the SLE-like phenotypes in MRL/lpr mice. SHED-EVs were isolated from the culture supernatant of SHED. SHED-EVs were treated with or without RNase and systemically administered to MRL/lpr mice. Subsequently, recipient bone marrow mesenchymal stem cells (BMMSCs) isolated from SHED-EV-administered MRL/lpr mice were examined for the in vitro and in vivo activity of hematopoietic niche formation and immunoregulation. Furthermore, the recipient BMMSCs were secondarily transplanted into MRL/lpr mice. The systemic SHED-EV infusion ameliorated the SLE-like phenotypes in MRL/lpr mice and improved the functions of recipient BMMSCs by rescuing Tert mRNA-associated telomerase activity, hematopoietic niche formation, and immunoregulation. The secondary transplantation of recipient BMMSCs recovered the immune condition and renal functions of MRL/lpr mice. The RNase treatment depleted RNAs, such as microRNAs, within SHED-EVs, and the RNA-depleted SHED-EVs attenuated the benefits of SHED-EVs in MRL/lpr mice. Collectively, our findings suggest that SHED-secreted RNAs, such as microRNAs, play a crucial role in treating SLE by targeting the telomerase activity of recipient BMMSCs.
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Affiliation(s)
- Soichiro Sonoda
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
| | - Sara Murata
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
| | - Hiroki Kato
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
| | - Fouad Zakaria
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
| | - Yukari Kyumoto-Nakamura
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
| | - Norihisa Uehara
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
| | - Haruyoshi Yamaza
- Department of Pediatric Dentistry, Division of Oral Health, Growth and Development, Kyushu University Graduate School of Dental Science, Fukuoka, Japan
| | - Toshio Kukita
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
| | - Takayoshi Yamaza
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
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Aquino-Martinez R, Eckhardt BA, Rowsey JL, Fraser DG, Khosla S, Farr JN, Monroe DG. Senescent cells exacerbate chronic inflammation and contribute to periodontal disease progression in old mice. J Periodontol 2020; 92:1483-1495. [PMID: 33341947 DOI: 10.1002/jper.20-0529] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 12/02/2020] [Accepted: 12/13/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Coinciding with other chronic comorbidities, the prevalence of periodontal disease increases with aging. Mounting evidence has established that senescent cells accumulate at sites of age-related pathologies, where they promote "non-microbial" inflammation. We hypothesized that alveolar bone osteocytes develop senescence characteristics in old age. METHODS Alveolar bone samples were obtained from young (6 months) and old (20 to 22 months) mice to evaluate the expression of senescence biomarkers by immunofluorescent staining. Osteocyte-enriched fractions were used to characterize the age-related senescence-associated secretory phenotype (SASP) gene expression profile. Primary alveolar bone cells were exposed to the SASP via in vitro senescent conditioned media (SCM) administration. A multiplex assay confirmed protein levels of specific cytokines. Interactions with bacterial components were evaluated by stimulating cells with lipopolysaccharide (LPS). RESULTS Increased senescence-associated distension of satellites (SADS) and p16Ink4a mRNA expression were identified in alveolar bone osteocytes with aging. These findings were associated with increased levels of DNA damage, and activated p38 MAPK, both inducers of senescence. Furthermore, interleukin-6 (IL6), IL17, IGFBP4, and MMP13 were significantly upregulated with aging in osteocyte-enriched samples. Interestingly, SCM potentiated the LPS-induced expression of IL1α, IL1β, and IL6. Cell migration and differentiation were also impeded by SCM. These in vitro effects were ameliorated by the p38 MAPK inhibitor SB202190. CONCLUSIONS Accumulation of senescent osteocytes contributes to deterioration of the periodontal environment by exacerbating chronic inflammation and reducing regeneration in old age. Cellular senescence is a cell-intrinsic response to DNA damage, and a host-related mechanism associated with aging that could potentiate inflammation induced by bacterial components.
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Affiliation(s)
- Ruben Aquino-Martinez
- Department of Medicine, Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN
| | - Brittany A Eckhardt
- Department of Medicine, Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN
| | - Jennifer L Rowsey
- Department of Medicine, Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN
| | - Daniel G Fraser
- Department of Medicine, Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN
| | - Sundeep Khosla
- Department of Medicine, Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN.,Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN
| | - Joshua N Farr
- Department of Medicine, Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN.,Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN
| | - David G Monroe
- Department of Medicine, Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN.,Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN
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Jin Y, Hong F, Bao Q, Xu Q, Duan R, Zhu Z, Zhang W, Ma C. MicroRNA-145 suppresses osteogenic differentiation of human jaw bone marrow mesenchymal stem cells partially via targeting semaphorin 3A. Connect Tissue Res 2020; 61:577-585. [PMID: 31305177 DOI: 10.1080/03008207.2019.1643334] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Purpose: Human jaw bone marrow mesenchymal stem cells (h-JBMMSCs) are multipotent progenitor cells with osteogenic differentiation potential. MicroRNAs (miRNAs) have emerged as crucial modulators of osteoblast differentiation. In this study, we focus on the role of miR-145 and its target protein in osteoblast differentiation of h-JBMMSCs. Materials and Methods: h-JBMMSCs were isolated and cultured in osteogenic medium. miR-145 mimics and inhibitors were used to elevate and inhibit miR-145 expression, respectively. Osteogenic differentiation was determined by Alkaline phosphatase (ALP) and Alizarin red S (ARS) staining, and osteogenic marker detection using quantitative real-time reverse transcription PCR (qRT-PCR) assay. Bioinformatic analysis and luciferase reporter assay were used to identify the target gene of miR-145. Results: MiR-145 was down-regulated during osteogenesis of h-JBMMSCs. Inhibition of miR-145 promoted osteogenic differentiation of h-JBMMSCs, revealed by enhanced activity of alkaline phosphatase (ALP), greater mineralisation, and increased expression levels of the osteogenic markers, such as Runt-related transcription factor 2 (RUNX2), Osterix (OSX), ALP and COL1A1. MiR-145 could negatively regulate semaphorin3A (SEMA3A), which acts as a positive regulator of osteogenesis. MiR-145 inhibitor induced osteogenesis could be partially attenuated by SEMA3A siRNA treatment in h-JBMMSCs. Conclusions: Our data show that miR-145 directly targets SEMA3A, and also suggest miR-145 as a suppressor, plays an important role in the osteogenic differentiation of h-JBMMSCs.
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Affiliation(s)
- Yucui Jin
- Research Institute of Stomatology, Nanjing Medical University, Stomatological Hospital of Jiangsu Province , Nanjing, Jiangsu, P.R. China.,Department of Medical Genetics, Nanjing Medical University , Nanjing, P.R. China
| | - Fangling Hong
- Department of Medical Genetics, Nanjing Medical University , Nanjing, P.R. China
| | - Qianyi Bao
- Department of Medical Genetics, Nanjing Medical University , Nanjing, P.R. China
| | - Qiufan Xu
- Department of Medical Genetics, Nanjing Medical University , Nanjing, P.R. China
| | - Rui Duan
- Department of Medical Genetics, Nanjing Medical University , Nanjing, P.R. China
| | - Zhu Zhu
- Research Institute of Stomatology, Nanjing Medical University, Stomatological Hospital of Jiangsu Province , Nanjing, Jiangsu, P.R. China
| | - Wei Zhang
- Research Institute of Stomatology, Nanjing Medical University, Stomatological Hospital of Jiangsu Province , Nanjing, Jiangsu, P.R. China
| | - Changyan Ma
- Department of Medical Genetics, Nanjing Medical University , Nanjing, P.R. China
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34
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He L, Sun X, Liu Z, Qiu Y, Niu Y. Pathogenesis and multidisciplinary management of medication-related osteonecrosis of the jaw. Int J Oral Sci 2020; 12:30. [PMID: 33087699 PMCID: PMC7578793 DOI: 10.1038/s41368-020-00093-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 08/17/2020] [Accepted: 08/18/2020] [Indexed: 12/11/2022] Open
Abstract
Medication-related osteonecrosis of the jaw (MRONJ) is a serious side effect of bone-modifying agents and inhibits angiogenesis agents. Although the pathogenesis of MRONJ is not entirely clear, multiple factors may be involved in specific microenvironments. The TGF-β1 signalling pathway may have a key role in the development of MRONJ. According to the clinical stage, multiple variables should be considered when selecting the most appropriate treatment. Therefore, the prevention and management of treatment of MRONJ should be conducted in patient-centred multidisciplinary team collaborative networks with oncologists, dentists and dental specialists. This would comprise a closed responsibility treatment loop with all benefits directed to the patient. Thus, in the present review, we aimed to summarise the pathogenesis, risk factors, imaging features, clinical staging, therapeutic methods, prevention and treatment strategies associated with MRONJ, which may provide a reference that can inform preventive strategies and improve the quality of life for patients in the future.
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Affiliation(s)
- Lina He
- The First Affiliated Hospital of Harbin Medical University, Harbin, China.,School of Stomatology, Harbin Medical University, Harbin, China
| | - Xiangyu Sun
- The First Affiliated Hospital of Harbin Medical University, Harbin, China.,School of Stomatology, Harbin Medical University, Harbin, China
| | - Zhijie Liu
- The First Affiliated Hospital of Harbin Medical University, Harbin, China.,School of Stomatology, Harbin Medical University, Harbin, China
| | - Yanfen Qiu
- The First Affiliated Hospital of Harbin Medical University, Harbin, China.,School of Stomatology, Harbin Medical University, Harbin, China
| | - Yumei Niu
- The First Affiliated Hospital of Harbin Medical University, Harbin, China. .,School of Stomatology, Harbin Medical University, Harbin, China.
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35
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Sun JL, Yan JF, Yu SB, Zhao J, Lin QQ, Jiao K. MicroRNA-29b Promotes Subchondral Bone Loss in TMJ Osteoarthritis. J Dent Res 2020; 99:1469-1477. [PMID: 32693649 DOI: 10.1177/0022034520937617] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Abnormal subchondral bone remodeling plays important roles during osteoarthritis (OA) pathology. Recent studies show that bone marrow mesenchymal stem cells (BMSCs) in osteoarthritic subchondral bones exhibit a prominent pro-osteoclastic effect that contributes to abnormal subchondral bone remodeling; however, the pathologic mechanism remains unclear. In the present study, we used a mouse model with OA-like change in the temporomandibular joint (TMJ) induced by an experimentally unilateral anterior crossbite (UAC) and found that the level of microRNA-29b (miR-29b), but not miR-29a or miR-29c, was markedly lower in BMSCs from subchondral bones of UAC mice as compared with that from the sham control mice. With an intra-articular aptamer delivery system, BMSC-specific overexpression of miR-29b by aptamer-agomiR-29b rescued subchondral bone loss and osteoclast hyperfunction in UAC mice, as demonstrated by a significant increase in bone mineral density, bone volume fraction, trabecular thickness, and the gene expression of osteocalcin and Runx2 but decreased trabecular separation, osteoclast number and osteoclast surface/bone surface, and the gene expression of cathepsin K, Trap, Wnt5a, Rankl, and Rank as compared with those in the UAC mice treated by aptamer-NC (all P < 0.05). In addition, BMSC-specific inhibition of miR-29b by aptamer-antagomiR-29b exacerbated those responses in UAC mice. Notably, although it primarily affected miR-29b levels in the subchondral bone (but not in cartilage and synovium), BMSC-specific overexpression of miR-29b in UAC mice largely rescued OA-like cartilage degradation, including decreased chondrocyte density, cartilage thickness, and the percentage areas of proteoglycans and type II collagen, while BMSC-specific inhibition of miR-29b aggravated these characteristics of cartilage degradation in UAC mice. Moreover, we identified Wnt5a, but not Rankl or Sdf-1, as the direct target of miR-29b. The results of the present study indicate that miR-29b is a key regulator of the pro-osteoclastic effects of BMSCs in TMJ-OA subchondral bones and plays important roles in the TMJ-OA progression.
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Affiliation(s)
- J L Sun
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi'an, China.,Department of Stomatology, Sixth Medical Center of PLA General Hospital, Beijing, China
| | - J F Yan
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - S B Yu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - J Zhao
- Department of Stomatology, Sixth Medical Center of PLA General Hospital, Beijing, China
| | - Q Q Lin
- Department of Stomatology, Sixth Medical Center of PLA General Hospital, Beijing, China
| | - K Jiao
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi'an, China
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Svandova E, Peterkova R, Matalova E, Lesot H. Formation and Developmental Specification of the Odontogenic and Osteogenic Mesenchymes. Front Cell Dev Biol 2020; 8:640. [PMID: 32850793 PMCID: PMC7396701 DOI: 10.3389/fcell.2020.00640] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 06/25/2020] [Indexed: 12/15/2022] Open
Abstract
Within the mandible, the odontogenic and osteogenic mesenchymes develop in a close proximity and form at about the same time. They both originate from the cranial neural crest. These two condensing ecto-mesenchymes are soon separated from each other by a very loose interstitial mesenchyme, whose cells do not express markers suggesting a neural crest origin. The two condensations give rise to mineralized tissues while the loose interstitial mesenchyme, remains as a soft tissue. This is crucial for proper anchorage of mammalian teeth. The situation in all three regions of the mesenchyme was compared with regard to cell heterogeneity. As the development progresses, the early phenotypic differences and the complexity in cell heterogeneity increases. The differences reported here and their evolution during development progressively specifies each of the three compartments. The aim of this review was to discuss the mechanisms underlying condensation in both the odontogenic and osteogenic compartments as well as the progressive differentiation of all three mesenchymes during development. Very early, they show physical and structural differences including cell density, shape and organization as well as the secretion of three distinct matrices, two of which will mineralize. Based on these data, this review highlights the consecutive differences in cell-cell and cell-matrix interactions, which support the cohesion as well as mechanosensing and mechanotransduction. These are involved in the conversion of mechanical energy into biochemical signals, cytoskeletal rearrangements cell differentiation, or collective cell behavior.
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Affiliation(s)
- Eva Svandova
- Laboratory of Odontogenesis and Osteogenesis, Institute of Animal Physiology and Genetics, Academy of Sciences, Brno, Czechia
| | - Renata Peterkova
- Department of Histology and Embryology, Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Eva Matalova
- Laboratory of Odontogenesis and Osteogenesis, Institute of Animal Physiology and Genetics, Academy of Sciences, Brno, Czechia.,Department of Physiology, University of Veterinary and Pharmaceutical Sciences, Brno, Czechia
| | - Herve Lesot
- Laboratory of Odontogenesis and Osteogenesis, Institute of Animal Physiology and Genetics, Academy of Sciences, Brno, Czechia
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Huang X, Cheng B, Song W, Wang L, Zhang Y, Hou Y, Song Y, Kong L. Superior CKIP-1 sensitivity of orofacial bone-derived mesenchymal stem cells in proliferation and osteogenic differentiation compared to long bone-derived mesenchymal stem cells. Mol Med Rep 2020; 22:1169-1178. [PMID: 32626993 PMCID: PMC7339610 DOI: 10.3892/mmr.2020.11239] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 04/09/2020] [Indexed: 01/02/2023] Open
Abstract
Maxillofacial bone defects caused by multiple factors, including congenital deformations and tumors, have become a research focus in the field of oral medicine. Bone tissue engineering is increasingly regarded as a potential approach for maxillofacial bone repair. Mesenchymal stem cells (MSCs) with different origins display various biological characteristics. The aim of the present study was to investigate the effects of casein kinase‑2 interaction protein‑1 (CKIP‑1) on MSCs, including femoral bone marrow‑derived MSCs (BMMSCs) and orofacial bone‑derived MSCs (OMSCs), isolated from the femoral and orofacial bones of wild‑type (WT) and CKIP‑1 knockout (KO) mice. MSCs were isolated using collagenase II and the main biological characteristics, including proliferation, apoptosis and osteogenic differentiation, were investigated. Subcutaneous transplantation of MSCs in mice was also performed to assess ectopic bone formation. MTT and clone formation assay results indicated that cell proliferation in the KO group was increased compared with the WT group, and OMSCs exhibited significantly increased levels of proliferation compared with BMMSCs. However, the proportion of apoptotic cells was not significantly different between CKIP‑1 KO OMSCs and BMMSCs. Furthermore, it was revealed that osteogenic differentiation was increased in CKIP‑1 KO MSCs compared with WT MSCs, particularly in OMSCs. Consistent with the in vitro results, enhanced ectopic bone formation was observed in CKIP‑1 KO mice compared with WT mice, particularly in OMSCs compared with BMMSCs. In conclusion, the present results indicated that OMSCs may have a superior sensitivity to CKIP‑1 in promoting osteogenesis compared with BMMSCs; therefore, CKIP‑1 KO in OMSCs may serve as an efficient strategy for maxillofacial bone repair.
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Affiliation(s)
- Xin Huang
- School of Stomatology of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Bingkun Cheng
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Wen Song
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Le Wang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Yanyuan Zhang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Yan Hou
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Yu Song
- Department of Orthodontics, Qingdao Stomatological Hospital, Qingdao, Shandong 266001, P.R. China
| | - Liang Kong
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
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38
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Watanabe K, Lewis S, Guo X, Ni A, Lee BS, Deguchi T, Kim DG. Regional variations of jaw bone characteristics in an ovariectomized rat model. J Mech Behav Biomed Mater 2020; 110:103952. [PMID: 32957244 DOI: 10.1016/j.jmbbm.2020.103952] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 06/21/2020] [Accepted: 06/22/2020] [Indexed: 12/22/2022]
Abstract
Postmenopausal osteoporosis causes severe loss of bone quantity and quality in limb bone but has a lesser effect on jaw bone. Thus, the objective of this study was to examine whether ovariectomy (OVX) and mastication alter the regional variation of jaw bone characteristics. Sprague-Dawley female rats (6 months) were given a bilateral OVX or a sham operation (SHAM) (n = 10 for each group). After 2 months post-OVX, the hemi-mandible from each rat was dissected. A micro-computed tomography based mean, standard deviation (SD), the lower and upper 5th percentile (Low5 and High5) values of tissue mineral density (TMD) histograms were assessed for whole bone (WB), alveolar bone (AB), cortical bone (CB), and trabecular bone (TB) regions. Morphology of TB and periodontal ligament (PDL) was also obtained. Layers of AB were segmented up to 400 μm from the PDL. Mechanical properties at the tissue level were measured by nanoindentation at the same site by a single loading-unloading cycle of indentation in hydration. The AB and TB regions had significantly lower TMD Mean, Low5, and High5 but higher SD than the CB region for both sham and OVX groups (p < 0.01). TMD parameters of the OVX group rapidly increased up to 60 μm away from the PDL and were significantly higher than those of the sham group starting at 280 μm and farther in the CB region (p < 0.05). All values of morphological and nanoindentation parameters were not significantly different between sham and OVX groups (p > 0.06). Estrogen deficiency induced by OVX did not deteriorate bone characteristics including mineral density, morphology, and nanoindentation parameters in rat mandibles. Masticatory loading had an effect on the TMD parameters at the limited region of AB. These results provide insight into why osteoporosis-associated jaw bone fractures are extremely rare.
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Affiliation(s)
- Keiichiro Watanabe
- Division of Orthodontics, College of Dentistry, The Ohio State University, Columbus, OH, 43210, USA
| | - Samantha Lewis
- Division of Orthodontics, College of Dentistry, The Ohio State University, Columbus, OH, 43210, USA
| | - Xiaohan Guo
- Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, OH, 43210, USA
| | - Ai Ni
- Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, OH, 43210, USA
| | - Beth S Lee
- Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Toru Deguchi
- Division of Orthodontics, College of Dentistry, The Ohio State University, Columbus, OH, 43210, USA
| | - Do-Gyoon Kim
- Division of Orthodontics, College of Dentistry, The Ohio State University, Columbus, OH, 43210, USA.
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39
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Cui C, Bi R, Liu W, Guan S, Li P, Song D, Xu R, Zheng L, Yuan Q, Zhou X, Fan Y. Role of PTH1R Signaling in Prx1 + Mesenchymal Progenitors during Eruption. J Dent Res 2020; 99:1296-1305. [PMID: 32585127 DOI: 10.1177/0022034520934732] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Tooth eruption is a complex process requiring precise interaction between teeth and adjacent tissues. Molecular analysis demonstrates that bone remodeling plays an essential role during eruption, suggesting that a parathyroid hormone 1 receptor (PTH1R) gene mutation is associated with disturbances in bone remodeling and results in primary failure of eruption (PFE). Recent research reveals the function of PTH1R signaling in mesenchymal progenitors, whereas the function of PTH1R in mesenchymal stem cells during tooth eruption remains incompletely understood. We investigated the specific role of PTH1R in Prx1+ progenitor expression during eruption. We found that Prx1+-progenitors occur in mesenchymal stem cells residing in alveolar bone marrow surrounding incisors, at the base of molars and in the dental follicle and pulp of incisors. Mice with conditional deletion of PTH1R using the Prx1 promoter exhibited arrested mandibular incisor eruption and delayed molar eruption. Micro-computed tomography, histomorphometry, and molecular analyses revealed that mutant mice had significantly reduced alveolar bone formation concomitant with downregulated gene expression of key regulators of osteogenesis in PTH1R-deficient cells. Moreover, culturing orofacial bone-marrow-derived mesenchymal stem cells (OMSCs) from Prx1Cre;PTH1Rfl/fl mice or from transfecting Cre recombinase adenovirus in OMSCs from PTH1Rfl/fl mice suggested that lack of Pth1r expression inhibited osteogenic differentiation in vitro. However, bone resorption was not affected by PTH1R ablation, indicating the observed reduced alveolar bone volume was mainly due to impaired bone formation. Furthermore, we found irregular periodontal ligaments and reduced Periostin expression in mutant incisors, implying loss of PTH1R results in aberrant differentiation of periodontal ligament cells. Collectively, these data suggest that PTH1R signaling in Prx1+ progenitors plays a critical role in alveolar bone formation and periodontal ligament development during eruption. These findings have implications for our understanding of the physiologic and pathologic function of PTH1R signaling in tooth eruption and the progression of PFE.
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Affiliation(s)
- C Cui
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - R Bi
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - W Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - S Guan
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - P Li
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - D Song
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - R Xu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - L Zheng
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - Q Yuan
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - X Zhou
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - Y Fan
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
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40
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Li C, Wang F, Zhang R, Qiao P, Liu H. Comparison of Proliferation and Osteogenic Differentiation Potential of Rat Mandibular and Femoral Bone Marrow Mesenchymal Stem Cells In Vitro. Stem Cells Dev 2020; 29:728-736. [PMID: 32122257 DOI: 10.1089/scd.2019.0256] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Chuanjie Li
- Medical College of Naikai University, Tianjin, People's Republic of China
- Institute of Stomatology, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Feifan Wang
- Medical College of Naikai University, Tianjin, People's Republic of China
- Institute of Stomatology, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Rong Zhang
- Institute of Stomatology, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Pengyan Qiao
- Institute of Stomatology, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Hongchen Liu
- Medical College of Naikai University, Tianjin, People's Republic of China
- Institute of Stomatology, Chinese PLA General Hospital, Beijing, People's Republic of China
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41
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Cui C, Zheng L, Fan Y, Zhang J, Xu R, Xie J, Zhou X. Parathyroid hormone ameliorates temporomandibular joint osteoarthritic-like changes related to age. Cell Prolif 2020; 53:e12755. [PMID: 32154622 PMCID: PMC7162802 DOI: 10.1111/cpr.12755] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 12/16/2019] [Accepted: 12/17/2019] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES Ageing could be a contributing factor to the progression of temporomandibular joint osteoarthritis (TMJ OA), whereas its pathogenesis and potential therapeutic strategy have not been comprehensively investigated. MATERIALS AND METHODS We generated ageing mouse models (45-week and 60-week; 12-week mice as control) and intermittently injected 45-week mice with parathyroid hormone (PTH(1-34)) or vehicle for 4 weeks. Cartilage and subchondral bone of TMJ were analysed by microCT, histological and immunostaining. Western blot, qRT-PCR, ChIP, ELISA and immunohistochemical analysis were utilized to examination the mechanism of PTH(1-34)'s function. RESULTS We showed apparent OA-like phenotypes in ageing mice. PTH treatment could ameliorate the degenerative changes and improve bone microarchitecture in the subchondral bone by activating bone remodelling. Moreover, PTH inhibited phosphorylation level of Smad3, which can combine with p16ink4a gene promoter region, resulting in reduced senescent cells accumulation and increased cellular proliferation of marrow mesenchymal stem cells (MSCs). ELISA also showed relieved levels of specific senescent-associated secretory phenotype (SASP) in ageing mice after PTH treatment. CONCLUSIONS In summary, PTH may reduce the accumulation of senescent cells in subchondral bone by inhibiting p16ink4a and improve bone marrow microenvironment to active bone remodelling process, indicating PTH administration could be a potential preventative and therapeutic treatment for age-related TMJ OA.
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Affiliation(s)
- Chen Cui
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - Liwei Zheng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - Yi Fan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - Jun Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China.,School of Stomatology, Kunming Medical University, Kunming, China
| | - Ruoshi Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - Jing Xie
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China
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42
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Cao C, Tarlé S, Kaigler D. Characterization of the immunomodulatory properties of alveolar bone-derived mesenchymal stem cells. Stem Cell Res Ther 2020; 11:102. [PMID: 32138791 PMCID: PMC7059346 DOI: 10.1186/s13287-020-01605-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 01/22/2020] [Accepted: 02/14/2020] [Indexed: 02/07/2023] Open
Abstract
Background Recently, mesenchymal stem cells (MSCs) have been shown to have immunomodulatory properties which hold promise for their clinical use to treat inflammatory conditions. Relative to bone marrow-derived MSCs (BMSCs), which are typically isolated from the iliac crest, we have recently demonstrated that MSCs can be predictably isolated from the alveolar bone (aBMSCs) by less invasive means. As such, the aim of this study was to characterize the immunomodulatory properties of aBMSCs relative to BMSCs. Methods aBMSCs isolated from the human alveolar bone and BMSCs isolated from the human bone marrow of the iliac crest were cultured in the same conditions. Cytokine arrays and enzyme-linked immunosorbent assays (ELISA) of a conditioned medium were used to evaluate differences in the secretion of cytokines. In different functional assays, aBMSCs and BMSCs were cocultured with different types of immune cells including THP-1 monocytes, macrophages, and peripheral blood mononuclear cells (PBMCs) to evaluate their effects on important immune cell functions including proliferation, differentiation, and activation. Results The protein arrays identified interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 to be the major cytokines secreted by aBMSCs and BMSCs. ELISA determined that aBMSCs secreted 268.64 ± 46.96 pg/mL of IL-6 and 196.14 ± 97.31 pg/mL of MCP-1 per microgram of DNA, while BMSCs secreted 774.86 ± 414.29 pg/mL of IL-6 and 856.37 ± 433.03 pg/mL of MCP-1 per microgram of DNA. The results of the coculture studies showed that aBMSCs exhibited immunosuppressive effects on monocyte activation and T cell activation and proliferation similar to BMSCs. Both aBMSCs and BMSCs drove macrophages into an anti-inflammatory phenotype with increased phagocytic ability. Taken together, these data suggest that aBMSCs have potent immunomodulatory properties comparable to those of BMSCs. Conclusions The findings of this study have important implications for the development of immunomodulatory stem cell therapies aimed to treat inflammatory conditions using aBMSCs, a more feasible tissue source of MSCs.
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Affiliation(s)
- Chen Cao
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, 1011 N. University, Ann Arbor, MI, 48109, USA
| | - Susan Tarlé
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, 1011 N. University, Ann Arbor, MI, 48109, USA
| | - Darnell Kaigler
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, 1011 N. University, Ann Arbor, MI, 48109, USA. .,Department of Biomedical Engineering, College of Engineering, University of Michigan, 1011 N. University, Ann Arbor, MI, 48109, USA.
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Iezzi G, Mangano C, Barone A, Tirone F, Baggi L, Tromba G, Piattelli A, Giuliani A. Jawbone remodeling: a conceptual study based on Synchrotron High-resolution Tomography. Sci Rep 2020; 10:3777. [PMID: 32123216 PMCID: PMC7052147 DOI: 10.1038/s41598-020-60718-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 02/10/2020] [Indexed: 12/13/2022] Open
Abstract
One of the most important aspects of bone remodeling is the constant turnover mainly driven by the mechanical loading stimulus. The remodeling process produces changes not only in the bone microarchitecture but also in the density distribution of the mineralized matrix - i.e. in calcium concentrations- and in the osteocyte lacunar network. Synchrotron radiation-based X-ray microtomography (microCT) has proven to be an efficient technique, capable to achieve the analysis of 3D bone architecture and of local mineralization at different hierarchical length scales, including the imaging of the lacuno-canalicular network. In the present study, we used microCT within a conceptual study of jawbone remodeling, demonstratively focusing the investigation in two critical contexts, namely in the peri-dental and the peri-implant tissues. The microCT analysis showed that a relevant inhomogeneity was clearly present in both peri-dental and peri-implant biopsies, not only in terms of microarchitecture and mineralization degree, but also considering the lacunar network, i.e. size and numerical density of the osteocyte lacunae. The correlated histological results obtained on the same samples confirmed these observations, also adding information related to non-mineralized tissues. Despite its demonstrative nature, it was concluded that the proposed method was powerful in studying jawbone remodeling because it revealed a direct correlation of its rate with the lacunar density, as achieved by the analysis of the osteocyte lacunar network, and an inverse correlation with the local bone mineral density, as revealed with the Roschger approach.
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Affiliation(s)
- Giovanna Iezzi
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Chieti Scalo, CH, Italy
| | | | - Antonio Barone
- Department of Medical, Surgical, Molecular and of the Critical Area Pathologies, University of Pisa, Pisa, Italy
| | | | - Luigi Baggi
- Department of Social Dentistry, National Institute for Health, Migration and Poverty, Rome, Italy.,School of Dentistry, University of Rome "Tor Vergata", Rome, Italy
| | | | - Adriano Piattelli
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Chieti Scalo, CH, Italy.,Chair of Biomaterials Engineering, Catholic University of Murcia (UCAM), Murcia, Spain.,Villa Serena Foundation for Research, Città Sant'Angelo (Pescara), Italy
| | - Alessandra Giuliani
- Department of Clinical Sciences, Polytechnic University of Marche, Ancona, Italy.
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Ouchi T, Nakagawa T. Mesenchymal stem cell-based tissue regeneration therapies for periodontitis. Regen Ther 2020; 14:72-78. [PMID: 31970269 PMCID: PMC6962327 DOI: 10.1016/j.reth.2019.12.011] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 11/05/2019] [Accepted: 12/24/2019] [Indexed: 02/06/2023] Open
Abstract
Periodontitis is commonly observed and is an important concern in dental health. It is characterized by a multifactorial etiology, including imbalance of oral microbiota, mechanical stress, and systemic diseases such as diabetes mellitus. The current standard treatments for periodontitis include elimination of the microbial pathogen and application of biomaterials for treating bone defects. However, the periodontal tissue regeneration via a process consistent with the natural tissue formation process has not yet been achieved. Developmental biology studies state that periodontal tissue is composed of neural crest-derived ectomesenchyme. To elucidate the process of periodontal regeneration, it is essential to understand the developmental background and intercellular cross-talk. Several recent studies have reported the efficacy of transplantation of mesenchymal stem cells for periodontal tissue regeneration. In this review, we discuss the basic knowledge of periodontal tissue regeneration using mesenchymal stem cells and highlight the potential of stem cell-based periodontal regenerative medicine.
Neural crest cells regulate the development and homeostasis of periodontal tissues. Dental mesenchymal stem cells (MSCs) are used for treating alveolar bone defects. Non-odontogenic MSCs can be investigated for periodontal tissue regeneration. Using appropriate growth factors and scaffold may improve periodontium regeneration.
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Key Words
- BMMSCs, bone marrow MSCs
- BMP, bone morphogenetic protein
- C-MSCs, clumps of MSC/ECM complexes
- DFSCs, dental follicle stem cells
- ECM, extracellular matrix
- FGF, fibroblast growth factor
- GDF-5, growth/differentiation factor-5
- HERS, Hertwig epithelial root sheath
- IFN-γ, interferon-gamma
- IGFBP-6, insulin-like growth factor binding protein-6
- LepR, leptin receptor
- MSCs, mesenchymal stem cells
- Mesenchymal stem cells
- NCCs, neural crest cells
- PDGFRα, platelet derived growth factor receptor α
- PDL, periodontal ligament
- PDLSCs, periodontal ligament stem cells
- Periodontal tissue
- Periodontitis
- Pluripotent stem cells
- TNF-α, tumor necrosis factor-alpha
- Tissue regeneration
- Wnt, wingless-INT
- iPSC-MSCs, iPSC-derived MSCs
- iPSCs, induced pluripotent stem cells
- scRNA-seq, single-cell RNA sequence
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Affiliation(s)
- Takehito Ouchi
- Department of Dentistry and Oral Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Taneaki Nakagawa
- Department of Dentistry and Oral Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan
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Liu H, Gu R, Li W, Xue J, Cong Z, Wei Q, Zhou Y. Probiotics protect against tenofovir-induced mandibular bone loss in mice by rescuing mandible-derived mesenchymal stem cell proliferation and osteogenic differentiation. J Oral Rehabil 2019; 47 Suppl 1:83-90. [PMID: 31209890 DOI: 10.1111/joor.12840] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 04/27/2019] [Accepted: 06/09/2019] [Indexed: 02/01/2023]
Abstract
BACKGROUND Tenofovir disoproxil fumarate (TDF), a primary antiretroviral agent used to treat AIDS, triggers systematic bone loss. However, the effect of TDF on osteopenia or osteoporosis in the jaw remains unclear. TDF-induced bone loss in the jaw, if any, likely involves mandible-derived mesenchymal stem cells (MMSCs), which play a key role in jawbone metabolism. Probiotics prevent long bone loss, and could prove efficacious in treating TDF-induced mandibular bone loss. OBJECTIVES To determine whether TDF triggers mandibular bone loss, elucidate the underlying mechanisms, and study the effect of Lactobacillus rhamnosus GG (LGG) on TDF-induced bone loss in the jaw. METHODS Tenofovir disoproxil fumarate was administered orally daily and LGG semiweekly from eight weeks to the end of the study (LGG group) to male C57BL6/J mice. The mice were sacrificed, and body weight (BW) and serum Ca and P were measured. Mandibular histomorphometry was evaluated by micro-CT. MMSCs and LGG culture supernatants were isolated, and MMSC proliferation and ALP production when treated with different concentrations of LGG supernatant and/or TDF were measured. Relative abundance of osteogenic markers was assessed by qPCR. RESULTS Orally administered LGG protected against bone mass loss and deterioration of bone microarchitecture and increased serum P levels. The BW of the TDF group was highest among the study groups. TDF partially impaired osteogenesis and proliferation of MMSCs. LGG culture supernatant rescued MMSC osteogenesis and proliferation, and osteogenic gene expression. CONCLUSIONS Lactobacillus rhamnosus GG protected against tenofovir-induced mandibular bone loss in mice by rescuing MMSC proliferation and osteogenesis.
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Affiliation(s)
- Hao Liu
- Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Ranli Gu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Wei Li
- Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Jing Xue
- Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Zhe Cong
- Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Qiang Wei
- Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Yongsheng Zhou
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
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A New Face Subunit Transplant Model in Mice, Containing Skin, Mandible, and Oral Mucosa for Future Face Vascularized Composite Allotransplantation Studies. Plast Reconstr Surg 2019; 144:115-123. [PMID: 31246813 DOI: 10.1097/prs.0000000000005774] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Wang H, Hu Z, Wu J, Mei Y, Zhang Q, Zhang H, Miao D, Sun W. Sirt1 Promotes Osteogenic Differentiation and Increases Alveolar Bone Mass via Bmi1 Activation in Mice. J Bone Miner Res 2019; 34:1169-1181. [PMID: 30690778 DOI: 10.1002/jbmr.3677] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 12/27/2018] [Accepted: 01/11/2019] [Indexed: 12/16/2022]
Abstract
Sirtuin 1 (Sirt1), a protein deacetylase, is a novel target for bone metabolism. To investigate whether overexpression of Sirt1 in mandibular mesenchymal stem cells (M-MSCs) increased alveolar bone mass in vivo, we generated Sirt1 transgenic mice (Sirt1TG ), with Sirt1 gene expression driven by the Prx1 gene, which represents the mesenchymal lineage. Our results demonstrated that overexpression of Sirt1 in M-MSCs increased the alveolar bone volume in 1-month-old, 9-month-old, and 18-month-old Sirt1TG mice compared with age-matched wild-type (WT) mice, and in ovariectomized Sirt1TG mice compared with ovariectomized WT mice by stimulating M-MSC differentiation into osteoblasts. Treatment with resveratrol, a Sirt1 activator, increased Sirt1 binding with Bmi1 and reduced Bmi1 acetylation in a dose-dependent manner demonstrated in M-MSC cultures. Both treatment with resveratrol in M-MSC cultures and overexpressed Sirt1 in M-MSCs ex vivo cultures increased nuclear translocation of Bmi1. Furthermore, we demonstrated that deletion of Bmi1 blocked the increased alveolar bone volume in Sirt1TG mice. The Sirt1 activator resveratrol inhibited human MSC senescence and promoted their differentiation into osteoblasts, which were associated with upregulating the expression levels of Sirt1 and nuclear translocation of Bmi1. The present results suggested that Sirt1 promotes MSC proliferation and osteogenic differentiation, inhibits MSC senescence to increase alveolar bone volume by promoting the deacetylation and nuclear translocation of Bmi1. Thus, our study elucidated the mechanism by which Sirt1 increases alveolar bone mass, and these findings are important for the clinical application of the Sirt1 activator resveratrol for the promotion of alveolar bone formation and prevention of alveolar bone loss. © 2019 American Society for Bone and Mineral Research.
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Affiliation(s)
- Hua Wang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Department of Basic Science of Stomatology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Zixuan Hu
- State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China
| | - Jun Wu
- State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China
| | - Yukun Mei
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Department of Basic Science of Stomatology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Qian Zhang
- State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China
| | - Hengwei Zhang
- Center for Musculoskeletal Research (CMSR), Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Dengshun Miao
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Department of Basic Science of Stomatology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.,State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China
| | - Wen Sun
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.,Department of Basic Science of Stomatology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
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Lee DJ, Kwon J, Current L, Yoon K, Zalal R, Hu X, Xue P, Ko CC. Osteogenic potential of mesenchymal stem cells from rat mandible to regenerate critical sized calvarial defect. J Tissue Eng 2019; 10:2041731419830427. [PMID: 30886687 PMCID: PMC6415471 DOI: 10.1177/2041731419830427] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 01/19/2019] [Indexed: 12/19/2022] Open
Abstract
Although bone marrow–derived mesenchymal stem cells (MSCs) have been extensively explored in bone tissue engineering, only few studies using mesenchymal stem cells from mandible (M-MSCs) have been reported. However, mesenchymal stem cells from mandible have the potential to be as effective as femur-derived mesenchymal stem cells (F-MSCs) in regenerating bone, especially in the orofacial regions, which share embryonic origin, proximity, and accessibility. M-MSCs were isolated and characterized using mesenchymal stem cell–specific markers, colony forming assay, and multi-potential differentiation. In vitro osteogenic potential, including proliferation, osteogenic gene expression, alkaline phosphatase activity, and mineralization, was examined and compared. Furthermore, in vivo bone formations of F-MSCs and M-MSCs in rat critical sized defect were evaluated using microCT and histology. M-MSCs from rat could be successfully isolated and expanded while preserving their MSC’s characteristics. M-MSCs demonstrated a comparable proliferation and mineralization potentials and in vivo bone formation as F-MSCs. M-MSCs is a promising cell source candidate for craniofacial bone tissue engineering.
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Affiliation(s)
- Dong Joon Lee
- Oral and Craniofacial Health Sciences Research and North Carolina Oral Health Institute, School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jane Kwon
- Oral and Craniofacial Health Sciences Research and North Carolina Oral Health Institute, School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Luke Current
- Oral and Craniofacial Health Sciences Research and North Carolina Oral Health Institute, School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kun Yoon
- Oral and Craniofacial Health Sciences Research and North Carolina Oral Health Institute, School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Rahim Zalal
- Oral and Craniofacial Health Sciences Research and North Carolina Oral Health Institute, School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Xiangxiang Hu
- Oral and Craniofacial Health Sciences Research and North Carolina Oral Health Institute, School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Peng Xue
- Oral and Craniofacial Health Sciences Research and North Carolina Oral Health Institute, School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Ching-Chang Ko
- Oral and Craniofacial Health Sciences Research and North Carolina Oral Health Institute, School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,Department of Orthodontics, School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Titanium Surface Properties Influence the Biological Activity and FasL Expression of Craniofacial Stromal Cells. Stem Cells Int 2019; 2019:4670560. [PMID: 30733806 PMCID: PMC6348805 DOI: 10.1155/2019/4670560] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 10/21/2018] [Indexed: 12/31/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) can be easily isolated form craniofacial bones during routine dentistry procedures. Due to their embryological origin from neural crest, they represent a suitable cell population to study cell-biomaterial interaction in the craniofacial field, including osteoinductive/osteointegrative processes. The biological and immunomodulatory properties of MSCs may be influenced by chemistry and topography of implant surfaces. We investigated if and how three different titanium surfaces, machined (MCH), sandblasted with resorbable blasting medium (RBM), and Ca++-nanostructured (NCA), may affect biological activity, osseointegration, and immunomodulatory properties of craniofacial MSCs. Cell proliferation, morphology, osteogenic markers, and FasL were evaluated on MSCs isolated from the mandibular bone after seeding on these three different surfaces. No statistically significant differences in cell proliferation were observed whereas different morphologies and growth patterns were detected for each type of surface. No difference in the expression of osteogenic markers was revealed. Interestingly, FasL expression, involved in the immunomodulatory activity of stem cells, was influenced by surface properties. Particularly, immunofluorescence analysis indicated that FasL expression increased on MCH surface compared to the others confirming the suggested role of FasL in promoting osteogenic differentiation. Titanium surface treatments and topography might reflect different biological behaviours of craniofacial MSCs and influence their osseointegration/immunomodulation properties.
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50
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Osteogenic and angiogenic characterization of mandible and femur osteoblasts. J Mol Histol 2019; 50:105-117. [PMID: 30635760 DOI: 10.1007/s10735-019-09810-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 01/06/2019] [Indexed: 12/13/2022]
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