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Dong Y, Wu X, Hao Y, Liu W, Hu X, Zhou J, Li X, Wang B. Epiregulin ameliorates ovariectomy-induced bone loss through orchestrating the differentiation of osteoblasts and osteoclasts. J Bone Miner Res 2025; 40:428-444. [PMID: 39862425 DOI: 10.1093/jbmr/zjaf017] [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: 07/09/2024] [Revised: 01/09/2025] [Accepted: 01/18/2025] [Indexed: 01/27/2025]
Abstract
Epiregulin plays a role in a range of biological activities including malignancies. This study aims to investigate the potential contribution of epiregulin to bone cell differentiation and bone homeostasis. The data showed that epiregulin expression was upregulated during osteogenesis but downregulated during adipogenesis. Functionally, epiregulin promoted osteoblast differentiation while inhibiting adipocyte differentiation from mesenchymal progenitor cells. Epidermal growth factor receptor (EGFR), one of the two known receptors for epiregulin, exerted opposing effects compared to epiregulin. Intriguingly, silencing EGFR almost completely abolished the dysregulation of osteoblast and adipocyte differentiation induced by epiregulin, suggesting that EGFR is indispensable for mediating epiregulin function. Further mechanistic exploration indicated that epiregulin/EGFR signaled via the inactivation of mechanistic target of rapamycin complex 1 (mTORC1) pathway. Moreover, epiregulin downregulated RANKL expression in bone marrow stromal cells (BMSCs) and inhibited the differentiation of bone marrow osteoclast precursor cells into osteoclasts. Treatment of ovariectomized female mice with recombinant epiregulin increased osteoblasts and bone formation, decreased osteoclasts and bone resorption, and ameliorated cancellous bone loss. Consistently, epiregulin treatment improved the potential of BMSCs to differentiate into osteoblasts. Collectively, this study has identified a critical role of epiregulin in regulating osteoblast differentiation through EGFR-mediated inactivation of the mTORC1 pathway, as well as osteoclast differentiation via a mechanism associated with RANKL signaling. Additionally, it highlights the potential of epiregulin as a strategy for combating osteoporosis.
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Affiliation(s)
- Yuan Dong
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital, and Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Xiaowen Wu
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital, and Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Yinglong Hao
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital, and Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Wei Liu
- College of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Xingli Hu
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital, and Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Jie Zhou
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital, and Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Xiaoxia Li
- College of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Baoli Wang
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital, and Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
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Xiao T, Shi Y, Ye Y, Wang J, Wang W, Yu H, Yan M, Yu J. Circ-SPATA13 regulates the osteogenic differentiation of human periodontal ligament stem cells through the miR-485-5p_R + 1/BMP7 axis. Cell Signal 2025; 127:111561. [PMID: 39667547 DOI: 10.1016/j.cellsig.2024.111561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/29/2024] [Accepted: 12/08/2024] [Indexed: 12/14/2024]
Abstract
BACKGROUND Human periodontal ligament stem cells (PDLSCs) are widely available and have strong osteogenic differentiation ability, which makes them promising tools for bone regeneration. Circular RNAs (circRNAs) play a variety of functions in the process of cell differentiation and are potential therapeutic targets. Here, we identified a new circRNA, circ-SPATA13, and found that it was highly positively correlated with the osteogenic differentiation of PDLSCs. Therefore, in this study, we revealed the significance and mechanism of circ-SPATA13 in the osteogenic differentiation of PDLSCs. METHODS PDLSCs were isolated from third molars with incomplete apical development and induced to undergo chondrogenic, adipogenic, or osteogenic differentiation. Surface markers were detected via flow cytometry. Proliferation was assessed with EdU and CCK-8 assays. The circ-SPATA13 and miR-485-5p_R + 1-mediated control of mineral deposition was evaluated through alizarin red and alkaline phosphatase staining. Osteogenesis-related factor expression was detected through western blotting, immunofluorescence, and qRT-PCR. Fluorescence in situ hybridization was used to examine circ-SPATA13 localization within PDLSCs. The relationships among circ-SPATA13, miR-485-5p_R + 1, and BMP7 during PDLSCs osteogenesis were assessed through western blotting, qRT-PCR, dual-luciferase assay, rescue experiment, and bioinformatics approaches. RESULTS Primary PDLSCs expressing mesenchymal stem cell surface markers were isolated. Circ-SPATA13 was identified and found to have no impact on PDLSC proliferation, whereas it was a positive regulator of their osteogenic differentiation, a process which was antagonized by miR-485-5p_R + 1. Dual-luciferase reporter assays revealed that circ-SPATA13 was able to function as a molecular sponge to sequester miR-485-5p_R + 1 within PDLSCs, while this miRNA was able to bind to the 3'-UTR of the target mRNA BMP7. In rescue experiments, circ-SPATA13 was confirmed to regulate the osteogenic differentiation of PDLSCs via this miR-485-5p_R + 1/BMP7 axis. Moreover, in vivo experiments in rats demonstrated that the overexpression of circ-SPATA13 in PDLSCs was associated with the promotion of bone formation in a skull defect model system. CONCLUSION These data supported the osteogenic functions of circ-SPATA13 in PDLSCs. Mechanistically, this circRNA was found to function as a molecular sponge for miR-485-5p_R + 1, in turn targeting BMP7 to promote the osteogenic differentiation of PDLSCs. This circ-SPATA13/miR-485-5p_R + 1/BMP7 axis may be a novel target for treatments promoting PDLSCs osteogenic differentiation.
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Affiliation(s)
- Tong Xiao
- Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Yijia Shi
- Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Yu Ye
- Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Jing Wang
- Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Wenmin Wang
- Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Haowen Yu
- Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Maoshen Yan
- Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Jinhua Yu
- Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing 210029, China; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing 210029, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, China.
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Khanka S, Rastogi SK, Singh KB, Sharma K, Parwez S, Siddiqi MI, Sinha AK, Kumar R, Singh D. Pym-18a, a novel pyrimidine derivative ameliorates glucocorticoid induced osteoblast apoptosis and promotes osteogenesis via autophagy and PINK 1/Parkin mediated mitophagy induction. Biochem Pharmacol 2025; 233:116751. [PMID: 39800267 DOI: 10.1016/j.bcp.2025.116751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 12/11/2024] [Accepted: 01/09/2025] [Indexed: 01/15/2025]
Abstract
Glucocorticoid-induced osteoporosis (GIOP) is the most common type of secondary osteoporosis, marked by reduced bone density and impaired osteoblast function. Current treatments have serious side effects, highlighting the need for new drug candidates. Pyrimidine derivatives have been noted for their potential in suppressing osteoclastogenesis, but their effects on osteogenesis and GIOP remain underexplored. Our recent study identified a novel pyrimidine derivative, Pym-18a, which enhances osteoblast functions. In this study, Pym-18a was found to mitigate the detrimental effects of Dexamethasone (Dex) in osteoblast cells and in GIOP in Balb/C mice. Pretreatment with Pym-18a followed by Dex (100 µM) for 24 h restored osteoblast alkaline phosphatase activity and viability. Pym-18a reduced Dex-induced apoptosis and reactive oxygen species (ROS) generation at cellular and mitochondrial levels and preserved mitochondrial membrane potential. Dex impaired autophagy and mitophagy, however but Pym-18a pretreatment increased expression of autophagy markers (LC3II) and mitophagy markers (PINK1, Parkin, TOM20) while decreasing P62 expression. The osteogenic effects of Pym-18a were diminished in the presence of 3-MA (an autophagy inhibitor). In silico studies showed mTOR inhibition by Pym-18a, corroborated by its suppression of Dex-induced mTOR activation. In vivo, Pym-18a (10 mg/kg) significantly improved bone microarchitecture, trabecular connectivity, and strength, and corrected P1NP and CTX levels altered by Dex. Pym-18a also promoted autophagy, mitophagy, and suppressed mTOR activation in GIOP mice. Overall, Pym-18a mitigates detrimental effect of Dex by modulating autophagy and PINK/Parkin-mediated mitophagy through mTOR inhibition, suggesting it as a potential novel therapeutic option for GIOP.
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Affiliation(s)
- Sonu Khanka
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Sumit K Rastogi
- Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Krishna Bhan Singh
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Kriti Sharma
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Shahid Parwez
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Mohammad Imran Siddiqi
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Arun K Sinha
- Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Ravindra Kumar
- Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Divya Singh
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India.
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AlYafie R, Velayutham D, van Panhuys N, Jithesh PV. The genetics of hyper IgE syndromes. Front Immunol 2025; 16:1516068. [PMID: 40040707 PMCID: PMC11876172 DOI: 10.3389/fimmu.2025.1516068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 01/29/2025] [Indexed: 03/06/2025] Open
Abstract
Hyper IgE syndromes (HIES) form a rare group of primary immunodeficiency disorders (PIDs) distinguished by persistent skin abscesses, dermatitis, allergies, and infections, in addition to their characteristic high serum IgE levels. Autosomal dominant (AD) and autosomal recessive (AR) genetic defects have been reported in HIES. From a clinical perspective, AD-HIES cases generally exhibit several non-immunologic features, including connective tissue, dental and skeletal abnormalities, whilst AR-HIES conditions have a higher incidence of neurologic complications and cutaneous viral infections. Genetic defects associated with HIES lead to impaired immune signaling, affecting pathways crucial for immune cell development, function, and immune response to pathogens/allergens. As a result, HIES patients are predisposed to recurrent bacterial and/or fungal infections, as well as atopic allergic responses. In many cases, the exact biological mechanisms responsible for the variations observed in the clinical phenotypes between the two inherited forms of HIES are still unclear. In this review, we describe the genetic basis of HIES with a distinction between the AR-HIES and AD-HIES forms, to better comprehend the different underlying molecular mechanisms, a distinction which is imperative for the accurate diagnosis, management, and development of targeted therapies for HIES patients.
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Affiliation(s)
- Randa AlYafie
- College of Health and Life Sciences, Hamad bin Khalifa University, Doha, Qatar
- Laboratory of Immunoregulation, Research Department, Sidra Medicine, Doha, Qatar
| | - Dinesh Velayutham
- College of Health and Life Sciences, Hamad bin Khalifa University, Doha, Qatar
| | - Nicholas van Panhuys
- College of Health and Life Sciences, Hamad bin Khalifa University, Doha, Qatar
- Laboratory of Immunoregulation, Research Department, Sidra Medicine, Doha, Qatar
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Lim YJ, Park SA, Wang D, Jin W, Ku WL, Zhang D, Xu J, Patiño LC, Liu N, Chen W, Kazmi R, Zhao K, Zhang YE, Sun L, Chen W. MicroRNA-19b exacerbates systemic sclerosis through promoting Th9 cells. Cell Rep 2024; 43:114565. [PMID: 39083380 PMCID: PMC11440512 DOI: 10.1016/j.celrep.2024.114565] [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: 02/21/2024] [Revised: 06/19/2024] [Accepted: 07/16/2024] [Indexed: 08/02/2024] Open
Abstract
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and multiple vital organs, but the immunological pathogenesis of SSc remains unclear. We show here that miR-19b promotes Th9 cells that exacerbate SSc. Specifically, miR-19b and interleukin (IL)-9 increase in CD4+ T cells in experimental SSc in mice induced with bleomycin. Inhibiting miR-19b reduces Th9 cells and ameliorates the disease. Mechanistically, transforming growth factor beta (TGF-β) plus IL-4 activates pSmad3-Ser213 and TRAF6-K63 ubiquitination by suppressing NLRC3. Activated TRAF6 sequentially promotes TGF-β-activated kinase 1 (TAK1) and nuclear factor κB (NF-κB) p65 phosphorylation, leading to the upregulation of miR-19b. Notably, miR-19b activated Il9 gene expression by directly suppressing atypical E2F family member E2f8. In patients with SSc, higher levels of IL9 and MIR-19B correlate with worse disease progression. Our findings reveal miR-19b as a key factor in Th9 cell-mediated SSc pathogenesis and should have clinical implications for patients with SSc.
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Affiliation(s)
- Yun-Ji Lim
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
| | - Sang-A Park
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
| | - Dandan Wang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China
| | - Wenwen Jin
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
| | - Wai Lim Ku
- Systemic Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, 31 Center Drive, Bethesda, MD 20892, USA
| | - Dunfang Zhang
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
| | - Junji Xu
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
| | - Liliana C Patiño
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
| | - Na Liu
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
| | - Weiwei Chen
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China
| | - Rida Kazmi
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA
| | - Keji Zhao
- Systemic Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, 31 Center Drive, Bethesda, MD 20892, USA
| | - Ying E Zhang
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA
| | - Lingyun Sun
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
| | - WanJun Chen
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA.
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Saberian E, Jenča A, Zafari Y, Jenča A, Petrášová A, Zare-Zardini H, Jenčová J. Scaffold Application for Bone Regeneration with Stem Cells in Dentistry: Literature Review. Cells 2024; 13:1065. [PMID: 38920693 PMCID: PMC11202130 DOI: 10.3390/cells13121065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 06/14/2024] [Accepted: 06/18/2024] [Indexed: 06/27/2024] Open
Abstract
Bone tissue injuries within oral and dental contexts often present considerable challenges because traditional treatments may not be able to fully restore lost or damaged bone tissue. Novel approaches involving stem cells and targeted 3D scaffolds have been investigated in the search for workable solutions. The use of scaffolds in stem cell-assisted bone regeneration is a crucial component of tissue engineering techniques designed to overcome the drawbacks of traditional bone grafts. This study provides a detailed review of scaffold applications for bone regeneration with stem cells in dentistry. This review focuses on scaffolds and stem cells while covering a broad range of studies explaining bone regeneration in dentistry through the presentation of studies conducted in this field. The role of different stem cells in regenerative medicine is covered in great detail in the reviewed literature. These studies have addressed a wide range of subjects, including the effects of platelet concentrates during dental surgery or specific combinations, such as human dental pulp stem cells with scaffolds for animal model bone regeneration, to promote bone regeneration in animal models. Noting developments, research works consider methods to improve vascularization and explore the use of 3D-printed scaffolds, secretome applications, mesenchymal stem cells, and biomaterials for oral bone tissue regeneration. This thorough assessment outlines possible developments within these crucial regenerative dentistry cycles and provides insights and suggestions for additional study. Furthermore, alternative creative methods for regenerating bone tissue include biophysical stimuli, mechanical stimulation, magnetic field therapy, laser therapy, nutritional supplements and diet, gene therapy, and biomimetic materials. These innovative approaches offer promising avenues for future research and development in the field of bone tissue regeneration in dentistry.
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Affiliation(s)
- Elham Saberian
- Klinika of Stomatology and Maxillofacial Surgery Akadémia Košice Bacikova, Pavol Jozef Šafárik University, 040 01 Kosice, Slovakia
| | - Andrej Jenča
- Klinika of Stomatology and Maxillofacial Surgery Akadémia Košice Bacikova, Pavol Jozef Šafárik University, 040 01 Kosice, Slovakia
| | - Yaser Zafari
- Lyles School of Civil Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Andrej Jenča
- Klinika of Stomatology and Maxillofacial Surgery Akadémia Košice Bacikova, Pavol Jozef Šafárik University, 040 01 Kosice, Slovakia
| | - Adriána Petrášová
- Klinika of Stomatology and Maxillofacial Surgery Akadémia Košice Bacikova, Pavol Jozef Šafárik University, 040 01 Kosice, Slovakia
| | - Hadi Zare-Zardini
- Department of Biomedical Engineering, Meybod University, Meybod 89616-99557, Iran
| | - Janka Jenčová
- Klinika of Stomatology and Maxillofacial Surgery Akadémia Košice Bacikova, Pavol Jozef Šafárik University, 040 01 Kosice, Slovakia
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Wang LL, Lu ZJ, Luo SK, Li Y, Yang Z, Lu HY. Unveiling the role of hypoxia-inducible factor 2alpha in osteoporosis: Implications for bone health. World J Stem Cells 2024; 16:389-409. [PMID: 38690514 PMCID: PMC11056635 DOI: 10.4252/wjsc.v16.i4.389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 01/12/2024] [Accepted: 02/21/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND Osteoporosis (OP) has become a major public health problem worldwide. Most OP treatments are based on the inhibition of bone resorption, and it is necessary to identify additional treatments aimed at enhancing osteogenesis. In the bone marrow (BM) niche, bone mesenchymal stem cells (BMSCs) are exposed to a hypoxic environment. Recently, a few studies have demonstrated that hypoxia-inducible factor 2alpha (HIF-2α) is involved in BMSC osteogenic differentiation, but the molecular mechanism involved has not been determined. AIM To investigate the effect of HIF-2α on the osteogenic and adipogenic differentiation of BMSCs and the hematopoietic function of hematopoietic stem cells (HSCs) in the BM niche on the progression of OP. METHODS Mice with BMSC-specific HIF-2α knockout (Prx1-Cre;Hif-2αfl/fl mice) were used for in vivo experiments. Bone quantification was performed on mice of two genotypes with three interventions: Bilateral ovariectomy, semilethal irradiation, and dexamethasone treatment. Moreover, the hematopoietic function of HSCs in the BM niche was compared between the two mouse genotypes. In vitro, the HIF-2α agonist roxadustat and the HIF-2α inhibitor PT2399 were used to investigate the function of HIF-2α in BMSC osteogenic and adipogenic differentiation. Finally, we investigated the effect of HIF-2α on BMSCs via treatment with the mechanistic target of rapamycin (mTOR) agonist MHY1485 and the mTOR inhibitor rapamycin. RESULTS The quantitative index determined by microcomputed tomography indicated that the femoral bone density of Prx1-Cre;Hif-2αfl/fl mice was lower than that of Hif-2αfl/fl mice under the three intervention conditions. In vitro, Hif-2αfl/fl mouse BMSCs were cultured and treated with the HIF-2α agonist roxadustat, and after 7 d of BMSC adipogenic differentiation, the oil red O staining intensity and mRNA expression levels of adipogenesis-related genes in BMSCs treated with roxadustat were decreased; in addition, after 14 d of osteogenic differentiation, BMSCs treated with roxadustat exhibited increased expression of osteogenesis-related genes. The opposite effects were shown for mouse BMSCs treated with the HIF-2α inhibitor PT2399. The mTOR inhibitor rapamycin was used to confirm that HIF-2α regulated BMSC osteogenic and adipogenic differentiation by inhibiting the mTOR pathway. Consequently, there was no significant difference in the hematopoietic function of HSCs between Prx1-Cre;Hif-2αfl/fl and Hif-2αfl/fl mice. CONCLUSION Our study showed that inhibition of HIF-2α decreases bone mass by inhibiting the osteogenic differentiation and increasing the adipogenic differentiation of BMSCs through inhibition of mTOR signaling in the BM niche.
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Affiliation(s)
- Ling-Ling Wang
- Department of Gerontology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China
| | - Zhan-Jin Lu
- Department of Endocrinology and Metabolism, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China
| | - Shun-Kui Luo
- Department of Endocrinology and Metabolism, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China
| | - Yun Li
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China
| | - Zhe Yang
- Department of Endocrinology and Metabolism, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University, the First Hospital Affiliated with Medical College of Macao University of Science and Technology), Zhuhai 519000, Guangdong Province, China
| | - Hong-Yun Lu
- Department of Endocrinology and Metabolism, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University, the First Hospital Affiliated with Medical College of Macao University of Science and Technology), Zhuhai 519000, Guangdong Province, China.
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Yang L, Chen H, Yang C, Hu Z, Jiang Z, Meng S, Liu R, Huang L, Yang K. Research progress on the regulatory mechanism of integrin-mediated mechanical stress in cells involved in bone metabolism. J Cell Mol Med 2024; 28:e18183. [PMID: 38506078 PMCID: PMC10951882 DOI: 10.1111/jcmm.18183] [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: 10/15/2023] [Revised: 01/14/2024] [Accepted: 02/04/2024] [Indexed: 03/21/2024] Open
Abstract
Mechanical stress is an internal force between various parts of an object that resists external factors and effects that cause an object to deform, and mechanical stress is essential for various tissues that are constantly subjected to mechanical loads to function normally. Integrins are a class of transmembrane heterodimeric glycoprotein receptors that are important target proteins for the action of mechanical stress stimuli on cells and can convert extracellular physical and mechanical signals into intracellular bioelectrical signals, thereby regulating osteogenesis and osteolysis. Integrins play a bidirectional regulatory role in bone metabolism. In this paper, relevant literature published in recent years is reviewed and summarized. The characteristics of integrins and mechanical stress are introduced, as well as the mechanisms underlying responses of integrin to mechanical stress stimulation. The paper focuses on integrin-mediated mechanical stress in different cells involved in bone metabolism and its associated signalling mechanisms. The purpose of this review is to provide a theoretical basis for the application of integrin-mediated mechanical stress to the field of bone tissue repair and regeneration.
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Affiliation(s)
- Li Yang
- Department of Periodontology, Hospital of StomatologyZunyi Medical UniversityZunyiChina
| | - Hong Chen
- Department of Periodontology, Hospital of StomatologyZunyi Medical UniversityZunyiChina
| | - Chanchan Yang
- Department of Periodontology, Hospital of StomatologyZunyi Medical UniversityZunyiChina
| | - Zhengqi Hu
- Department of Periodontology, Hospital of StomatologyZunyi Medical UniversityZunyiChina
| | - Zhiliang Jiang
- Department of Periodontology, Hospital of StomatologyZunyi Medical UniversityZunyiChina
| | - Shengzi Meng
- Department of Periodontology, Hospital of StomatologyZunyi Medical UniversityZunyiChina
| | | | - Lan Huang
- Department of Periodontology, Hospital of StomatologyZunyi Medical UniversityZunyiChina
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9
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Li L, Huang J, Liu Y. The extracellular matrix glycoprotein fibrillin-1 in health and disease. Front Cell Dev Biol 2024; 11:1302285. [PMID: 38269088 PMCID: PMC10806136 DOI: 10.3389/fcell.2023.1302285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 12/19/2023] [Indexed: 01/26/2024] Open
Abstract
Fibrillin-1 (FBN1) is a large, cysteine-rich, calcium binding extracellular matrix glycoprotein encoded by FBN1 gene. It serves as a structural component of microfibrils and provides force-bearing mechanical support in elastic and nonelastic connective tissue. As such, mutations in the FBN1 gene can cause a wide variety of genetic diseases such as Marfan syndrome, an autosomal dominant disorder characterized by ocular, skeletal and cardiovascular abnormalities. FBN1 also interacts with numerous microfibril-associated proteins, growth factors and cell membrane receptors, thereby mediating a wide range of biological processes such as cell survival, proliferation, migration and differentiation. Dysregulation of FBN1 is involved in the pathogenesis of many human diseases, such as cancers, cardiovascular disorders and kidney diseases. Paradoxically, both depletion and overexpression of FBN1 upregulate the bioavailability and signal transduction of TGF-β via distinct mechanisms in different settings. In this review, we summarize the structure and expression of FBN1 and present our current understanding of the functional role of FBN1 in various human diseases. This knowledge will allow to develop better strategies for therapeutic intervention of FBN1 related diseases.
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Affiliation(s)
- Li Li
- State Key Laboratory of Organ Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangzhou, China
| | - Junxin Huang
- State Key Laboratory of Organ Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangzhou, China
| | - Youhua Liu
- State Key Laboratory of Organ Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangzhou, China
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10
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Milner JD. ERBIN and phosphoglucomutase 3 deficiency. Curr Opin Immunol 2023; 84:102353. [PMID: 37369151 PMCID: PMC11583051 DOI: 10.1016/j.coi.2023.102353] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 02/14/2023] [Accepted: 05/12/2023] [Indexed: 06/29/2023]
Abstract
ERBIN and phosphoglucomutase 3 (PGM3) mutations both lead to rare primary atopic disorders characterized by allergic disease and connective tissue abnormalities, though each disorder has its own rather unique pattern of multisystem presentations. Pathway studies show how ERBIN mutations allow for enhanced TGFb signaling, and prevent STAT3 from negative-regulating TGFb signaling. This likely explains many elements of clinical overlap between disorders of STAT3 and TGFb signaling. The excessive TGFb signaling leading to increased IL-4 receptor expression also provides the rationale for precision-based therapy blocking the IL-4 receptor to treat the atopic disease. The mechanism by which PGM3 deficiency leads to atopic phenotypes is not well understood, nor is the broad variability in disease penetrance and expressivity, though preliminary studies suggest an overlap with IL-6 receptor signaling defects.
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Affiliation(s)
- Joshua D Milner
- Department of Pediatrics, Columbia University Irving Medical Center, USA.
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11
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Liu J, Han X, Qu L, Du B. Identification of key ferroptosis-related biomarkers in steroid-induced osteonecrosis of the femoral head based on machine learning. J Orthop Surg Res 2023; 18:327. [PMID: 37120553 PMCID: PMC10148479 DOI: 10.1186/s13018-023-03800-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 04/13/2023] [Indexed: 05/01/2023] Open
Abstract
BACKGROUND This study was aimed to identify key ferroptosis-related biomarkers in steroid-induced osteonecrosis of the femoral head (SONFH) based on machine learning algorithm. METHODS The SONFH dataset GSE123568 (including 30 SONFH patients and 10 controls) was used in this study. The differentially expressed genes (DEGs) were selected between SONFH and control groups, which were subjected to WGCNA. Ferroptosis-related genes were downloaded from FerrDb V2, which were then compared with DEGs and module genes. Two machine learning algorithms were utilized to identify key ferroptosis-related genes, and the underlying mechanisms were analyzed by GSEA. Correlation analysis between key ferroptosis-related genes and immune cells was analyzed by Spearman method. The drug-gene relationships were predicted in CTD. RESULTS Total 2030 DEGs were obtained. WGCNA identified two key modules and obtained 1561 module genes. Finally, 43 intersection genes were identified as disease-related ferroptosis-related genes. After LASSO regression and RFE-SVM algorithms, 4 intersection genes (AKT1S1, BACH1, MGST1 and SETD1B) were considered as key ferroptosis-related gene. The 4 genes were correlated with osteoclast differentiation pathway. Twenty immune cells with significant differences were obtained between the groups, and the 4 key ferroptosis-related genes were correlated with most immune cells. In CTD, 41 drug-gene relationship pairs were finally obtained. CONCLUSIONS The 4 key ferroptosis-related genes, AKT1S1, BACH1, MGST1 and SETD1B, were identified to play a critical role in SONFH progression through osteoclast differentiation and immunologic mechanisms. Additionally, all the 4 genes had good disease prediction effect and could act as biomarkers for the diagnosis and treatment of SONFH.
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Affiliation(s)
- Jian Liu
- Department of Orthopedic, Sunshine Union Hospital, 9000 Yingqian Road, High-Tech Zone, Weifang, 261000, Shandong, China
| | - Xueliang Han
- Department of Orthopedic, Sunshine Union Hospital, 9000 Yingqian Road, High-Tech Zone, Weifang, 261000, Shandong, China
| | - Lianjun Qu
- Department of Orthopedic, Sunshine Union Hospital, 9000 Yingqian Road, High-Tech Zone, Weifang, 261000, Shandong, China
| | - Bencai Du
- Department of Orthopedic, Sunshine Union Hospital, 9000 Yingqian Road, High-Tech Zone, Weifang, 261000, Shandong, China.
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12
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Liu P, An Y, Zhu T, Tang S, Huang X, Li S, Fu F, Chen J, Xuan K. Mesenchymal stem cells: Emerging concepts and recent advances in their roles in organismal homeostasis and therapy. Front Cell Infect Microbiol 2023; 13:1131218. [PMID: 36968100 PMCID: PMC10034133 DOI: 10.3389/fcimb.2023.1131218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 02/03/2023] [Indexed: 03/11/2023] Open
Abstract
Stem cells play a crucial role in re-establishing homeostasis in the body, and the search for mechanisms by which they interact with the host to exert their therapeutic effects remains a key question currently being addressed. Considering their significant regenerative/therapeutic potential, research on mesenchymal stem cells (MSCs) has experienced an unprecedented advance in recent years, becoming the focus of extensive works worldwide to develop cell-based approaches for a variety of diseases. Initial evidence for the effectiveness of MSCs therapy comes from the restoration of dynamic microenvironmental homeostasis and endogenous stem cell function in recipient tissues by systemically delivered MSCs. The specific mechanisms by which the effects are exerted remain to be investigated in depth. Importantly, the profound cell-host interplay leaves persistent therapeutic benefits that remain detectable long after the disappearance of transplanted MSCs. In this review, we summarize recent advances on the role of MSCs in multiple disease models, provide insights into the mechanisms by which MSCs interact with endogenous stem cells to exert therapeutic effects, and refine the interconnections between MSCs and cells fused to damaged sites or differentiated into functional cells early in therapy.
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Affiliation(s)
- Peisheng Liu
- The College of Life Science, Northwest University, Xi’an, Shaanxi, China
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yongqian An
- Department of Stomatology, 962 Hospital of People's Liberation Army of China, Harbin, Heilongjiang, China
| | - Ting Zhu
- The College of Life Science, Northwest University, Xi’an, Shaanxi, China
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Siyuan Tang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- School of Basic Medicine, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Xiaoyao Huang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Shijie Li
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Fei Fu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Ji Chen
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Oral Implantology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
- *Correspondence: Ji Chen, ; Kun Xuan,
| | - Kun Xuan
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
- *Correspondence: Ji Chen, ; Kun Xuan,
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13
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Li W, Jiang WS, Su YR, Tu KW, Zou L, Liao CR, Wu Q, Wang ZH, Zhong ZM, Chen JT, Zhu SY. PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products. Cell Death Dis 2023; 14:88. [PMID: 36750550 PMCID: PMC9905061 DOI: 10.1038/s41419-023-05595-5+10.1038/s41419-020-2298-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/14/2023] [Accepted: 01/16/2023] [Indexed: 01/22/2024]
Abstract
Osteoblast apoptosis plays an important role in age-related bone loss and osteoporosis. Our previous study revealed that advanced oxidation protein products (AOPPs) could induce nicotinamide adenine dinucleotide phosphate oxidase (NOX)-derived reactive oxygen species (ROS) production, cause mitochondrial membrane potential (ΔΨm) depolarization, trigger the mitochondria-dependent intrinsic apoptosis pathway, and lead to osteoblast apoptosis and ultimately osteopenia and bone microstructural destruction. In this study, we found that AOPPs also induced mitochondrial ROS (mtROS) generation in osteoblastic MC3T3-E1 cells, which was closely related to NOX-derived ROS, and aggravated the oxidative stress condition, thereby further promoting apoptosis. Removing excessive ROS and damaged mitochondria is the key factor in reversing AOPP-induced apoptosis. Here, by in vitro studies, we showed that rapamycin further activated PINK1/Parkin-mediated mitophagy in AOPP-stimulated MC3T3-E1 cells and significantly alleviated AOPP-induced cell apoptosis by eliminating ROS and damaged mitochondria. Our in vivo studies revealed that PINK1/Parkin-mediated mitophagy could decrease the plasma AOPP concentration and inhibit AOPP-induced osteoblast apoptosis, thus ameliorating AOPP accumulation-related bone loss, bone microstructural destruction and bone mineral density (BMD) loss. Together, our study indicated that therapeutic strategies aimed at upregulating osteoblast mitophagy and preserving mitochondrial function might have potential for treating age-related osteoporosis.
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Affiliation(s)
- Wei Li
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wang-Sheng Jiang
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ya-Ru Su
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ke-Wu Tu
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lin Zou
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Orthopedics, Nanfang Hospital Taihe Branch, Southern Medical University, Guangzhou, China
| | - Cong-Rui Liao
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qian Wu
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zi-Han Wang
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhao-Ming Zhong
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian-Ting Chen
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Si-Yuan Zhu
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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14
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Li W, Jiang WS, Su YR, Tu KW, Zou L, Liao CR, Wu Q, Wang ZH, Zhong ZM, Chen JT, Zhu SY. PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products. Cell Death Dis 2023; 14:88. [PMID: 36750550 PMCID: PMC9905061 DOI: 10.1038/s41419-023-05595-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/14/2023] [Accepted: 01/16/2023] [Indexed: 02/09/2023]
Abstract
Osteoblast apoptosis plays an important role in age-related bone loss and osteoporosis. Our previous study revealed that advanced oxidation protein products (AOPPs) could induce nicotinamide adenine dinucleotide phosphate oxidase (NOX)-derived reactive oxygen species (ROS) production, cause mitochondrial membrane potential (ΔΨm) depolarization, trigger the mitochondria-dependent intrinsic apoptosis pathway, and lead to osteoblast apoptosis and ultimately osteopenia and bone microstructural destruction. In this study, we found that AOPPs also induced mitochondrial ROS (mtROS) generation in osteoblastic MC3T3-E1 cells, which was closely related to NOX-derived ROS, and aggravated the oxidative stress condition, thereby further promoting apoptosis. Removing excessive ROS and damaged mitochondria is the key factor in reversing AOPP-induced apoptosis. Here, by in vitro studies, we showed that rapamycin further activated PINK1/Parkin-mediated mitophagy in AOPP-stimulated MC3T3-E1 cells and significantly alleviated AOPP-induced cell apoptosis by eliminating ROS and damaged mitochondria. Our in vivo studies revealed that PINK1/Parkin-mediated mitophagy could decrease the plasma AOPP concentration and inhibit AOPP-induced osteoblast apoptosis, thus ameliorating AOPP accumulation-related bone loss, bone microstructural destruction and bone mineral density (BMD) loss. Together, our study indicated that therapeutic strategies aimed at upregulating osteoblast mitophagy and preserving mitochondrial function might have potential for treating age-related osteoporosis.
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Affiliation(s)
- Wei Li
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wang-Sheng Jiang
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ya-Ru Su
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ke-Wu Tu
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lin Zou
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Orthopedics, Nanfang Hospital Taihe Branch, Southern Medical University, Guangzhou, China
| | - Cong-Rui Liao
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qian Wu
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zi-Han Wang
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhao-Ming Zhong
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian-Ting Chen
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Si-Yuan Zhu
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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15
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Li W, Jiang WS, Su YR, Tu KW, Zou L, Liao CR, Wu Q, Wang ZH, Zhong ZM, Chen JT, Zhu SY. PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products. Cell Death Dis 2023; 14:88. [PMID: 36750550 PMCID: PMC9905061 DOI: 10.1038/s41419-023-05595-5 10.1038/s41419-020-2298-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/14/2023] [Accepted: 01/16/2023] [Indexed: 07/11/2023]
Abstract
Osteoblast apoptosis plays an important role in age-related bone loss and osteoporosis. Our previous study revealed that advanced oxidation protein products (AOPPs) could induce nicotinamide adenine dinucleotide phosphate oxidase (NOX)-derived reactive oxygen species (ROS) production, cause mitochondrial membrane potential (ΔΨm) depolarization, trigger the mitochondria-dependent intrinsic apoptosis pathway, and lead to osteoblast apoptosis and ultimately osteopenia and bone microstructural destruction. In this study, we found that AOPPs also induced mitochondrial ROS (mtROS) generation in osteoblastic MC3T3-E1 cells, which was closely related to NOX-derived ROS, and aggravated the oxidative stress condition, thereby further promoting apoptosis. Removing excessive ROS and damaged mitochondria is the key factor in reversing AOPP-induced apoptosis. Here, by in vitro studies, we showed that rapamycin further activated PINK1/Parkin-mediated mitophagy in AOPP-stimulated MC3T3-E1 cells and significantly alleviated AOPP-induced cell apoptosis by eliminating ROS and damaged mitochondria. Our in vivo studies revealed that PINK1/Parkin-mediated mitophagy could decrease the plasma AOPP concentration and inhibit AOPP-induced osteoblast apoptosis, thus ameliorating AOPP accumulation-related bone loss, bone microstructural destruction and bone mineral density (BMD) loss. Together, our study indicated that therapeutic strategies aimed at upregulating osteoblast mitophagy and preserving mitochondrial function might have potential for treating age-related osteoporosis.
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Affiliation(s)
- Wei Li
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wang-Sheng Jiang
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ya-Ru Su
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ke-Wu Tu
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lin Zou
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Orthopedics, Nanfang Hospital Taihe Branch, Southern Medical University, Guangzhou, China
| | - Cong-Rui Liao
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qian Wu
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zi-Han Wang
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhao-Ming Zhong
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian-Ting Chen
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Si-Yuan Zhu
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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16
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Xin L, Wen Y, Song J, Chen T, Zhai Q. Bone regeneration strategies based on organelle homeostasis of mesenchymal stem cells. Front Endocrinol (Lausanne) 2023; 14:1151691. [PMID: 37033227 PMCID: PMC10081449 DOI: 10.3389/fendo.2023.1151691] [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: 01/26/2023] [Accepted: 03/06/2023] [Indexed: 04/11/2023] Open
Abstract
The organelle modulation has emerged as a crucial contributor to the organismal homeostasis. The mesenchymal stem cells (MSCs), with their putative functions in maintaining the regeneration ability of adult tissues, have been identified as a major driver to underlie skeletal health. Bone is a structural and endocrine organ, in which the organelle regulation on mesenchymal stem cells (MSCs) function has most been discovered recently. Furthermore, potential treatments to control bone regeneration are developing using organelle-targeted techniques based on manipulating MSCs osteogenesis. In this review, we summarize the most current understanding of organelle regulation on MSCs in bone homeostasis, and to outline mechanistic insights as well as organelle-targeted approaches for accelerated bone regeneration.
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Affiliation(s)
- Liangjing Xin
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Yao Wen
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Jinlin Song
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
- *Correspondence: Qiming Zhai, ; Tao Chen, ; Jinlin Song,
| | - Tao Chen
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
- *Correspondence: Qiming Zhai, ; Tao Chen, ; Jinlin Song,
| | - Qiming Zhai
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
- *Correspondence: Qiming Zhai, ; Tao Chen, ; Jinlin Song,
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17
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Kartogenin Improves Osteogenesis of Bone Marrow Mesenchymal Stem Cells via Autophagy. Stem Cells Int 2022; 2022:1278921. [PMID: 36591373 PMCID: PMC9800103 DOI: 10.1155/2022/1278921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 11/27/2022] [Accepted: 11/29/2022] [Indexed: 12/24/2022] Open
Abstract
Kartogenin (KGN), a novel small-molecule compound, has been considered a promising chondrogenic promoter in cartilage regeneration. However, whether KGN also participates in osteogenesis and bone regeneration remains unclear. This research was designed to explore the roles of KGN on osteogenic differentiation in bone marrow mesenchymal stem cells (BMMSCs) as well as determine the possible mechanism of osteogenesis. We revealed that KGN enhanced the osteogenic differentiation capacity of BMMSCs without affecting cell proliferation, during which autophagic activities and the expression of autophagy-related genes were promoted. Moreover, KGN upregulated the phosphorylation level of the Smad1/5/9 signaling, and inhibition and activation of Smad signaling were also applied to validate the involvement of Smad in BMMSCs during KGN treatment. In summary, this study shows that KGN promotes osteogenic differentiation of BMMSCs through enhancing autophagic levels and upregulating Smad1/5/9 signaling mechanically.
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[Progress of pathogenesis and genetics of alcohol-induced osteonecrosis of femoral head]. ZHONGGUO XIU FU CHONG JIAN WAI KE ZA ZHI = ZHONGGUO XIUFU CHONGJIAN WAIKE ZAZHI = CHINESE JOURNAL OF REPARATIVE AND RECONSTRUCTIVE SURGERY 2022; 36:1420-1427. [PMID: 36382462 PMCID: PMC9681594 DOI: 10.7507/1002-1892.202206072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
OBJECTIVE To review the research progress of pathogenesis and genetics of alcohol-induced osteonecrosis of the femoral head (AIONFH). METHODS The relevant domestic and foreign literature in recent years was extensively reviewed. The pathogenesis, the relationship between gene polymorphism and susceptibility, the related factors of disease progression, and the potential therapeutic targets of AIONFH were summarized. RESULTS AIONFH is a refractory orthopedic disease caused by excessive drinking, seriously affecting the daily life of patients due to its high disability rate. The pathogenesis of AIONFH includes lipid metabolism disorder, endothelial dysfunction, bone homeostasis imbalance, and et al. Gene polymorphism and non-coding RNA are also involved. The hematological and molecular changes involved in AIONFH may be used as early diagnostic markers and potential therapeutic targets of the disease. CONCLUSION The pathogenesis of AIONFH has not been fully elucidated. Research based on genetics, including gene polymorphism and non-coding RNA, combined with next-generation sequencing technology, may provide directions for future research on the mechanism and discovery of potential therapeutic targets.
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19
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Bae S, Oh B, Tsai J, Park PSU, Greenblatt MB, Giannopoulou EG, Park-Min KH. The crosstalk between MYC and mTORC1 during osteoclastogenesis. Front Cell Dev Biol 2022; 10:920683. [PMID: 36060812 PMCID: PMC9437285 DOI: 10.3389/fcell.2022.920683] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 07/19/2022] [Indexed: 12/02/2022] Open
Abstract
Osteoclasts are bone-resorbing cells that undergo extensive changes in morphology throughout their differentiation. Altered osteoclast differentiation and activity lead to changes in pathological bone resorption. The mammalian target of rapamycin (mTOR) is a kinase, and aberrant mTOR complex 1 (mTORC1) signaling is associated with altered bone homeostasis. The activation of mTORC1 is biphasically regulated during osteoclastogenesis; however, the mechanism behind mTORC1-mediated regulation of osteoclastogenesis and bone resorption is incompletely understood. Here, we found that MYC coordinates the dynamic regulation of mTORC1 activation during osteoclastogenesis. MYC-deficiency blocked the early activation of mTORC1 and also reversed the decreased activity of mTORC1 at the late stage of osteoclastogenesis. The suppression of mTORC1 activity by rapamycin in mature osteoclasts enhances bone resorption activity despite the indispensable role of high mTORC1 activation in osteoclast formation in both mouse and human cells. Mechanistically, MYC induces Growth arrest and DNA damage-inducible protein (GADD34) expression and suppresses mTORC1 activity at the late phase of osteoclastogenesis. Taken together, our findings identify a MYC-GADD34 axis as an upstream regulator of dynamic mTORC1 activation in osteoclastogenesis and highlight the interplay between MYC and mTORC1 pathways in determining osteoclast activity.
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Affiliation(s)
- Seyeon Bae
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, United States
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
| | - Brian Oh
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, United States
| | - Jefferson Tsai
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, United States
| | - Peter Sang Uk Park
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, United States
| | | | - Eugenia G. Giannopoulou
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, United States
- Biological Sciences Department, New York City College of Technology, City University of New York, Brooklyn, NY, United States
| | - Kyung-Hyun Park-Min
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, United States
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
- BCMB Allied Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, United States
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20
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Li W, Huang X, Yu W, Xu Y, Huang R, Park J, Moshaverinia A, Arora P, Chen C. Activation of Functional Somatic Stem Cells Promotes Endogenous Tissue Regeneration. J Dent Res 2022; 101:802-811. [PMID: 35114850 PMCID: PMC9218498 DOI: 10.1177/00220345211070222] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Periodontal ligament derived stem cells (PDLSCs) are capable of differentiating into multiple cell types and inducing a promising immunomodulation for tissue regeneration and disease treatment. However, it is still challenging to develop a practical approach to activate endogenous stem cells for tissue self-healing and regeneration. In this study, transcriptome analysis reveals that resveratrol promotes PDLSC stemness through activation of stem cell, osteoprogenitor, and chondroprogenitor markers. Self-renewal and multipotent differentiation abilities are also improved in resveratrol-treated PDLSCs. In addition, immunomodulation of PDLSCs is dramatically increased after resveratrol treatment. Mechanistically, we show that resveratrol activates ERK/WNT crosstalk through elevation of olfactory and growth factor signaling pathways to upregulate the expression levels of RUNX2 and FASL for osteogenesis and immunomodulation, respectively. By using a periodontitis animal model, administration of resveratrol partially rescues bone loss through activation of endogenous somatic stem cells and inhibition of inflammatory T-cell infiltration. Taken together, our findings identify a novel pharmacological approach to achieve autotherapies for endogenous tissue regeneration.
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Affiliation(s)
- W. Li
- Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - X. Huang
- Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - W. Yu
- Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Y. Xu
- Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - R. Huang
- Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - J. Park
- Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - A. Moshaverinia
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, USA
| | - P. Arora
- Early-Research Oral Care, Colgate-Palmolive Company, Piscataway, NJ, USA
| | - C. Chen
- Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center of Innovation and Precision Dentistry, School of Dental Medicine, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA
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21
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Liu Y, Cheng L, Zhan H, Li H, Li X, Huang Y, Li Y. The Roles of Noncoding RNAs in Systemic Sclerosis. Front Immunol 2022; 13:856036. [PMID: 35464474 PMCID: PMC9024074 DOI: 10.3389/fimmu.2022.856036] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 03/17/2022] [Indexed: 12/12/2022] Open
Abstract
Noncoding RNAs (ncRNAs) constitute more than 90% of the RNAs in the human genome. In the past decades, studies have changed our perception of ncRNAs from “junk” transcriptional products to functional regulatory molecules that mediate critical processes, including chromosomal modifications, mRNA splicing and stability, and translation, as well as key signaling pathways. Emerging evidence suggests that ncRNAs are abnormally expressed in not only cancer but also autoimmune diseases, such as systemic sclerosis (SSc), and may serve as novel biomarkers and therapeutic targets for the diagnosis and treatment of SSc. However, the functions and underlying mechanisms of ncRNAs in SSc remain incompletely understood. In this review, we discuss the current findings on the biogenetic processes and functions of ncRNAs, including microRNAs and long noncoding RNAs, as well as explore emerging ncRNA-based diagnostics and therapies for SSc.
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Affiliation(s)
- Yongmei Liu
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Complex, Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Linlin Cheng
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Complex, Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Haoting Zhan
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Complex, Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Haolong Li
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Complex, Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xiaomeng Li
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Complex, Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yuan Huang
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Complex, Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yongzhe Li
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Complex, Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- *Correspondence: Yongzhe Li,
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22
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Metabolic Reconfiguration Activates Stemness and Immunomodulation of PDLSCs. Int J Mol Sci 2022; 23:ijms23074038. [PMID: 35409397 PMCID: PMC8999739 DOI: 10.3390/ijms23074038] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/29/2022] [Accepted: 04/01/2022] [Indexed: 02/07/2023] Open
Abstract
Periodontal ligament derived stem cells (PDLSC) are adult multipotent mesenchymal-like stem cells (MSCs) that can induce a promising immunomodulation to interact with immune cells for disease treatment. Metabolic reconfiguration has been shown to be involved in the immunomodulatory activity of MSCs. However, the underlying mechanisms are largely unknown, and it remains a challenging to establish a therapeutic avenue to enhance immunomodulation of endogenous stem cells for disease management. In the present study, RNA-sequencing (RNA-seq) analysis explores that curcumin significantly promotes PDLSC function through activation of MSC-related markers and metabolic pathways. In vitro stem cell characterization further confirms that self-renewal and multipotent differentiation capabilities are largely elevated in curcumin treated PDLSCs. Mechanistically, RNA-seq reveals that curcumin activates ERK and mTOR cascades through upregulating growth factor pathways for metabolic reconfiguration toward glycolysis. Interestingly, PDLSCs immunomodulation is significantly increased after curcumin treatment through activation of prostaglandin E2-Indoleamine 2,3 dioxygenase (PGE2-IDO) signaling, whereas inhibition of glycolysis activity by 2-deoxyglucose (2-DG) largely blocked immunomodulatory capacity of PDLSCs. Taken together, this study provides a novel pharmacological approach to activate endogenous stem cells through metabolic reprogramming for immunomodulation and tissue regeneration.
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23
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Maruyama M, Moeinzadeh S, Guzman RA, Zhang N, Storaci HW, Utsunomiya T, Lui E, Huang EE, Rhee C, Gao Q, Yao Z, Takagi M, Yang YP, Goodman SB. The efficacy of lapine preconditioned or genetically modified IL4 over-expressing bone marrow-derived mesenchymal stromal cells in corticosteroid-associated osteonecrosis of the femoral head in rabbits. Biomaterials 2021; 275:120972. [PMID: 34186237 DOI: 10.1016/j.biomaterials.2021.120972] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 05/29/2021] [Accepted: 06/10/2021] [Indexed: 02/09/2023]
Abstract
Cell-based therapy for augmentation of core decompression (CD) using mesenchymal stromal cells (MSCs) is a promising treatment for early stage osteonecrosis of the femoral head (ONFH). Recently, the therapeutic potential for immunomodulation of osteogenesis using preconditioned (with pro-inflammatory cytokines) MSCs (pMSCs), or by the timely resolution of inflammation using MSCs that over-express anti-inflammatory cytokines has been described. Here, pMSCs exposed to tumor necrosis factor-alpha and lipopolysaccharide for 3 days accelerated osteogenic differentiation in vitro. Furthermore, injection of pMSCs encapsulated with injectable hydrogels into the bone tunnel facilitated angiogenesis and osteogenesis in the femoral head in vivo, using rabbit bone marrow-derived MSCs and a model of corticosteroid-associated ONFH in rabbits. In contrast, in vitro and in vivo studies demonstrated that genetically-modified MSCs that over-express IL4 (IL4-MSCs), established by using a lentiviral vector carrying the rabbit IL4 gene under the cytomegalovirus promoter, accelerated proliferation of MSCs and decreased the percentage of empty lacunae in the femoral head. Therefore, adjunctive cell-based therapy of CD using pMSCs and IL4-MSCs may hold promise to heal osteonecrotic lesions in the early stage ONFH. These interventions must be applied in a temporally sensitive fashion, without interfering with the mandatory acute inflammatory phase of bone healing.
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Affiliation(s)
- Masahiro Maruyama
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Seyedsina Moeinzadeh
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Roberto Alfonso Guzman
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Ning Zhang
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Hunter W Storaci
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Takeshi Utsunomiya
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Elaine Lui
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA; Mechanical Engineering, Stanford University School of Medicine, Stanford, CA, USA
| | - Elijah Ejun Huang
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Claire Rhee
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Qi Gao
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Zhenyu Yao
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Michiaki Takagi
- Department of Orthopaedic Surgery, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Yunzhi Peter Yang
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA; Material Science and Engineering, Stanford University School of Medicine, Stanford, CA, USA; Bioengineering, Stanford University School of Medicine, Stanford, CA, USA.
| | - Stuart B Goodman
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA; Bioengineering, Stanford University School of Medicine, Stanford, CA, USA.
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Yao Z, Li J, Xiong H, Cui H, Ning J, Wang S, Ouyang X, Qian Y, Fan C. MicroRNA engineered umbilical cord stem cell-derived exosomes direct tendon regeneration by mTOR signaling. J Nanobiotechnology 2021; 19:169. [PMID: 34090456 PMCID: PMC8180131 DOI: 10.1186/s12951-021-00906-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 05/21/2021] [Indexed: 12/27/2022] Open
Abstract
Background Exosomes are extracellular vesicles of nano-structures and represent an emerging nano-scale acellular therapy in recent years. Tendon regeneration is a sophisticated process in the field of microsurgery due to its poor natural healing ability. To date, no successful long-term solution has been provided for the healing of tendon injuries. Functional recovery requires advanced treatment strategies. Human umbilical cord mesenchymal stem cell-derived exosomes (HUMSC-Exos) are considered as promising cell-free therapeutic agents. However, few studies reported their potential in the tendon repair previously. In this study, we explored the roles and underlying mechanisms of HUMSC-Exos in the tendon regeneration. Results Expression of tendon‐specific markers in, and collagen deposition by, tendon-derived stem cells (TDSCs) treated with HUMSC-Exos increased in vitro. In a rat Achilles tendon injury model, treatment with HUMSC-Exos improved the histological structure, enhanced tendon-specific matrix components, and optimized biomechanical properties of the Achilles tendon. Findings in miRNA sequencing indicated a significant increase in miR-29a-3p in HUMSC-Exo-treated Achilles tendons. Next, luciferase assay in combination with western blot identified phosphatase and tensin homolog (PTEN) as the specific target of miR-29a-3p. Furthermore, we applied a miR-29a-3p-specific agonist to engineer HUMSC-Exos. These HUMSC-Exos overexpressing miR-29a-3p amplified the gain effects of HUMSC-Exos on tendon healing in vivo. To explore the underlying mechanisms, a transforming growth factor-β1 (TGF-β1) inhibitor (SB-431542), mTOR inhibitor (rapamycin), and engineered HUMSC-Exos were employed. The results showed that TGF-β1 and mTOR signaling were involved in the beneficial effects of HUMSC-Exos on tendon regeneration. Conclusion The findings in our study suggest that PTEN/mTOR/TGF-β1 signaling cascades may be a potential pathway for HUMSC-Exos to deliver miR-29a-3p for tendon healing and implicate a novel therapeutic strategy for tendon regeneration via engineered stem cell-derived exosomes. Graphic abstract ![]()
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Affiliation(s)
- Zhixiao Yao
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Juehong Li
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Hao Xiong
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Haomin Cui
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Jiexin Ning
- Department of Plastics, Binzhou People's Hospital, Binzhou, 256610, China
| | - Shikun Wang
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Xingyu Ouyang
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Yun Qian
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
| | - Cunyi Fan
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
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25
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Lin T, Chen W, Yang P, Li Z, Wei Q, Liang D, Wang H, He W, Zhang Q. Bioinformatics analysis and identification of genes and molecular pathways in steroid-induced osteonecrosis of the femoral head. J Orthop Surg Res 2021; 16:327. [PMID: 34016144 PMCID: PMC8136174 DOI: 10.1186/s13018-021-02464-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 05/06/2021] [Indexed: 11/10/2022] Open
Abstract
Background Steroid-induced osteonecrosis of the femoral head (ONFH) is a common hip joint disease and is difficult to be diagnosed early. At present, the pathogenesis of steroid-induced ONFH remains unclear, and recognized and effective diagnostic biomarkers are deficient. The present study aimed to identify potentially important genes and signaling pathways involved in steroid-induced ONFH and investigate their molecular mechanisms. Methods Microarray data sets GSE123568 (peripheral blood) and GSE74089 (cartilage) were obtained from the Gene Expression Omnibus database, including 34 ONFH samples and 14 control samples. Morpheus software and Venn diagram were used to identify DEGs and co-expressed DEGs, respectively. Besides, we conducted Kyoto Encyclopedia of Genome (KEGG) and gene ontology (GO) pathway enrichment analysis. We construct a protein-protein interaction (PPI) network through GEO2R and used cytoHubba to divide the PPI network into multiple sub-networks. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify the bioinformatics analysis results. Results A total of 118 intersecting DEGs were obtained between the peripheral blood and cartilage samples, including 40 upregulated genes and 78 downregulated genes. Then, GO and KEGG pathway enrichment analysis revealed that upregulated DEGs focused on the signaling pathways related to staphylococcus aureus infection, leishmaniasis, antigen processing, and presentation, as well as asthma and graft-versus-host disease. Downregulated genes were concentrated in the FoxO signaling pathway, AMPK signaling pathway, signaling pathway regulating stem cell pluripotency, and mTOR signaling pathway. Some hub genes with high interactions such as CXCR1, FPR1, MAPK1, FOXO3, FPR2, CXCR2, and TYROBP were identified in the PPI network. The results of qRT-PCR demonstrated that CXCR1, FPR1, and TYROBP were upregulated while MAPK1 was downregulated in peripheral blood of steroid-induced ONFH patients. This was consistent with the bioinformatics analysis. Conclusions The present study would provide novel insight into the genes and associated pathways involved in steroid-induced ONFH. CXCR1, FPR1, TYROBP, and MAPK1 may be used as potential drug targets and biomarkers for the diagnosis and prognosis of steroid-induced ONFH.
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Affiliation(s)
- Tianye Lin
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.,Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.,The Lab of Orthopaedics of Chinese Medicine of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.,Department of Joint Orthopaedic, the Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.,Institute of Orthopedics, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Weijian Chen
- Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.,Guangzhou Orthopedic Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510045, Guangdong, China.,The Lab of Orthopaedics of Chinese Medicine of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Peng Yang
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.,The Lab of Orthopaedics of Chinese Medicine of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.,Department of Joint Orthopaedic, the Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.,Institute of Orthopedics, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Ziqi Li
- Department of Joint Orthopaedic, the Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.,Institute of Orthopedics, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Qiushi Wei
- Department of Joint Orthopaedic, the Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.,Institute of Orthopedics, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Du Liang
- Guangzhou Orthopedic Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510045, Guangdong, China
| | - Haibin Wang
- Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.,The Lab of Orthopaedics of Chinese Medicine of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Wei He
- Department of Joint Orthopaedic, the Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.,Institute of Orthopedics, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Qingwen Zhang
- Department of Joint Orthopaedic, the Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China. .,Institute of Orthopedics, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.
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The emerging roles of exosomes in autoimmune diseases, with special emphasis on microRNAs in exosomes. Pharmacol Res 2021; 169:105680. [PMID: 34010670 DOI: 10.1016/j.phrs.2021.105680] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 04/29/2021] [Accepted: 05/11/2021] [Indexed: 02/07/2023]
Abstract
Autoimmune diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic vasculitis, dermatomyositis, systemic sclerosis (SSc), mixed connective tissue disease, autoimmune hemolytic anemia, autoimmune thyroiditis (AITD) and ulcerative colitis. Exosomes exist in body fluids, including blood, saliva, urine, cerebrospinal fluid and milk. They are mainly derived from the invagination of intracellular lysosomal particles, which are released into the extracellular matrix after fusion of the outer membrane of the exosomes with the cell membrane. Exosomes mediate intercellular communication and regulate the biological activity of receptor cells by carrying proteins, nucleic acids and lipids. Evidences show that exosomes are involved in the pathogenesis of various autoimmune diseases. In view of the important roles of exosomes in autoimmune diseases, this work systematically reviewed the effects of exosomes on the pathogenesis of autoimmune diseases, especially the regulatory roles of exosome derived microRNAs (miRNAs) in the pathogenesis of RA, SLE, dermatomyositis, SSc, AITD and ulcerative colitis. The review of the roles of exosomes in autoimmune diseases will help to clarify the pathogenesis of these diseases and explore new diagnostic markers and therapeutic targets.
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27
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Xing H, Li R, Qing Y, Ying B, Qin Y. Biomaterial-based osteoimmunomodulatory strategies via the TLR4-NF-κB signaling pathway: A review. APPLIED MATERIALS TODAY 2021; 22:100969. [DOI: 10.1016/j.apmt.2021.100969] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Dynamic proteomic profiling of human periodontal ligament stem cells during osteogenic differentiation. Stem Cell Res Ther 2021; 12:98. [PMID: 33536073 PMCID: PMC7860046 DOI: 10.1186/s13287-020-02123-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 12/25/2020] [Indexed: 01/07/2023] Open
Abstract
Background Human periodontal ligament stem cells (hPDLSCs) are ideal seed cells for periodontal regeneration. A greater understanding of the dynamic protein profiles during osteogenic differentiation contributed to the improvement of periodontal regeneration tissue engineering. Methods Tandem Mass Tag quantitative proteomics was utilized to reveal the temporal protein expression pattern during osteogenic differentiation of hPDLSCs on days 0, 3, 7 and 14. Differentially expressed proteins (DEPs) were clustered and functional annotated by Gene Ontology (GO) terms. Pathway enrichment analysis was performed based on the Kyoto Encyclopedia of Genes and Genomes database, followed by the predicted activation using Ingenuity Pathway Analysis software. Interaction networks of redox-sensitive signalling pathways and oxidative phosphorylation (OXPHOS) were conducted and the hub protein SOD2 was validated with western blotting. Results A total of 1024 DEPs were identified and clustered in 5 distinctive clusters representing dynamic tendencies. The GO enrichment results indicated that proteins with different tendencies show different functions. Pathway enrichment analysis found that OXPHOS was significantly involved, which further predicted continuous activation. Redox-sensitive signalling pathways with dynamic activation status showed associations with OXPHOS to various degrees, especially the sirtuin signalling pathway. SOD2, an important component of the sirtuin pathway, displays a persistent increase during osteogenesis. Data are available via ProteomeXchange with identifier PXD020908. Conclusion This is the first in-depth dynamic proteomic analysis of osteogenic differentiation of hPDLSCs. It demonstrated a dynamic regulatory mechanism of hPDLSC osteogenesis and might provide a new perspective for research on periodontal regeneration. Graphical abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13287-020-02123-6.
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Zhang N, Lo CW, Utsunomiya T, Maruyama M, Huang E, Rhee C, Gao Q, Yao Z, Goodman SB. PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration. Stem Cell Res Ther 2021; 12:40. [PMID: 33413614 PMCID: PMC7792350 DOI: 10.1186/s13287-020-02086-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 12/07/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Mesenchymal stem cell (MSC)-based therapy has the potential for immunomodulation and enhancement of tissue regeneration. Genetically modified MSCs that over-express specific cytokines, growth factors, or chemokines have shown great promise in pre-clinical studies. In this regard, the anti-inflammatory cytokine interleukin (IL)-4 converts pro-inflammatory M1 macrophages into an anti-inflammatory M2 phenotype; M2 macrophages mitigate chronic inflammation and enhance osteogenesis by MSC lineage cells. However, exposure to IL-4 prematurely inhibits osteogenesis of MSCs in vitro; furthermore, IL-4 overexpressing MSCs inhibit osteogenesis in vivo during the acute inflammatory period. Platelet-derived growth factor (PDGF)-BB has been shown to enhance osteogenesis of MSCs with a dose-dependent effect. METHODS In this study, we generated a lentiviral vector that produces PDGF-BB under a weak promoter (phosphoglycerate kinase, PGK) and lentiviral vector producing IL-4 under a strong promoter (cytomegalovirus, CMV). We infected MSCs with PDGF-BB and IL-4-producing lentiviral vectors separately or in combination to investigate cell proliferation and viability, protein expression, and the capability for osteogenesis. RESULTS PDGF-BB and IL-4 co-overexpression was observed in the co-infected MSCs and shown to enhance cell proliferation and viability, and osteogenesis compared to IL-4 overexpressing MSCs alone. CONCLUSIONS Overexpression of PDGF-BB together with IL-4 mitigates the inhibitory effect of IL-4 on osteogenesis by IL-4 overexpressing MSCS. PDGF-BB and IL-4 overexpressing MSCs may be a potential strategy to facilitate osteogenesis in scenarios of both acute and chronic inflammation.
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Affiliation(s)
- Ning Zhang
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA
| | - Chi-Wen Lo
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA
| | - Takeshi Utsunomiya
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA
| | - Masahiro Maruyama
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA
| | - Ejun Huang
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA
| | - Claire Rhee
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA
| | - Qi Gao
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA
| | - Zhenyu Yao
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA.
| | - Stuart B Goodman
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA.
- Department of Bioengineering, Stanford University, Stanford, CA, USA.
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Mechanical force-driven TNFα endocytosis governs stem cell homeostasis. Bone Res 2021; 8:44. [PMID: 33384406 PMCID: PMC7775432 DOI: 10.1038/s41413-020-00117-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 07/22/2020] [Accepted: 08/24/2020] [Indexed: 02/05/2023] Open
Abstract
Mesenchymal stem cells (MSCs) closely interact with the immune system, and they are known to secrete inflammatory cytokines in response to stress stimuli. The biological function of MSC-derived inflammatory cytokines remains elusive. Here, we reveal that even under physiological conditions, MSCs produce and release a low level of tumor necrosis factor alpha (TNFα), which is unexpectedly required for preserving the self-renewal and differentiation of MSCs via autocrine/paracrine signaling. Furthermore, TNFα critically maintains MSC function in vivo during bone homeostasis. Mechanistically, we unexpectedly discovered that physiological levels of TNFα safeguard MSC homeostasis in a receptor-independent manner through mechanical force-driven endocytosis and that endocytosed TNFα binds to mammalian target of rapamycin (mTOR) complex 2 and restricts mTOR signaling. Importantly, inhibition of mTOR signaling by rapamycin serves as an effective osteoanabolic therapeutic strategy to protect against TNFα deficiency and mechanical unloading. Collectively, these findings unravel the physiological framework of the dynamic TNFα shuttle-based mTOR equilibrium that governs MSC and bone homeostasis.
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Yao Q, Wu Q, Xu X, Xing Y, Liang J, Lin Q, Huang M, Chen Y, Lin B, Chen W. Resveratrol Ameliorates Systemic Sclerosis via Suppression of Fibrosis and Inflammation Through Activation of SIRT1/mTOR Signaling. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:5337-5348. [PMID: 33293795 PMCID: PMC7719308 DOI: 10.2147/dddt.s281209] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 10/28/2020] [Indexed: 12/12/2022]
Abstract
Purpose Resveratrol (Res) is a natural polyphenolic compound found in several plants and reported as a promising biological molecule with effective anti-fibrosis and anti-inflammatory activities. However, the underlying mechanism of Res on systemic sclerosis (SSc) remains unclear. In the study, we identified the key cellular signaling pathways involved in the Res regulatory process on SSc. Methods Res-targeted genes interaction network was constructed using the STITCH database, and the shared Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in both SSc and Res-targeted genes were then identified. The top five enriched KEGG pathways were visualized by GOplot. KEGG pathways associated with Res-targeted genes were established by Pathway Builder Tool 2.0. Quantitative real-time PCR (qRT-PCR) was used to assess the expression of sirtuin 1 (SIRT1), mammalian targeted of rapamycin (mTOR), and cytokines. Results Enrichment analysis of Res-targeted genes showed 79 associated pathways, 27 of which were also involved in SSc. Particularly, SIRT1/mTOR signaling was found as one of the crucial regulatory pathways. In vitro results suggested that SIRT1-mediated mTOR degradation ameliorated bleomycin (BLM)-induced fibrosis and inflammation. Res was capable of elevating the SIRT1 level in fibroblasts and partially reversing mTOR-dependent induction of fibrosis and inflammation. Conclusion These results indicated that Res is a feasible and effective choice for SSc and therapeutic target of mTOR could be a potential alternative for treatment of SSc.
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Affiliation(s)
- Qicen Yao
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People's Republic of China
| | - Qingchao Wu
- Department of Rheumatology and Immunology, Minda Hospital of Hubei Minzu University, Enshi, Hubei Province, People's Republic of China
| | - Xiayu Xu
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People's Republic of China
| | - Yixi Xing
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People's Republic of China
| | - Jin Liang
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People's Republic of China
| | - Qianqi Lin
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People's Republic of China
| | - Meiqiong Huang
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People's Republic of China
| | - Yiling Chen
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People's Republic of China
| | - Bo Lin
- Department of Pharmacy, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, People's Republic of China
| | - Weifei Chen
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People's Republic of China
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Shang F, Yu Y, Liu S, Ming L, Zhang Y, Zhou Z, Zhao J, Jin Y. Advancing application of mesenchymal stem cell-based bone tissue regeneration. Bioact Mater 2020; 6:666-683. [PMID: 33005830 PMCID: PMC7509590 DOI: 10.1016/j.bioactmat.2020.08.014] [Citation(s) in RCA: 153] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 08/07/2020] [Accepted: 08/15/2020] [Indexed: 12/11/2022] Open
Abstract
Reconstruction of bone defects, especially the critical-sized defects, with mechanical integrity to the skeleton is important for a patient's rehabilitation, however, it still remains challenge. Utilizing biomaterials of human origin bone tissue for therapeutic purposes has provided a facilitated approach that closely mimics the critical aspects of natural bone tissue with regard to its properties. However, not only efficacious and safe but also cost-effective and convenient are important for regenerative biomaterials to achieve clinical translation and commercial success. Advances in our understanding of regenerative biomaterials and their roles in new bone formation potentially opened a new frontier in the fast-growing field of regenerative medicine. Taking inspiration from the role and multicomponent construction of native extracellular matrix (ECM) for cell accommodation, the ECM-mimicking biomaterials and the naturally decellularized ECM scaffolds were used to create new tissues for bone restoration. On the other hand, with the going deep in understanding of mesenchymal stem cells (MSCs), they have shown great promise to jumpstart and facilitate bone healing even in diseased microenvironments with pharmacology-based endogenous MSCs rescue/mobilization, systemic/local infusion of MSCs for cytotherapy, biomaterials-based approaches, cell-sheets/-aggregates technology and usage of subcellular vesicles of MSCs to achieve scaffolds-free or cell-free delivery system, all of them have been shown can improve MSCs-mediated regeneration in preclinical studies and several clinical trials. Here, following an overview discussed autogenous/allogenic and ECM-based bone biomaterials for reconstructive surgery and applications of MSCs-mediated bone healing and tissue engineering to further offer principles and effective strategies to optimize MSCs-based bone regeneration.
Focusing on MSCs based bone regeneration. Discussed cytotherapy, cell-free therapies and cell-aggregates technology in detail. Stating the approaches of MSCs in diseased microenvironments.
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Affiliation(s)
- Fengqing Shang
- State Key Laboratory of Military Stomatology & National Clinical Research, Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Department of Stomatology, The 306th Hospital of PLA, Beijing, 100101, China
| | - Yang Yu
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong, 250012, China
| | - Shiyu Liu
- State Key Laboratory of Military Stomatology & National Clinical Research, Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Leiguo Ming
- State Key Laboratory of Military Stomatology & National Clinical Research, Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Yongjie Zhang
- State Key Laboratory of Military Stomatology & National Clinical Research, Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Zhifei Zhou
- Department of Stomatology, General Hospital of Tibetan Military Command, Lhasa, 850000, China
| | - Jiayu Zhao
- Bureau of Service for Veteran Cadres of PLA in Beijing, Beijing, 100001, China
| | - Yan Jin
- State Key Laboratory of Military Stomatology & National Clinical Research, Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Corresponding author.
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Impact of Alcohol on Bone Health, Homeostasis and Fracture repair. CURRENT PATHOBIOLOGY REPORTS 2020; 8:75-86. [PMID: 33767923 DOI: 10.1007/s40139-020-00209-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Purpose of review Alcohol use continues to rise globally. We review the current literature on the effect of alcohol on bone health, homeostasis and fracture repair to highlight what has been learned in people and animal models of alcohol consumption. Recent findings Recently, forkhead box O (FoxO) has been found to be upregulated and activated in mesenchymal stem cells (MSC) exposed to alcohol. FoxO has also been found to modulate Wnt/β-catenin signaling, which is necessary for MSC differentiation. Recent evidence suggests alcohol activates FoxO signaling, which may be dysregulating Wnt/β-catenin signaling in MSCs cultured in alcohol. Summary This review highlights the negative health effects learned from people and chronic and episodic binge alcohol consumption animal models. Studies using chronic alcohol exposure or alcohol exposure then bone fracture repair model have explored several different cellular and molecular signaling pathways important for bone homeostasis and fracture repair, and offer potential for future experiments to explore additional signaling pathways that may be dysregulated by alcohol exposure.
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Chen C, Zhang Q, Yu W, Chang B, Le AD. Oral Mucositis: An Update on Innate Immunity and New Interventional Targets. J Dent Res 2020; 99:1122-1130. [PMID: 32479139 DOI: 10.1177/0022034520925421] [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: 12/12/2022] Open
Abstract
Oral mucositis (OM), a common debilitating toxicity associated with chemo- and radiation therapies, is a significant unmet clinical need for head and neck cancer patients. The biological complexities of chemoradiotherapy-induced OM involve interactions among disrupted tissue structures, inflammatory infiltrations, and oral microbiome, whereby several master inflammatory pathways constitute the complicated regulatory networks. Oral mucosal damages triggered by chemoradiotherapy-induced cell apoptosis were further exacerbated by the amplified inflammatory cascades dominantly governed by the innate immune responses. The coexistence of microbiome and innate immune components in oral mucosal barriers indicates that a signaling hub coordinates the interaction between environmental cues and host cells during tissue and immune homeostasis. Dysbiotic shifts in oral microbiota caused by cytotoxic cancer therapies may also contribute to the progression and severity of chemoradiotherapy-induced OM. In this review, we have updated the mechanisms involving innate immunity-governed inflammatory cascades in the pathobiology of chemoradiotherapy-induced OM and the development of new interventional targets for the management of this severe morbidity in head and neck cancer patients.
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Affiliation(s)
- C Chen
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Center of Innovation & Precision Dentistry, School of Dental Medicine, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Q Zhang
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - W Yu
- Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - B Chang
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Department of Oral & Maxillofacial Surgery, Penn Medicine Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - A D Le
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Center of Innovation & Precision Dentistry, School of Dental Medicine, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.,Department of Oral & Maxillofacial Surgery, Penn Medicine Hospital of the University of Pennsylvania, Philadelphia, PA, USA
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Abstract
Primary atopic disorders describes a series of monogenic diseases that have allergy- or atopic effector–related symptoms as a substantial feature. The underlying pathogenic genetic lesions help illustrate fundamental pathways in atopy, opening up diagnostic and therapeutic options for further study in those patients, but ultimately for common allergic diseases as well. Key pathways affected in these disorders include T cell receptor and B cell receptor signaling, cytokine signaling, skin barrier function, and mast cell function, as well as pathways that have not yet been elucidated. While comorbidities such as classically syndromic presentation or immune deficiency are often present, in some cases allergy alone is the presenting symptom, suggesting that commonly encountered allergic diseases exist on a spectrum of monogenic and complex genetic etiologies that are impacted by environmental risk factors.
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Affiliation(s)
- Joshua D. Milner
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA
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36
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Yang M, Li CJ, Xiao Y, Guo Q, Huang Y, Su T, Luo XH, Jiang TJ. Ophiopogonin D promotes bone regeneration by stimulating CD31 hi EMCN hi vessel formation. Cell Prolif 2020; 53:e12784. [PMID: 32080957 PMCID: PMC7106967 DOI: 10.1111/cpr.12784] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/02/2020] [Accepted: 02/04/2020] [Indexed: 12/11/2022] Open
Abstract
Objectives CD31hiEMCNhi vessels (CD31, also known as PECAM1 [platelet and endothelial cell adhesion molecule 1]; EMCN, endomucin), which are strongly positive for CD31 and endomucin, couple angiogenesis and osteogenesis. However, the role of CD31hiEMCNhi vessels in bone regeneration remains unknown. In the present study, we investigated the role of CD31hiEMCNhi vessels in the process of bone regeneration. Materials and Methods We used endothelial‐specific Krüppel like factor 3 (Klf3) knockout mice and ophiopogonin D treatment to interfere with CD31hiEMCNhi vessel formation. We constructed a bone regeneration model by surgical ablation of the trabecular bone. Immunofluorescence and micro‐computed tomography (CT) were used to detect CD31hiEMCNhi vessels and bone formation. Results CD31hiEMCNhi vessels participate in the process of bone regeneration, such that endothelial‐specific Klf3 knockout mice showed increased CD31hiEMCNhi vessels and osteoprogenitors in the bone regeneration area, and further accelerated bone formation. We also demonstrated that the natural compound, ophiopogonin D, acts as a KLF3 inhibitor to promote vessels formation both in vitro and in vivo. Administration of ophiopogonin D increased the abundance of CD31hiEmcnhi vessels and accelerated bone healing. Conclusions Our findings confirmed the important role of CD31hiEmcnhi vessels in bone regeneration and provided a new target to treat bone fracture or promote bone regeneration.
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Affiliation(s)
- Mi Yang
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Chang-Jun Li
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Ye Xiao
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Qi Guo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Yan Huang
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Tian Su
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Xiang-Hang Luo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
| | - Tie-Jian Jiang
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, China
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Sui BD, Zheng CX, Li M, Jin Y, Hu CH. Epigenetic Regulation of Mesenchymal Stem Cell Homeostasis. Trends Cell Biol 2020; 30:97-116. [DOI: 10.1016/j.tcb.2019.11.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/19/2019] [Accepted: 11/26/2019] [Indexed: 12/24/2022]
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Bastidas‐Coral AP, Hogervorst JMA, Forouzanfar T, Kleverlaan CJ, Koolwijk P, Klein‐Nulend J, Bakker AD. IL-6 counteracts the inhibitory effect of IL-4 on osteogenic differentiation of human adipose stem cells. J Cell Physiol 2019; 234:20520-20532. [PMID: 31016754 PMCID: PMC6767193 DOI: 10.1002/jcp.28652] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 02/10/2019] [Accepted: 02/25/2019] [Indexed: 12/16/2022]
Abstract
Fracture repair is characterized by cytokine production and hypoxia. To better predict cytokine modulation of mesenchymal stem cell (MSC)-aided bone healing, we investigated whether interleukin 4 (IL-4), IL-6, and their combination, affect osteogenic differentiation, vascular endothelial growth factor (VEGF) production, and/or mammalian target of rapamycin complex 1 (mTORC1) activation by MSCs under normoxia or hypoxia. Human adipose stem cells (hASCs) were cultured with IL-4, IL-6, or their combination for 3 days under normoxia (20% O 2 ) or hypoxia (1% O 2 ), followed by 11 days without cytokines under normoxia or hypoxia. Hypoxia did not alter IL-4 or IL-6-modulated gene or protein expression by hASCs. IL-4 alone decreased runt-related transcription factor 2 (RUNX2) and collagen type 1 (COL1) gene expression, alkaline phosphatase (ALP) activity, and VEGF protein production by hASCs under normoxia and hypoxia, and decreased mineralization of hASCs under hypoxia. In contrast, IL-6 increased mineralization of hASCs under normoxia, and enhanced RUNX2 gene expression under normoxia and hypoxia. Neither IL-4 nor IL-6 affected phosphorylation of the mTORC1 effector protein P70S6K. IL-4 combined with IL-6 diminished the inhibitory effect of IL-4 on ALP activity, bone nodule formation, and VEGF production, and decreased RUNX2 and COL1 expression, similar to IL-4 alone, under normoxia and hypoxia. In conclusion, IL-4 alone, but not in combination with IL-6, inhibits osteogenic differentiation and angiogenic stimulation potential of hASCs under normoxia and hypoxia, likely through pathways other than mTORC1. These results indicate that cytokines may differentially affect bone healing and regeneration when applied in isolation or in combination.
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Affiliation(s)
- Angela P. Bastidas‐Coral
- Department of Oral Cell BiologyAcademic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement SciencesAmsterdamThe Netherlands
| | - Jolanda M. A. Hogervorst
- Department of Oral Cell BiologyAcademic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement SciencesAmsterdamThe Netherlands
| | - Tymour Forouzanfar
- Department of Oral and Maxillofacial SurgeryAmsterdam University Medical Centers (Amsterdam UMC)/ACTA, location VUmc, Amsterdam Movement SciencesAmsterdamThe Netherlands
| | - Cornelis J. Kleverlaan
- Department of Dental Materials ScienceAcademic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement SciencesAmsterdamThe Netherlands
| | - Pieter Koolwijk
- Department of PhysiologyAmsterdam Cardiovascular Sciences, Amsterdam University Medical Centers (Amsterdam UMC)AmsterdamThe Netherlands
| | - Jenneke Klein‐Nulend
- Department of Oral Cell BiologyAcademic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement SciencesAmsterdamThe Netherlands
| | - Astrid D. Bakker
- Department of Oral Cell BiologyAcademic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement SciencesAmsterdamThe Netherlands
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Abstract
Autoimmune diseases, such as rheumatoid arthritis, systematic lupus erythematosus and Sjögren's syndrome, are a group of diseases characterized by the activation of immune cells and excessive production of autoantibodies. Although the pathogenesis of these diseases is still not completely understood, studies have shown that multiple factors including genetics, environment and immune responses play important roles in the development and progression of the diseases. In China, there are great achievements in the mechanisms of autoimmune diseases during the last decades. These studies provide new insight to understand the diseases and also shed light on the development of novel therapy.
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Affiliation(s)
- Ru Li
- Department of Rheumatology & Immunology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
| | - Xing Sun
- Department of Rheumatology & Immunology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Xu Liu
- Department of Rheumatology & Immunology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yue Yang
- Department of Rheumatology & Immunology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Zhanguo Li
- Department of Rheumatology & Immunology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
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Zhao J, Wu J, Xu B, Yuan Z, Leng Y, Min J, Lan X, Luo J. Kaempferol promotes bone formation in part via the mTOR signaling pathway. Mol Med Rep 2019; 20:5197-5207. [PMID: 31638215 PMCID: PMC6854588 DOI: 10.3892/mmr.2019.10747] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 07/09/2019] [Indexed: 12/27/2022] Open
Abstract
Previous research indicates that kaempferol (Kae) promotes osteogenesis, but its underlying mechanism of action remains unclear. The present study hypothesized that the osteogenic effects of Kae were mediated through mammalian target of rapamycin (mTOR). To validate this hypothesis, bone marrow mesenchymal stem cells (BMSCs) from ovariectomized (OVX) rats were differentiated into osteoblasts. The bone mineral density and bone microarchitecture of the OVX rats was measured in vivo, while osteogenesis was evaluated in vitro via Alizarin Red S staining and alkaline phosphatase activity measurements in cultured BMSCs. The levels of phosphorylated eukaryotic translation initiation factor 4E‑binding protein 1 (p‑4E/BP1) and phosphorylated ribosomal protein S6 kinase B1 (p‑S6K), and the expression of Runt‑related transcription factor 2 and Osterix, were concurrently quantified by western blot analysis. The data suggested that Kae prevented OVX‑induced osteoporosis in rats by promoting osteoblastogenesis. Furthermore, treatment with Kae in rat BMSCs enhanced mineralization, elevated ALP activity, increased the expression levels of Runx‑2 and Osterix and increased the levels of p‑S6K and decreased the levels of p‑4E/BP1 and, consistent with its ability to promote osteoblast differentiation. In contrast, treatment with rapamycin, an mTOR inhibitor, produced the opposite phenotype. Taken together, these data suggested that the protective effects of Kae in BMSCs and in the OVX rat model resulted from the induction of osteogenesis via mTOR signaling, or at least partially via the regulation of downstream effectors of the mTOR pathway.
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Affiliation(s)
- Jing Zhao
- Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, P.R. China
| | - Jue Wu
- Laboratory of Translational Medicine, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Binwu Xu
- Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, P.R. China
| | - Zhen Yuan
- Regeneration and Rehabilitation Engineering Research Institute on Bone and Nerve of Jiangxi, Nanchang, Jiangxi 330000, P.R. China
| | - Yu Leng
- Department of Emergency, The First People's Hospital of Jiujiang City, Jiujiang, Jiangxi 332000, P.R. China
| | - Jun Min
- Department of Rehabilitation, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Xiaoyong Lan
- Department of Orthopedics, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Jun Luo
- Regeneration and Rehabilitation Engineering Research Institute on Bone and Nerve of Jiangxi, Nanchang, Jiangxi 330000, P.R. China
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Yang Q, Yin W, Chen Y, Zhu D, Yin J, Zhang C, Gao Y. Betaine alleviates alcohol-induced osteonecrosis of the femoral head via mTOR signaling pathway regulation. Biomed Pharmacother 2019; 120:109486. [PMID: 31586901 DOI: 10.1016/j.biopha.2019.109486] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 09/14/2019] [Accepted: 09/22/2019] [Indexed: 02/07/2023] Open
Abstract
Osteonecrosis of the femoral head (ONFH) is usually caused by chronic and excessive alcohol dependency, and this condition largely suppresses the osteogenic differentiation of bone mesenchymal stem cells (BMSCs). As a trimethyl derivative of glycine, betaine is an important human nutrient that regulates a series of vital biological processes, including oxidative stress, inflammatory responses, osteoblast differentiation and cellular apoptosis. However, no study has investigated the role of betaine in alcohol-induced ONFH. In this study, we hypothesized that betaine might have protective effects on ethanol-treated BMSCs and decrease the morbidity of alcohol-induced ONFH in a rat model. In vitro, we found that ethanol significantly downregulated the expression of osteocalcin (OCN), collagen 1 (COL1) and RUNX2 via activating the mammalian target of rapamycin (mTOR) signaling cascade. However, the inhibitory effects were rescued by betaine co-treatment at concentrations of 1 mM and 10 mM. In vivo, the typical ONFH pathological changes in a rat model of alcohol-induced ONFH were investigated by using multiple methods, including hematoxylin-eosin staining, micro-CT scans, TdT-mediated dUTP nick end labeling (TUNEL) assays and immunohistochemical staining for OCN and COL1. Osteonecrotic lesions of the femoral head could be alleviated by betaine as evidenced by significant histological and radiological improvements. Collectively, betaine plays a protective role against ethanol-induced suppression of osteogenesis and mineralization of hBMSCs and is thus a potential pharmacotherapy for alcohol-induced ONFH in vivo.
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Affiliation(s)
- Qianhao Yang
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Wenjing Yin
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Yixuan Chen
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Daoyu Zhu
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Junhui Yin
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China; Institute of Microsurgery on Extremities, Shanghai, 200233, China
| | - Changqing Zhang
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China; Institute of Microsurgery on Extremities, Shanghai, 200233, China.
| | - Youshui Gao
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
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42
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Stem cell-based bone and dental regeneration: a view of microenvironmental modulation. Int J Oral Sci 2019; 11:23. [PMID: 31423011 PMCID: PMC6802669 DOI: 10.1038/s41368-019-0060-3] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 05/28/2019] [Accepted: 06/12/2019] [Indexed: 02/06/2023] Open
Abstract
In modern medicine, bone and dental loss and defects are common and widespread morbidities, for which regenerative therapy has shown great promise. Mesenchymal stem cells, obtained from various sources and playing an essential role in organ development and postnatal repair, have exhibited enormous potential for regenerating bone and dental tissue. Currently, mesenchymal stem cells (MSCs)-based bone and dental regeneration mainly includes two strategies: the rescue or mobilization of endogenous MSCs and the application of exogenous MSCs in cytotherapy or tissue engineering. Nevertheless, the efficacy of MSC-based regeneration is not always fulfilled, especially in diseased microenvironments. Specifically, the diseased microenvironment not only impairs the regenerative potential of resident MSCs but also controls the therapeutic efficacy of exogenous MSCs, both as donors and recipients. Accordingly, approaches targeting a diseased microenvironment have been established, including improving the diseased niche to restore endogenous MSCs, enhancing MSC resistance to a diseased microenvironment and renormalizing the microenvironment to guarantee MSC-mediated therapies. Moreover, the application of extracellular vesicles (EVs) as cell-free therapy has emerged as a promising therapeutic strategy. In this review, we summarize current knowledge regarding the tactics of MSC-based bone and dental regeneration and the decisive role of the microenvironment, emphasizing the therapeutic potential of microenvironment-targeting strategies in bone and dental regenerative medicine.
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Zheng CX, Sui BD, Qiu XY, Hu CH, Jin Y. Mitochondrial Regulation of Stem Cells in Bone Homeostasis. Trends Mol Med 2019; 26:89-104. [PMID: 31126872 DOI: 10.1016/j.molmed.2019.04.008] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 04/10/2019] [Accepted: 04/19/2019] [Indexed: 12/13/2022]
Abstract
Mitochondria have emerged as key contributors to the organismal homeostasis, in which mitochondrial regulation of stem cells is becoming increasingly important. Originated from mesenchymal stem cell (MSC) and hematopoietic stem cell (HSC) lineage commitments and interactions, bone is a representative organ where the mitochondrial essentiality to stem cell function has most recently been discovered, underlying skeletal health, aging, and diseases. Furthermore, mitochondrial medications based on modulating stem cell specification are emerging to provide promising therapies to counteract bone aging and pathologies. Here we review the cutting-edge knowledge regarding mitochondrial regulation of stem cells in bone homeostasis, highlighting mechanistic insights as well as mitochondrial strategies for augmented bone healing and tissue regeneration.
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Affiliation(s)
- Chen-Xi Zheng
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi' an, Shaanxi 710032, China
| | - Bing-Dong Sui
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi' an, Shaanxi 710032, China
| | - Xin-Yu Qiu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi' an, Shaanxi 710032, China
| | - Cheng-Hu Hu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi' an, Shaanxi 710032, China; Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi 710032, China.
| | - Yan Jin
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi' an, Shaanxi 710032, China.
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Yu X, Shen G, Ren H, Zhang Z, Shang Q, Zhao W, Huang J, Yang Z, Liang D, Jiang X. TGFβ-induced factor homeobox 2 blocks osteoblastic differentiation through targeting pSmad3/HDAC4/H4ac/Runx2 axis. J Cell Physiol 2019; 234:21284-21293. [PMID: 31066043 DOI: 10.1002/jcp.28733] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 04/02/2019] [Accepted: 04/11/2019] [Indexed: 01/22/2023]
Abstract
TGFβ-induced factor homeobox 2 (Tgif2) has been reported as a functional role in cell homeostasis and a key activator of osteoclastogenesis and bone loss, as well. In the present study, we aimed to investigate the potential role of Tgif2 on osteogenic differentiation. Tgif2 expression was assessed during the osteogenic differentiation process of bone marrow-derived mesenchymal stem cells (BMSCs) and primary calvarial osteoblasts (OBs). The expression of Tgif2 in BMSCs and OBs increased by using lentivirus-mediated gene overexpression (OE). The effect of Tgif2 on osteogenic differentiation was compared between Tgif2 negative control (Tgif2-NC) and Tgif2-OE group in BMSCs/OBs via performing alkaline phosphatase (ALP) assay, mineralization assay, and gene expression analysis of some osteogenic markers. To investigate the molecular mechanism, the direct interaction of histone deacetylase 4 (HDAC4) and pSmad3, acetylated histone H4 (H4ac), and Runx2-binding site of the Ocn promoter was confirmed by performing co-immunoprecipitation (CoIP) and chromatin immunoprecipitation (ChIP) assay, respectively. The results showed that Tgif2 abundantly expressed in BMSCs and primary calvarial OBs, but decreased after osteogenic induction. In vitro, osteogenic differentiation was significantly inhibited with Tgif2 overexpression in both BMSCs and OBs, as well as the expression levels of osteogenic markers (Runx2, Sp7, Alp, and Ocn). Moreover, we found that Tgif2 overexpression significantly promoted the interaction of pSmad3 with HDAC4 in differentiated OBs, and sequentially decreased the abundance of H4ac at the Runx2-binding site of the Ocn promoter. These findings indicated that Tgif2 might block osteoblastic differentiation in vitro through targeting pSmad3/HDAC4/H4ac/Runx2 axis.
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Affiliation(s)
- Xiang Yu
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Gengyang Shen
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hui Ren
- Department of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhida Zhang
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qi Shang
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wenhua Zhao
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jinjing Huang
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhidong Yang
- Department of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - De Liang
- Department of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaobing Jiang
- Department of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, China
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45
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Kohno Y, Lin T, Pajarinen J, Jämsen E, Romero-Lopez M, Maruyama M, Lo CW, Ueno M, Nathan K, Yao Z, Goodman SB. Treating Titanium Particle-Induced Inflammation with Genetically Modified NF- κB Sensing IL-4 Secreting or Preconditioned Mesenchymal Stem Cells in Vitro. ACS Biomater Sci Eng 2019; 5:3032-3038. [PMID: 32391436 DOI: 10.1021/acsbiomaterials.9b00560] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Titanium and titanium-based alloys are widely used in orthopaedic implants. Total joint replacement is very successful; however, the foreign body response and chronic inflammation caused by implant-derived biomaterial debris still remain as unsolved issues. Aseptic loosening accompanied by wear debris-induced osteolysis (bone loss) is one of the most frequent causes for late failure and revision surgery. Mesenchymal stem cells (MSCs) and IL-4 may be possible treatment strategies because of their immunomodulatory properties. We investigated the efficacy of novel MSC-based treatments on immunomodulation and osteogenic differentiation in an innovative cell coculture model of titanium particle-induced inflammation in the periprosthetic tissues. MSCs and macrophages were collected from the bone marrow of Balb/c mice. Both MSCs and macrophages (representing endogenous cells at the periprosthetic tissue) were seeded on the bottom wells of the 24-well transwell plates. We generated genetically modified NF-κB sensing IL-4 secreting MSCs (inflammatory responsive MSCs) and MSCs preconditioned by lipopolysaccharide and TNF-α to further enhance their immunomodulatory function. These modified MSCs (representing exogenous therapeutic cells implanted to the periprosthetic tissue) were seeded on the upper chambers of the transwell plates. These cocultures were then exposed to titanium particles for 7 days. NF-κB sensing IL-4 secreting MSCs showed strong immunomodulation (significantly reduced TNF-α and induced Arg1 expression) and promoted early osteogenesis (significantly induced Runx2, ALP, and β-catenin as well as reduced Smurf2 expression) at day 7. IL-4 secreting MSCs also decreased TNF-α protein secretion as early as day 3 and increased IL-1ra protein secretion at day 7, suggesting efficacious immunomodulation of particle-induced inflammation. Preconditioned MSCs did not show significant immunomodulation in this short-term experiment, but ALP and β-catenin expression were significantly induced at day 7. Our results suggest that genetically modified IL-4 secreting MSCs and preconditioned MSCs have the potential to optimize bone regeneration in inflammatory conditions including periprosthetic osteolysis.
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Affiliation(s)
- Yusuke Kohno
- Department of Orthopaedic Surgery, Stanford University, Stanford, California 94063, United States
| | - Tzuhua Lin
- Department of Orthopaedic Surgery, Stanford University, Stanford, California 94063, United States
| | - Jukka Pajarinen
- Department of Orthopaedic Surgery, Stanford University, Stanford, California 94063, United States
| | - Eemeli Jämsen
- Department of Medicine, Clinicum, University of Helsinki and Helsinki University Hospital, Helsinki 00029, Finland
| | - Monica Romero-Lopez
- Department of Orthopaedic Surgery, Stanford University, Stanford, California 94063, United States
| | - Masahiro Maruyama
- Department of Orthopaedic Surgery, Stanford University, Stanford, California 94063, United States
| | - Chi-Wen Lo
- Department of Orthopaedic Surgery, Stanford University, Stanford, California 94063, United States
| | - Masaya Ueno
- Department of Orthopaedic Surgery, Stanford University, Stanford, California 94063, United States
| | - Karthik Nathan
- Department of Orthopaedic Surgery, Stanford University, Stanford, California 94063, United States
| | - Zhenyu Yao
- Department of Orthopaedic Surgery, Stanford University, Stanford, California 94063, United States
| | - Stuart B Goodman
- Department of Orthopaedic Surgery, Stanford University, Stanford, California 94063, United States.,Department of Bioengineering, Stanford University, Stanford, California 94305, United States
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Peng H, Yang M, Guo Q, Su T, Xiao Y, Xia ZY. Dendrobium officinale polysaccharides regulate age-related lineage commitment between osteogenic and adipogenic differentiation. Cell Prolif 2019; 52:e12624. [PMID: 31038249 PMCID: PMC6668967 DOI: 10.1111/cpr.12624] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 03/26/2019] [Accepted: 03/30/2019] [Indexed: 12/13/2022] Open
Abstract
Objectives Excessive oxidative stress and diminished antioxidant defences could contribute to age‐related tissue damage and various diseases including age‐related osteoporosis. Dendrobium officinale polysaccharides (DOPs), a major ingredient from a traditional Chinese medicine, have a great potential of antioxidative activity. In this study, we explore the role of DOP in age‐related osteoporosis that remains elusive. Materials and methods Oxidative stimulation and DOP were used to treat bone marrow mesenchymal stem cells (BMSCs), whose lineage commitment was measured by adipogenic‐ and osteoblastic‐induced differentiation analysis. The oxidative stress and antioxidant capacity of BMSCs under the treatment of DOP were analysed by the level of MDA, SOD. Related mechanism studies were confirmed by qRT‐PCR, Western blotting and siRNA transfection. DOP was orally administrated in aged mice whose phenotype was confirmed by micro‐CT, immunofluorescence, immunochemistry and calcein double‐labelling analysis. Results Dendrobium officinale polysaccharide treatment markedly increased osteogenic differentiation of BMSCs, while inhibiting adipogenic differentiation. In vitro, DOP could rescue H2O2‐induced switch of BMSCs differentiation fate. However, this effect was abolished in BMSCs when interfered with Nrf2 siRNA. Furthermore, administration of DOP to aged mice significantly increased the bone mass and reduced the marrow adipose tissue (MAT) accompanied with decreased oxidative stress of BMSCs. Conclusions Our study reveals that DOP can attenuate bone loss and MAT accumulation through NRF2 antioxidant signalling, which may represent as potential therapeutic agent for age‐related osteoporosis.
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Affiliation(s)
- Hui Peng
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Mi Yang
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Qi Guo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Tian Su
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ye Xiao
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhu-Ying Xia
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, China
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47
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Bateman JF, Sampurno L, Maurizi A, Lamandé SR, Sims NA, Cheng TL, Schindeler A, Little DG. Effect of rapamycin on bone mass and strength in the α2(I)-G610C mouse model of osteogenesis imperfecta. J Cell Mol Med 2018; 23:1735-1745. [PMID: 30597759 PMCID: PMC6378195 DOI: 10.1111/jcmm.14072] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 10/15/2018] [Accepted: 11/10/2018] [Indexed: 12/23/2022] Open
Abstract
Osteogenesis imperfecta (OI) is commonly caused by heterozygous type I collagen structural mutations that disturb triple helix folding and integrity. This mutant‐containing misfolded collagen accumulates in the endoplasmic reticulum (ER) and induces a form of ER stress associated with negative effects on osteoblast differentiation and maturation. Therapeutic induction of autophagy to degrade the mutant collagens could therefore be useful in ameliorating the ER stress and deleterious downstream consequences. To test this, we treated a mouse model of mild to moderate OI (α2(I) G610C) with dietary rapamycin from 3 to 8 weeks of age and effects on bone mass and mechanical properties were determined. OI bone mass and mechanics were, as previously reported, compromised compared to WT. While rapamycin treatment improved the trabecular parameters of WT and OI bones, the biomechanical deficits of OI bones were not rescued. Importantly, we show that rapamycin treatment suppressed the longitudinal and transverse growth of OI, but not WT, long bones. Our work demonstrates that dietary rapamycin offers no clinical benefit in this OI model and furthermore, the impact of rapamycin on OI bone growth could exacerbate the clinical consequences during periods of active bone growth in patients with OI caused by collagen misfolding mutations.
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Affiliation(s)
- John F Bateman
- Murdoch Children's Research Institute, Parkville, Victoria, Australia.,Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia
| | - Lisa Sampurno
- Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Antonio Maurizi
- Murdoch Children's Research Institute, Parkville, Victoria, Australia.,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Shireen R Lamandé
- Murdoch Children's Research Institute, Parkville, Victoria, Australia.,Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
| | - Natalie A Sims
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.,Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia
| | - Tegan L Cheng
- Orthopaedic Research and Biotechnology Unit, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
| | - Aaron Schindeler
- Orthopaedic Research and Biotechnology Unit, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
| | - David G Little
- Orthopaedic Research and Biotechnology Unit, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
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Abstract
Mesenchymal stem cells (MSCs) have been discovered in almost every organ and tissue. MSCs are a heterogeneous population of cells with the capacity to self-renew and show multilineage differentiation. MSCs possess immunomodulatory properties by regulating multiple types of immune cells. They are emerging as a promising therapeutic agent, and have been widely used for cell-based tissue regeneration and immune therapies. A further understanding of the biological characteristics of MSCs is a prerequisite to develop more efficient MSC-based therapies. This article reviews the current understanding of different MSC populations in orofacial tissue compared with those derived from bone marrow.
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Affiliation(s)
- Xueli Mao
- Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Affiliated Stomatological Hospital, Sun Yat-sen University, 55 West Lingyuan Rd, Yuexiu District, Guangzhou 510055, China
| | - Yao Liu
- Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pediatric Dentistry, School of Stomatology, China Medical University, 117 South Nanjing Street, Heping District, Shenyang 110002, China
| | - Chider Chen
- Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Songtao Shi
- Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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49
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Transplanted interleukin-4--secreting mesenchymal stromal cells show extended survival and increased bone mineral density in the murine femur. Cytotherapy 2018; 20:1028-1036. [PMID: 30077567 DOI: 10.1016/j.jcyt.2018.06.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 05/21/2018] [Accepted: 06/22/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Mesenchymal stromal cell (MSC)-based therapy has great potential to modulate chronic inflammation and enhance tissue regeneration. Crosstalk between MSC-lineage cells and polarized macrophages is critical for bone formation and remodeling in inflammatory bone diseases. However, the translational application of this interaction is limited by the short-term viability of MSCs after cell transplantation. METHODS Three types of genetically modified (GM) MSCs were created: (1) luciferase-expressing reporter MSCs; (2) MSCs that secrete interleukin (IL)-4 either constitutively; and (3) MSCs that secrete IL-4 as a response to nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) activation. Cells were injected into the murine distal femoral bone marrow cavity. MSC viability and bone formation were examined in vivo. Cytokine secretion was determined in a femoral explant organ culture model. RESULTS The reporter MSCs survived up to 4 weeks post-implantation. No difference in the number of viable cells was found between high (2.5 × 106) and low (0.5 × 106) cell-injected groups. Injection of 2.5 × 106 reporter MSCs increased local bone mineral density at 4 weeks post-implantation. Injection of 0.5 × 106 constitutive IL-4 or NFκB-sensing IL-4-secreting MSCs increased bone mineral density at 2 weeks post-implantation. In the femoral explant organ culture model, LPS treatment induced IL-4 secretion in the NFκB-sensing IL-4-secreting MSC group and IL-10 secretion in all the femur samples. No significant differences in tumor necrosis factor (TNF)α and IL-1β secretion were observed between the MSC-transplanted and control groups in the explant culture. DISCUSSION Transplanted GM MSCs demonstrated prolonged cell viability when transplanted to a compatible niche within the bone marrow cavity. GM IL-4-secreting MSCs may have great potential to enhance bone regeneration in disorders associated with chronic inflammation.
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50
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Yang R, Yu T, Kou X, Gao X, Chen C, Liu D, Zhou Y, Shi S. Tet1 and Tet2 maintain mesenchymal stem cell homeostasis via demethylation of the P2rX7 promoter. Nat Commun 2018; 9:2143. [PMID: 29858571 PMCID: PMC5984622 DOI: 10.1038/s41467-018-04464-6] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 05/02/2018] [Indexed: 12/13/2022] Open
Abstract
Ten-eleven translocation (Tet) family-mediated DNA oxidation represents an epigenetic modification capable of converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), which regulates various biological processes. However, it is unknown whether Tet family affects mesenchymal stem cells (MSCs) or the skeletal system. Here we show that depletion of Tet1 and Tet2 results in impaired self-renewal and differentiation of bone marrow MSCs (BMMSCs) and a significant osteopenia phenotype. Tet1 and Tet2 deficiency reduces demethylation of the P2rX7 promoter and downregulates exosome release, leading to intracellular accumulation of miR-297a-5p, miR-297b-5p, and miR-297c-5p. These miRNAs inhibit Runx2 signaling to impair BMMSC function. We show that overexpression of P2rX7 rescues the impaired BMMSCs and osteoporotic phenotype in Tet1 and Tet2 double knockout mice. These results indicate that Tet1 and Tet2 play a critical role in maintaining BMMSC and bone homeostasis through demethylation of P2rX7 to control exosome and miRNA release. This Tet/P2rX7/Runx2 cascade may serve as a target for the development of novel therapies for osteopenia disorders. Tet-mediated DNA oxidation converts 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), which is essential to regulate different biological processes. Here the authors show that Tet1 and Tet2 regulate mesenchymal stem cell and bone homeostasis through demethylation of P2rX7 promoter.
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Affiliation(s)
- Ruili Yang
- Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China.,Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA.,Sino-US joint Research Center of Oral Tissue-derived Stem Cells, PKU Industrial Park, Building 10 First Floor, Beiqing Road, Changping District, Beijing, 102200, China
| | - Tingting Yu
- Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China.,Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Xiaoxing Kou
- Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China.,Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Xiang Gao
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA.,College of Stomatology and Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Medical University, Chongqing, 401147, China
| | - Chider Chen
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Dawei Liu
- Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China.,Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Yanheng Zhou
- Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China. .,Sino-US joint Research Center of Oral Tissue-derived Stem Cells, PKU Industrial Park, Building 10 First Floor, Beiqing Road, Changping District, Beijing, 102200, China.
| | - Songtao Shi
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA. .,Sino-US joint Research Center of Oral Tissue-derived Stem Cells, PKU Industrial Park, Building 10 First Floor, Beiqing Road, Changping District, Beijing, 102200, China.
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