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Yadalam PK, Ardila CM. Deep Neural Networks Based on Sp7 Protein Sequence Prediction in Peri-Implant Bone Formation. Int J Dent 2025; 2025:7583275. [PMID: 40231202 PMCID: PMC11996267 DOI: 10.1155/ijod/7583275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 03/15/2025] [Indexed: 04/16/2025] Open
Abstract
Objective: Peri-implant bone regeneration is crucial for dental implant success, particularly in managing peri-implantitis, which causes inflammation and bone loss. SP7 (Osterix) is vital for osteoblast differentiation and bone matrix formation. Advances in deep neural networks (DNNs) offer new ways to analyze protein sequences, potentially improving our understanding of SP7's role in bone formation. This study aims to develop and utilize DNNs to predict the SP7 protein sequence and understand its role in peri-implant bone formation. Materials: and Methods: Sequences were retrieved from UniProt IDs Q8TDD2 and Q9V3Z2 using the UniProt dataset. The sequences were Sp7 fasta sequences. These sequences were located, and their quality was assessed. We built an architecture that can handle a wide range of input sequences using a DNN technique, with computing needs based on the length of the input sequences. Results: Protein sequences were analyzed using a DNN architecture with ADAM optimizer over 50 epochs, achieving a sensitivity of 0.89 and a specificity of 0.82. The receiver operating characteristic (ROC) curve demonstrated high true-positive rates and low false-positive rates, indicating robust model performance. Precision-recall analysis underscored the model's effectiveness in handling imbalanced data, with significant area under the curve (AUC-PR). Epoch plots highlighted consistent model accuracy throughout training, confirming its reliability for protein sequence analysis. Conclusion: The DNN employed with ADAM optimizer demonstrated robust performance in analyzing protein sequences, achieving an accuracy of 0.85 and high sensitivity and specificity. The ROC curve highlighted the model's effectiveness in distinguishing true positives from false positives, which is essential for reliable protein classification. These findings suggest that the developed model is promising for enhancing predictive capabilities in computational biology and biomedical research, particularly in protein function prediction and therapeutic development applications.
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Affiliation(s)
- Pradeep Kumar Yadalam
- Department of Periodontics, Saveetha Dental College, SIMATS, Saveetha University, Chennai, Tamil Nadu, India
| | - Carlos M. Ardila
- Department of Periodontics, Saveetha Dental College, SIMATS, Saveetha University, Chennai, Tamil Nadu, India
- Department of Basic Sciences, Biomedical Stomatology Research Group, Faculty of Dentistry, University of Antioquia, Medellín, Colombia
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Zhao C, Inada Y, Motoike S, Kamiya D, Hino K, Ikeya M. BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-β signaling. EMBO Mol Med 2025; 17:112-128. [PMID: 39627568 PMCID: PMC11729865 DOI: 10.1038/s44321-024-00174-3] [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: 05/31/2024] [Revised: 10/29/2024] [Accepted: 10/31/2024] [Indexed: 01/15/2025] Open
Abstract
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder presenting with progressive heterotopic ossification (HO) in soft tissues. Early-stage FOP is characterized by recurrent episodes of painful tissue swelling (flare-ups), with numerous proliferation-activated mesenchymal stromal cells (MSCs) subsequently causing HO. However, the mechanisms underlying flare-up progression remain unclear. In this study, we evaluated the proliferation of MSCs obtained from FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to elucidate the mechanisms underlying flare-ups and found that bone morphogenetic protein (BMP)-9 mediated enhanced proliferation by abnormal activation of transforming growth factor (TGF)-β signaling pathway in MSCs from FOP-iPSCs. In FOP model mice, elevated BMP-9 levels correlated with elevated phosphorylation of SMAD2/3 and increased cellular proliferation in the affected tissues, while systemic BMP-9 neutralization and knockout mitigated flare-ups and HO. Thus, BMP-9 aberrantly transduces TGF-β signaling and induces fibroproliferation, initiating flare-ups. This study provides novel insights into the development of future FOP therapies.
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Affiliation(s)
- Chengzhu Zhao
- Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China.
- Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
| | - Yoshiko Inada
- Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Souta Motoike
- Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Daisuke Kamiya
- Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
- Takeda-CiRA Joint Program, Fujisawa, Kanagawa, Japan
| | - Kyosuke Hino
- Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
- Regenerative & Cellular Medicine Kobe Center, Sumitomo Pharma Co., Ltd., Konohana-ku, Osaka, 554-0022, Japan
| | - Makoto Ikeya
- Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
- Takeda-CiRA Joint Program, Fujisawa, Kanagawa, Japan.
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Huang R, Hu C, Xu S, Chen H, Pan J, Xia J, Xie D, Jin Y, Wang Z, Zhao C. 3D-Printed Bifunctional Scaffold for Treatment of Critical Bone Defects Based on Osteoimmune Microenvironment Regulation and Osteogenetic Effects. ACS APPLIED MATERIALS & INTERFACES 2024; 16:63345-63357. [PMID: 39523994 DOI: 10.1021/acsami.4c15212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
The critical-sized bone defect resulting from trauma, tumor resection, and congenital deformity fails to undergo spontaneous healing due to its substantial size, while the ensuing inflammatory process and hypoxic environment further impede the regenerative process. Therefore, it has consistently presented a significant clinical challenge. In the present study, we incorporate a glycyrrhizic acid (GA)-functionalized hydrogel onto the surface of a Hydroxyapatite (Hap)-modified Polycaprolactone (PCL) scaffold to fabricate a composite scaffold. The composed scaffold showed favorable anti-inflammatory and antioxidative capabilities by modulating macrophage polarization and scavenging reactive oxygen species (ROS); the modification of Hap enhanced its osteogenic ability. An in vivo rat skull defect model confirmed that the composed scaffold efficiently promotes bone regeneration. In general, the composed scaffold with the ability of osteoimmune microenvironment regulation can effectively repair critical-sized bone defects. This strategy provides a promising method for the reconstruction of large segmental bone defects.
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Affiliation(s)
- Ruipeng Huang
- Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Chuan Hu
- Department of Interventional Radiology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Zhejiang Key Laboratory of Imaging and Interventional Medicine, Hangzhou, Zhejiang 310022, China
- Zhejiang Provincial Research Center for Innovative Technology and Equipment in Interventional Oncology, Hangzhou, Zhejiang 310022, China
| | - Shaoqing Xu
- Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Hongyu Chen
- Department of Orthopaedic Surgery, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou 310016, China
| | - Junpeng Pan
- Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Jiechao Xia
- Department of Emergency, Qingdao West Coast New Area Central Hospital, Qingdao 266000, China
| | - Dingqi Xie
- Department of Emergency, Qingdao West Coast New Area Central Hospital, Qingdao 266000, China
| | - Yang Jin
- Department of Emergency, Qingdao West Coast New Area Central Hospital, Qingdao 266000, China
| | - Zhijie Wang
- Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Chengliang Zhao
- Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
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Welsh IC, Feiler ME, Lipman D, Mormile I, Hansen K, Percival CJ. Palatal segment contributions to midfacial anterior-posterior growth. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.10.03.560703. [PMID: 37873353 PMCID: PMC10592893 DOI: 10.1101/2023.10.03.560703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Anterior-posterior (A-P) elongation of the palate is a critical aspect of integrated midfacial morphogenesis. Reciprocal epithelial-mesenchymal interactions drive secondary palate elongation that is coupled to the periodic formation of signaling centers within the rugae growth zone (RGZ). However, the relationship between RGZ-driven morphogenetic processes, the differentiative dynamics of underlying palatal bone mesenchymal precursors, and the segmental organization of the upper jaw has remained enigmatic. A detailed ontogenetic study of these relationships is important because palatal segment growth is a critical aspect of normal midfacial growth, can produce dysmorphology when altered, and is a likely basis for evolutionary differences in upper jaw morphology. We completed a combined whole mount gene expression and morphometric analysis of normal murine palatal segment growth dynamics and resulting upper jaw morphology. Our results demonstrated that the first formed palatal ruga (ruga 1), found just posterior to the RGZ, maintained an association with important nasal, neurovascular and palatal structures throughout early midfacial development. This suggested that these features are positioned at a proximal source of embryonic midfacial directional growth. Our detailed characterization of midfacial morphogenesis revealed a one-to-one relationship between palatal segments and upper jaw bones during the earliest stages of palatal elongation. Growth of the maxillary anlage within the anterior secondary palate is uniquely coupled to RGZ-driven morphogenesis. This may help drive the unequaled proportional elongation of the anterior secondary palate segment prior to palatal shelf fusion. Our results also demonstrated that the future maxillary-palatine suture, approximated by the position of ruga 1 and consistently associated with the palatine anlage, formed predominantly via the posterior differentiation of the maxilla within the expanding anterior secondary palate. Our ontogenetic analysis provides a novel and detailed picture of the earliest spatiotemporal dynamics of intramembranous midfacial skeletal specification and differentiation within the context of the surrounding palatal segment AP elongation and associated rugae formation.
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Affiliation(s)
- Ian C. Welsh
- Program in Craniofacial Biology, University of California at San Francisco, San Francisco, California 94143, USA
- Department of Orofacial Sciences, University of California at San Francisco, San Francisco, California 94143, USA
- Department of Anatomy, University of California at San Francisco, San Francisco, California 94143, USA
| | - Maria E. Feiler
- Interdepartmental Doctoral Program in Anthropological Sciences, Stony Brook University, Stony Brook, NY 11790
| | - Danika Lipman
- Department of Cell Biology and Anatomy, University of Calgary
| | - Isabel Mormile
- Interdepartmental Doctoral Program in Anthropological Sciences, Stony Brook University, Stony Brook, NY 11790
| | - Karissa Hansen
- Program in Craniofacial Biology, University of California San Francisco, San Francisco, CA 94143
- Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94143
- Department of Anatomy, University of California San Francisco, San Francisco, CA 94143
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Wang Y, Hang K, Wu X, Ying L, Wang Z, Ling Z, Hu H, Pan Z, Zou X. SLAMF8 regulates osteogenesis and adipogenesis of bone marrow mesenchymal stem cells via S100A6/Wnt/β-catenin signaling pathway. Stem Cell Res Ther 2024; 15:349. [PMID: 39380096 PMCID: PMC11462740 DOI: 10.1186/s13287-024-03964-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 09/29/2024] [Indexed: 10/10/2024] Open
Abstract
BACKGROUND The inflammatory microenvironment plays an essential role in bone healing after fracture. The signaling lymphocytic activation molecule family (SLAMF) members deeply participate in inflammatory response and make a vast difference. METHODS We identified SLAMF8 in GEO datasets (GSE129165 and GSE176086) and co-expression analyses were performed to define the relationships between SLAMF8 and osteogenesis relative genes (RUNX2 and COL1A1). In vitro, we established SLAMF8 knockdown and overexpression mouse bone marrow mesenchymal stem cells (mBMSCs) lines. qPCR, Western blot, ALP staining, ARS staining, Oil Red O staining and Immunofluorescence analyses were performed to investigate the effect of SLAMF8 in mBMSCs osteogenesis and adipogenesis. In vivo, mice femoral fracture model was performed to explore the function of SLAMF8. RESULTS SLAMF8 knockdown significantly suppressed the expression of osteogenesis relative genes (RUNX2, SP7 and COL1A1), ALP activity and mineral deposition, but increased the expression of adipogenesis relative genes (PPARγ and C/EBPα). Additionally, SLAMF8 overexpression had the opposite effects. The role SLAMF8 played in mBMSCs osteogenic and adipogenic differentiation were through S100A6 and Wnt/β-Catenin signaling pathway. Moreover, SLAMF8 overexpression mBMSCs promoted the healing of femoral fracture. CONCLUSIONS SLAMF8 promotes osteogenesis and inhibits adipogenesis of mBMSCs via S100A6 and Wnt/β-Catenin signaling pathway. SLAMF8 overexpression mBMSCs effectively accelerate the healing of femoral fracture in mice.
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Affiliation(s)
- Yibo Wang
- Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Kai Hang
- Department of Orthopaedics, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China
| | - Xiaoyong Wu
- Department of Orthopedic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, 310009, China
| | - Li Ying
- Department of Orthopedic, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, 317000, China
| | - Zhongxiang Wang
- Department of Orthopedic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, 310009, China
| | - Zemin Ling
- Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
- Department of Orthopedics, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China
| | - Hao Hu
- Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Zhijun Pan
- Department of Orthopedic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
- Orthopedics Research Institute of Zhejiang University, Hangzhou, 310009, China.
| | - Xuenong Zou
- Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
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6
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Lai M, Chen X, Feng J, Ruan Z, Lin J. Morinda officinalis polysaccharide boosts osteogenic differentiation of bone marrow mesenchymal stem cells by Wnt/β-catenin signaling. Am J Transl Res 2024; 16:4492-4503. [PMID: 39398614 PMCID: PMC11470318 DOI: 10.62347/wmli2601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 08/04/2024] [Indexed: 10/15/2024]
Abstract
OBJECTIVES To investigate the role of Morinda officinalis polysaccharide (MOP) in the protein expression of the Wnt/β-catenin signaling cascade during the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), and to elucidate the mechanisms by which MOP enhances osteogenic differentiation at the cellular level. METHODS BMSCs were isolated and cultured using the whole bone marrow adherence method, followed by flow cytometry for the detection of BMSC marker antigens. Two groups were prepared: a low-dose MOP (L-MOP, 10 µg/mL) group and a high-dose MOP (H-MOP, 40 µg/mL) group. MTT assays and cell clone formation assays were performed to evaluate the effects of different MOP doses on BMSC proliferation. Alizarin red staining (ARS) and alkaline phosphatase (ALP) staining were conducted to assess the impact of varying MOP doses on nodule calcification and ALP activity in BMSCs. Additionally, western blot assays were carried out to determine the effects of different MOP concentrations on the expression levels of osteogenesis-related factors and Wnt/β-catenin pathway proteins in BMSCs. RESULTS Highly purified BMSCs were successfully extracted. Subsequent assays demonstrated that BMSCs exhibited enhanced proliferation at all MOP doses, particularly at the H-MOP dose, compared to the control group. Both L-MOP and H-MOP increased calcium content and ALP activity in BMSCs, as well as elevated the expression of osteogenic factors and Wnt/β-catenin pathway proteins compared to the blank control group. However, the addition of Dickkopf-1 (DKK1) significantly reduced BMSC proliferation and osteogenic differentiation compared to the H-MOP group. CONCLUSIONS MOP can enhance BMSC proliferation and osteogenic differentiation by activating the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Manxiang Lai
- Department of Pharmacy, Guangdong Food and Drug Vocational CollegeGuangzhou 510520, Guangdong, China
| | - Xia Chen
- Department of Nursing, Guangdong Food and Drug Vocational CollegeGuangzhou 510520, Guangdong, China
| | - Juan Feng
- Department of Health Management and Biotechnology, Guangdong Food and Drug Vocational CollegeGuangzhou 510520, Guangdong, China
| | - Zhiyan Ruan
- Department of Pharmacy, Guangdong Food and Drug Vocational CollegeGuangzhou 510520, Guangdong, China
| | - Jiwei Lin
- Prevention and Treatment Center, Shenzhen Hospital of Traditional Chinese MedicineShenzhen 518000, Guangdong, China
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Arambula-Maldonado R, Mequanint K. Osteogenic Differentiation Potential of iMSCs on GelMA-BG-MWCNT Nanocomposite Hydrogels. Biomimetics (Basel) 2024; 9:338. [PMID: 38921218 PMCID: PMC11201442 DOI: 10.3390/biomimetics9060338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 05/22/2024] [Accepted: 05/29/2024] [Indexed: 06/27/2024] Open
Abstract
The ability of bone biomaterials to promote osteogenic differentiation is crucial for the repair and regeneration of osseous tissue. The development of a temporary bone substitute is of major importance in enhancing the growth and differentiation of human-derived stem cells into an osteogenic lineage. In this study, nanocomposite hydrogels composed of gelatin methacryloyl (GelMA), bioactive glass (BG), and multiwall carbon nanotubes (MWCNT) were developed to create a bone biomaterial that mimics the structural and electrically conductive nature of bone that can promote the differentiation of human-derived stem cells. GelMA-BG-MWCNT nanocomposite hydrogels supported mesenchymal stem cells derived from human induced pluripotent stem cells, hereinafter named iMSCs. Cell adhesion was improved upon coating nanocomposite hydrogels with fibronectin and was further enhanced when seeding pre-differentiated iMSCs. Osteogenic differentiation and mature mineralization were promoted in GelMA-BG-MWCNT nanocomposite hydrogels and were most evidently observed in the 70-30-2 hydrogels, which could be due to the stiff topography characteristic from the addition of MWCNT. Overall, the results of this study showed that GelMA-BG-MWCNT nanocomposite hydrogels coated with fibronectin possessed a favorable environment in which pre-differentiated iMSCs could better attach, proliferate, and further mature into an osteogenic lineage, which was crucial for the repair and regeneration of bone.
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Affiliation(s)
- Rebeca Arambula-Maldonado
- School of Biomedical Engineering, The University of Western Ontario, 1151 Richmond Street, London, ON N6A 5B9, Canada;
| | - Kibret Mequanint
- School of Biomedical Engineering, The University of Western Ontario, 1151 Richmond Street, London, ON N6A 5B9, Canada;
- Department of Chemical and Biochemical Engineering, The University of Western Ontario, 1151 Richmond Street, London, ON N6A 5B9, Canada
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Al-Mutairi DA, Jarragh AA, Alsabah BH, Wein MN, Mohammed W, Alkharafi L. A homozygous SP7/OSX mutation causes osteogenesis and dentinogenesis imperfecta with craniofacial anomalies. JBMR Plus 2024; 8:ziae026. [PMID: 38562913 PMCID: PMC10984723 DOI: 10.1093/jbmrpl/ziae026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 02/15/2024] [Accepted: 02/20/2024] [Indexed: 04/04/2024] Open
Abstract
Osteogenesis imperfecta (OI) is a heterogeneous spectrum of hereditary genetic disorders that cause bone fragility, through various quantitative and qualitative defects of type 1 collagen, a triple helix composed of two α1 and one α2 chains encoded by COL1A1 and COL1A2, respectively. The main extra-skeletal manifestations of OI include blue sclerae, opalescent teeth, and hearing impairment. Moreover, multiple genes involved in osteoblast maturation and type 1 collagen biosynthesis are now known to cause recessive forms of OI. In this study a multiplex consanguineous family of two affected males with OI was recruited for genetic screening. To determine the causative, pathogenic variant(s), genomic DNA from two affected family members were analyzed using whole exome sequencing, autozygosity mapping, and then validated with Sanger sequencing. The analysis led to the mapping of a homozygous variant previously reported in SP7/OSX, a gene encoding for Osterix, a transcription factor that activates a repertoire of genes involved in osteoblast and osteocyte differentiation and function. The identified variant (c.946C > T; p.Arg316Cys) in exon 2 of SP7/OSX results in a pathogenic amino acid change in two affected male siblings and develops OI, dentinogenesis imperfecta, and craniofacial anomaly. On the basis of the findings of the present study, SP7/OSX:c. 946C > T is a rare homozygous variant causing OI with extra-skeletal features in inbred Arab populations.
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Affiliation(s)
- Dalal A Al-Mutairi
- Department of Pathology, Faculty of Medicine, Kuwait University, 13110 Kuwait City, Kuwait
| | - Ali A Jarragh
- Department of Surgery, Faculty of Medicine, Kuwait University, 13110 Kuwait City, Kuwait
| | - Basel H Alsabah
- Zain Specialized Hospital for Ear, Nose and Throat, 70030 Kuwait City, Kuwait
| | - Marc N Wein
- Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
| | - Wasif Mohammed
- Department of Radiology, Al Sabah Hospital, 13041 Kuwait City, Kuwait
| | - Lateefa Alkharafi
- Cleft and Craniofacial Unit, Farwaniya Specialized Dental Center, Ministry of Health, 13001 Kuwait City, Kuwait
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Anitua E, Zalduendo M, Tierno R, Alkhraisat MH. Plasma Rich in Growth Factors in Bone Regeneration: The Proximity to the Clot as a Differential Factor in Osteoblast Cell Behaviour. Dent J (Basel) 2024; 12:122. [PMID: 38786520 PMCID: PMC11119057 DOI: 10.3390/dj12050122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/12/2024] [Accepted: 04/19/2024] [Indexed: 05/25/2024] Open
Abstract
The osteogenic differentiation process, by which bone marrow mesenchymal stem cells and osteoprogenitors transform into osteoblasts, is regulated by several growth factors, cytokines, and hormones. Plasma Rich in Growth Factors (PRGF) is a blood-derived preparation consisting of a plethora of bioactive molecules, also susceptible to containing epigenetic factors such as ncRNAs and EVs, that stimulates tissue regeneration. The aim of this study was to investigate the effect of the PRGF clot formulation on osteogenic differentiation. Firstly, osteoblast cells were isolated and characterised. The proliferation of bone cells cultured onto PRGF clots or treated with PRGF supernatant was determined. Moreover, the gene expression of Runx2 (ID: 860), SP7 (ID: 121340), and ALPL (ID: 249) was analysed by one-step real-time quantitative polymerase chain reaction (RT-qPCR). Additionally, alkaline phosphatase (ALPL) activity determination was performed. The highest proliferative effect was achieved by the PRGF supernatant in all the study periods analysed. Concerning gene expression, the logRGE of Runx2 increased significantly in osteoblasts cultured with PRGF formulations compared with the control group, while that of SP7 increased significantly in osteoblasts grown on the PRGF clots. On the other hand, despite the fact that the PRGF supernatant induced ALPL up-regulation, significantly higher enzyme activity was detected for the PRGF clots in comparison with the supernatant formulation. According to our results, contact with the PRGF clot could promote a more advanced phase in the osteogenic process, associated to higher levels of ALPL activity. Furthermore, the PRGF clot releasate stimulated a higher proliferation rate in addition to reduced SP7 expression in the cells located at a distant ubication, leading to a less mature osteoblast stage. Thus, the spatial relationship between the PRGF clot and the osteoprogenitors cells could be a factor that influences regenerative outcomes.
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Affiliation(s)
- Eduardo Anitua
- BTI-Biotechnology Institute, 01007 Vitoria, Spain; (M.Z.); (R.T.); (M.H.A.)
- University Institute for Regenerative Medicine & Oral Implantology, UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria, Spain
| | - Mar Zalduendo
- BTI-Biotechnology Institute, 01007 Vitoria, Spain; (M.Z.); (R.T.); (M.H.A.)
- University Institute for Regenerative Medicine & Oral Implantology, UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria, Spain
| | - Roberto Tierno
- BTI-Biotechnology Institute, 01007 Vitoria, Spain; (M.Z.); (R.T.); (M.H.A.)
- University Institute for Regenerative Medicine & Oral Implantology, UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria, Spain
| | - Mohammad Hamdan Alkhraisat
- BTI-Biotechnology Institute, 01007 Vitoria, Spain; (M.Z.); (R.T.); (M.H.A.)
- University Institute for Regenerative Medicine & Oral Implantology, UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria, Spain
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10
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Sadowska JM, Power RN, Genoud KJ, Matheson A, González-Vázquez A, Costard L, Eichholz K, Pitacco P, Hallegouet T, Chen G, Curtin CM, Murphy CM, Cavanagh B, Zhang H, Kelly DJ, Boccaccini AR, O'Brien FJ. A Multifunctional Scaffold for Bone Infection Treatment by Delivery of microRNA Therapeutics Combined With Antimicrobial Nanoparticles. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2307639. [PMID: 38009631 DOI: 10.1002/adma.202307639] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 11/18/2023] [Indexed: 11/29/2023]
Abstract
Treating bone infections and ensuring bone repair is one of the greatest global challenges of modern orthopedics, made complex by antimicrobial resistance (AMR) risks due to long-term antibiotic treatment and debilitating large bone defects following infected tissue removal. An ideal multi-faceted solution would will eradicate bacterial infection without long-term antibiotic use, simultaneously stimulating osteogenesis and angiogenesis. Here, a multifunctional collagen-based scaffold that addresses these needs by leveraging the potential of antibiotic-free antimicrobial nanoparticles (copper-doped bioactive glass, CuBG) to combat infection without contributing to AMR in conjunction with microRNA-based gene therapy (utilizing an inhibitor of microRNA-138) to stimulate both osteogenesis and angiogenesis, is developed. CuBG scaffolds reduce the attachment of gram-positive bacteria by over 80%, showcasing antimicrobial functionality. The antagomiR-138 nanoparticles induce osteogenesis of human mesenchymal stem cells in vitro and heal a large load-bearing defect in a rat femur when delivered on the scaffold. Combining both promising technologies results in a multifunctional antagomiR-138-activated CuBG scaffold inducing hMSC-mediated osteogenesis and stimulating vasculogenesis in an in vivo chick chorioallantoic membrane model. Overall, this multifunctional scaffold catalyzes killing mechanisms in bacteria while inducing bone repair through osteogenic and angiogenic coupling, making this platform a promising multi-functional strategy for treating and repairing complex bone infections.
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Affiliation(s)
- Joanna M Sadowska
- Tissue Engineering Research Group, Dept. of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
| | - Rachael N Power
- Tissue Engineering Research Group, Dept. of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
| | - Katelyn J Genoud
- Tissue Engineering Research Group, Dept. of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences and Trinity College Dublin (TCD), Dublin, D02 W085, Ireland
| | - Austyn Matheson
- Tissue Engineering Research Group, Dept. of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences and Trinity College Dublin (TCD), Dublin, D02 W085, Ireland
| | - Arlyng González-Vázquez
- Tissue Engineering Research Group, Dept. of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
| | - Lara Costard
- Tissue Engineering Research Group, Dept. of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
| | - Kian Eichholz
- Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences and Trinity College Dublin (TCD), Dublin, D02 W085, Ireland
- Trinity Centre for Biomedical Engineering, Trinity College Dublin (TCD), Dublin, D02 R590, Ireland
| | - Pierluca Pitacco
- Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences and Trinity College Dublin (TCD), Dublin, D02 W085, Ireland
- Trinity Centre for Biomedical Engineering, Trinity College Dublin (TCD), Dublin, D02 R590, Ireland
| | - Tanguy Hallegouet
- Tissue Engineering Research Group, Dept. of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
- University of Strasbourg, Strasbourg, 67412, France
| | - Gang Chen
- Microsurgical Research and Training Facility (MRTF), Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
| | - Caroline M Curtin
- Tissue Engineering Research Group, Dept. of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences and Trinity College Dublin (TCD), Dublin, D02 W085, Ireland
- Trinity Centre for Biomedical Engineering, Trinity College Dublin (TCD), Dublin, D02 R590, Ireland
| | - Ciara M Murphy
- Tissue Engineering Research Group, Dept. of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences and Trinity College Dublin (TCD), Dublin, D02 W085, Ireland
- Trinity Centre for Biomedical Engineering, Trinity College Dublin (TCD), Dublin, D02 R590, Ireland
| | - Brenton Cavanagh
- Cellular and Molecular Imaging Core, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
| | - Huijun Zhang
- Institute of Biomaterials, Friedrich-Alexander University Erlangen-Nuremberg, 91056, Erlangen, Germany
| | - Daniel J Kelly
- Tissue Engineering Research Group, Dept. of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences and Trinity College Dublin (TCD), Dublin, D02 W085, Ireland
- Trinity Centre for Biomedical Engineering, Trinity College Dublin (TCD), Dublin, D02 R590, Ireland
| | - Aldo R Boccaccini
- Institute of Biomaterials, Friedrich-Alexander University Erlangen-Nuremberg, 91056, Erlangen, Germany
| | - Fergal J O'Brien
- Tissue Engineering Research Group, Dept. of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences and Trinity College Dublin (TCD), Dublin, D02 W085, Ireland
- Trinity Centre for Biomedical Engineering, Trinity College Dublin (TCD), Dublin, D02 R590, Ireland
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11
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Bajpai AK, Gu Q, Jiao Y, Starlard-Davenport A, Gu W, Quarles LD, Xiao Z, Lu L. Systems genetics and bioinformatics analyses using ESR1-correlated genes identify potential candidates underlying female bone development. Genomics 2024; 116:110769. [PMID: 38141931 PMCID: PMC10811775 DOI: 10.1016/j.ygeno.2023.110769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 11/14/2023] [Accepted: 12/18/2023] [Indexed: 12/25/2023]
Abstract
Estrogen receptor α (ESR1) is involved in E2 signaling and plays a major role in postmenopausal bone loss. However, the molecular network underlying ESR1 has not been explored. We used systems genetics and bioinformatics to identify important genes associated with Esr1 in postmenopausal bone loss. We identified ~2300 Esr1-coexpressed genes in female BXD bone femur, functional analysis of which revealed 'osteoblast signaling' as the most enriched pathway. PPI network led to the identification of 25 'female bone candidates'. The gene-regulatory analysis revealed RUNX2 as a key TF. ANKRD1 and RUNX2 were significantly different between osteoporosis patients and healthy controls. Sp7, Col1a1 and Pth1r correlated with multiple femur bone phenotypes in BXD mice. miR-3121-3p targeted Csf1, Ankrd1, Sp7 and Runx2. β-estradiol treatment markedly increased the expression of these candidates in mouse osteoblast. Our study revealed that Esr1-correlated genes Ankrd1, Runx2, Csf1 and Sp7 may play important roles in female bone development.
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Affiliation(s)
- Akhilesh K Bajpai
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Qingqing Gu
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Cardiology, Affiliated Hospital of Nantong University, Jiangsu 226001, China
| | - Yan Jiao
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Athena Starlard-Davenport
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Weikuan Gu
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Leigh Darryl Quarles
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Zhousheng Xiao
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
| | - Lu Lu
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA.
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12
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Mercier-Guery A, Millet M, Merle B, Collet C, Bagouet F, Borel O, Sornay-Rendu E, Szulc P, Vignot E, Gensburger D, Fontanges E, Croset M, Chapurlat R. Dysregulation of MicroRNAs in Adult Osteogenesis Imperfecta: The miROI Study. J Bone Miner Res 2023; 38:1665-1678. [PMID: 37715362 DOI: 10.1002/jbmr.4912] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 08/23/2023] [Accepted: 09/09/2023] [Indexed: 09/17/2023]
Abstract
As epigenetic regulators of gene expression, circulating micro-RiboNucleic Acids (miRNAs) have been described in several bone diseases as potential prognostic markers. The aim of our study was to identify circulating miRNAs potentially associated with the severity of osteogenesis imperfecta (OI) in three steps. We have screened by RNA sequencing for the miRNAs that were differentially expressed in sera of a small group of OI patients versus controls and then conducted a validation phase by RT-qPCR analysis of sera of a larger patient population. In the first phase of miROI, we found 79 miRNAs that were significantly differentially expressed. We therefore selected 19 of them as the most relevant. In the second phase, we were able to validate the significant overexpression of 8 miRNAs in the larger OI group. Finally, we looked for a relationship between the level of variation of the validated miRNAs and the clinical characteristics of OI. We found a significant difference in the expression of two microRNAs in those patients with dentinogenesis imperfecta. After reviewing the literature, we found 6 of the 8 miRNAs already known to have a direct action on bone homeostasis. Furthermore, the use of a miRNA-gene interaction prediction model revealed a 100% probability of interaction between 2 of the 8 confirmed miRNAs and COL1A1 and/or COL1A2. This is the first study to establish the miRNA signature in OI, showing a significant modification of miRNA expression potentially involved in the regulation of genes involved in the physiopathology of OI. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Alexandre Mercier-Guery
- Hospices Civils de Lyon, Hôpital E. Herriot, Service de Rhumatologie et Pathologie Osseuse, Lyon, France
- Université de Lyon, Université Lyon 1, INSERM UMR 1033; LYOS Pathophysiology, Diagnosis & Treatments of Musculoskeletal Disorders, Lyon, France
| | - Marjorie Millet
- Université de Lyon, Université Lyon 1, INSERM UMR 1033; LYOS Pathophysiology, Diagnosis & Treatments of Musculoskeletal Disorders, Lyon, France
| | - Blandine Merle
- Université de Lyon, Université Lyon 1, INSERM UMR 1033; LYOS Pathophysiology, Diagnosis & Treatments of Musculoskeletal Disorders, Lyon, France
| | - Corinne Collet
- CHU Robert Debré, Université de Paris Cité, Département de Génétique, CHU Lariboisière, Paris, France
- INSERM UMR1132, CHU Lariboisière, Paris, France
| | - Flora Bagouet
- Hospices Civils de Lyon, Hôpital E. Herriot, Service de Rhumatologie et Pathologie Osseuse, Lyon, France
| | - Olivier Borel
- Université de Lyon, Université Lyon 1, INSERM UMR 1033; LYOS Pathophysiology, Diagnosis & Treatments of Musculoskeletal Disorders, Lyon, France
| | - Elisabeth Sornay-Rendu
- Université de Lyon, Université Lyon 1, INSERM UMR 1033; LYOS Pathophysiology, Diagnosis & Treatments of Musculoskeletal Disorders, Lyon, France
| | - Pawel Szulc
- Université de Lyon, Université Lyon 1, INSERM UMR 1033; LYOS Pathophysiology, Diagnosis & Treatments of Musculoskeletal Disorders, Lyon, France
| | - Emmanuelle Vignot
- Hospices Civils de Lyon, Hôpital E. Herriot, Service de Rhumatologie et Pathologie Osseuse, Lyon, France
| | - Deborah Gensburger
- Hospices Civils de Lyon, Hôpital E. Herriot, Service de Rhumatologie et Pathologie Osseuse, Lyon, France
| | - Elisabeth Fontanges
- Hospices Civils de Lyon, Hôpital E. Herriot, Service de Rhumatologie et Pathologie Osseuse, Lyon, France
| | - Martine Croset
- Université de Lyon, Université Lyon 1, INSERM UMR 1033; LYOS Pathophysiology, Diagnosis & Treatments of Musculoskeletal Disorders, Lyon, France
| | - Roland Chapurlat
- Hospices Civils de Lyon, Hôpital E. Herriot, Service de Rhumatologie et Pathologie Osseuse, Lyon, France
- Université de Lyon, Université Lyon 1, INSERM UMR 1033; LYOS Pathophysiology, Diagnosis & Treatments of Musculoskeletal Disorders, Lyon, France
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13
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Du Y, Liu G, Liu Z, Mo J, Zheng M, Wei Q, Xu Y. Avermectin reduces bone mineralization via the TGF-β signaling pathway in zebrafish. Comp Biochem Physiol C Toxicol Pharmacol 2023; 272:109702. [PMID: 37487806 DOI: 10.1016/j.cbpc.2023.109702] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 07/05/2023] [Accepted: 07/19/2023] [Indexed: 07/26/2023]
Abstract
Avermectin, a widely used insecticide, is primarily effective against animal parasites and insects. Given its extensive application in agriculture, a large amount of avermectin accumulates in natural water bodies. Studies have shown that avermectin has significant toxic effects on various organisms and on the nervous system, spine, and several other organs in humans. However, the effects of avermectin on bone development have not been reported yet. In this study, zebrafish embryos were treated with different concentrations of avermectin to explore the effects of avermectin on early bone development. The results showed that avermectin disturbed early bone development in zebrafish, caused abnormal craniofacial chondrogenesis, and reduced bone mineralization. Avermectin treatment significantly reduced mineralization in zebrafish scales and increased osteoclast activity. Real-time quantitative PCR results showed that avermectin decreased the expression of genes related to osteogenesis and transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling pathways. The TGF-β inhibitor SB431542 rescued avermectin-induced bone mineralization and osteogenesis related gene expression in zebrafish during early development. Thus, this study provides insight into the mechanism of damage caused by avermectin on bone development, thus helping demonstrate its toxicity.
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Affiliation(s)
- Yongwei Du
- Soochow University, Department Orthopedics, Affiliated Hospital 2, Suzhou 320505, China; Gannan Medical University, Department Orthopedics, Affiliated Hospital 1, Ganzhou 341000, China; Soochow University, Department Orthopedics, Suzhou 320505, China
| | - Gongwen Liu
- Suzhou Traditional Chinese Medicine Hospital, Suzhou 320505, China
| | - Zhen Liu
- Gannan Medical University, Department Orthopedics, Affiliated Hospital 1, Ganzhou 341000, China
| | - Jianwen Mo
- Gannan Medical University, Department Orthopedics, Affiliated Hospital 1, Ganzhou 341000, China
| | - Miao Zheng
- Osteoporosis Clinical Center of Second Affiliated Hospital, Soochow University, Suzhou 320505, China
| | - Qi Wei
- Osteoporosis Clinical Center of Second Affiliated Hospital, Soochow University, Suzhou 320505, China
| | - Youjia Xu
- Soochow University, Department Orthopedics, Affiliated Hospital 2, Suzhou 320505, China; Soochow University, Department Orthopedics, Suzhou 320505, China.
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14
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Panzaru MC, Florea A, Caba L, Gorduza EV. Classification of osteogenesis imperfecta: Importance for prophylaxis and genetic counseling. World J Clin Cases 2023; 11:2604-2620. [PMID: 37214584 PMCID: PMC10198117 DOI: 10.12998/wjcc.v11.i12.2604] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/18/2023] [Accepted: 03/27/2023] [Indexed: 04/25/2023] Open
Abstract
Osteogenesis imperfecta (OI) is a genetically heterogeneous monogenic disease characterized by decreased bone mass, bone fragility, and recurrent fractures. The phenotypic spectrum varies considerably ranging from prenatal fractures with lethal outcomes to mild forms with few fractures and normal stature. The basic mechanism is a collagen-related defect, not only in synthesis but also in folding, processing, bone mineralization, or osteoblast function. In recent years, great progress has been made in identifying new genes and molecular mechanisms underlying OI. In this context, the classification of OI has been revised several times and different types are used. The Sillence classification, based on clinical and radiological characteristics, is currently used as a grading of clinical severity. Based on the metabolic pathway, the functional classification allows identifying regulatory elements and targeting specific therapeutic approaches. Genetic classification has the advantage of identifying the inheritance pattern, an essential element for genetic counseling and prophylaxis. Although genotype-phenotype correlations may sometimes be challenging, genetic diagnosis allows a personalized management strategy, accurate family planning, and pregnancy management decisions including options for mode of delivery, or early antenatal OI treatment. Future research on molecular pathways and pathogenic variants involved could lead to the development of genotype-based therapeutic approaches. This narrative review summarizes our current understanding of genes, molecular mechanisms involved in OI, classifications, and their utility in prophylaxis.
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Affiliation(s)
- Monica-Cristina Panzaru
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Andreea Florea
- Department of Medical Genetics - Medical Genetics resident, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Lavinia Caba
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Eusebiu Vlad Gorduza
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
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15
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Wang JS, Tokavanich N, Wein MN. SP7: from Bone Development to Skeletal Disease. Curr Osteoporos Rep 2023; 21:241-252. [PMID: 36881265 PMCID: PMC10758296 DOI: 10.1007/s11914-023-00778-7] [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] [Accepted: 01/18/2023] [Indexed: 03/08/2023]
Abstract
PURPOSE OF REVIEW The purpose of this review is to summarize the different roles of the transcription factor SP7 in regulating bone formation and remodeling, discuss current studies in investigating the causal relationship between SP7 mutations and human skeletal disease, and highlight potential therapeutic treatments that targeting SP7 and the gene networks that it controls. RECENT FINDINGS Cell-type and stage-specific functions of SP7 have been identified during bone formation and remodeling. Normal bone development regulated by SP7 is strongly associated with human bone health. Dysfunction of SP7 results in common or rare skeletal diseases, including osteoporosis and osteogenesis imperfecta with different inheritance patterns. SP7-associated signaling pathways, SP7-dependent target genes, and epigenetic regulations of SP7 serve as new therapeutic targets in the treatment of skeletal disorders. This review addresses the importance of SP7-regulated bone development in studying bone health and skeletal disease. Recent advances in whole genome and exome sequencing, GWAS, multi-omics, and CRISPR-mediated activation and inhibition have provided the approaches to investigate the gene-regulatory networks controlled by SP7 in bone and the therapeutic targets to treat skeletal disease.
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Affiliation(s)
- Jialiang S Wang
- Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | - Nicha Tokavanich
- Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Marc N Wein
- Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Harvard Stem Cell Institute, Cambridge, MA, USA
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16
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Gao X, Zhang Y, Hou L, Zhao Y, Zhang H, Jia Z, Wang S, Li H, Pan X, Liu X, Wang L. Co-exposure to nanoplastics and acetaminophen causes skeletal dysplasia and behavioral abnormalities in zebrafish. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 253:114640. [PMID: 36796208 DOI: 10.1016/j.ecoenv.2023.114640] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 02/04/2023] [Accepted: 02/08/2023] [Indexed: 06/18/2023]
Abstract
Nanoplastics (NPs) and acetaminophen (APAP) are thought to be common contaminants and are invariably detected in the environment. Despite the increasing awareness of their toxicity to humans and animals, the embryonic toxicity, skeletal development toxicity, and mechanism of action of their combined exposure have not been clarified. This study was performed to investigate whether combined exposure to NPs and APAP induces abnormal embryonic and skeletal development in zebrafish and to explore the potential toxicological mechanisms. All zebrafish juveniles in the high-concentration compound exposure group showed some abnormal phenomena such as pericardial edema, spinal curvature, cartilage developmental abnormality and melanin inhibition together with a significant downward trend in body length. Behavioral data also implicated that the exposure of APAP alone, as well as the co-exposure of NPs and APAP, caused a depression in the total distance, swimming speed and the maximum acceleration. Furthermore, real-time polymerase chain reaction analysis showed that compared with exposure alone, the expression level of genes related to osteogenesis, runx2a, runx2b, Sp7, bmp2b and shh was significantly reduced with compound exposure. These results suggest that the compound exposure of NPs and APAP has adverse impacts on zebrafish embryonic development and skeletal growth.
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Affiliation(s)
- Xianlei Gao
- Department of Orthopedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Yilun Zhang
- Shandong Provincial Key Laboratory of Animal Resistance Biology, Key Laboratory of Food Nutrition and Safety of Shandong Normal University, College of Life Science, Shandong Normal University, Jinan 250014, China
| | - Lin Hou
- College of Life Science, Qilu Normal University, Jinan, Shandong 250200, China
| | - Yu Zhao
- Shandong Provincial Key Laboratory of Animal Resistance Biology, Key Laboratory of Food Nutrition and Safety of Shandong Normal University, College of Life Science, Shandong Normal University, Jinan 250014, China
| | - Hongyan Zhang
- Shandong Provincial Key Laboratory of Animal Resistance Biology, Key Laboratory of Food Nutrition and Safety of Shandong Normal University, College of Life Science, Shandong Normal University, Jinan 250014, China
| | - Zhenzhen Jia
- Shandong Provincial Key Laboratory of Animal Resistance Biology, Key Laboratory of Food Nutrition and Safety of Shandong Normal University, College of Life Science, Shandong Normal University, Jinan 250014, China
| | - Songgang Wang
- Department of Orthopedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Hao Li
- Department of Orthopedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Xin Pan
- Department of Orthopedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Xinyu Liu
- Department of Orthopedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
| | - Lianlei Wang
- Department of Orthopedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
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17
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Ngo ST, Lee WF, Wu YF, Salamanca E, Aung LM, Chao YQ, Tsao TC, Hseuh HW, Lee YH, Wang CC, Chang WJ. Fabrication of Solvent-Free PCL/β-TCP Composite Fiber for 3D Printing: Physiochemical and Biological Investigation. Polymers (Basel) 2023; 15:polym15061391. [PMID: 36987176 PMCID: PMC10053981 DOI: 10.3390/polym15061391] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/06/2023] [Accepted: 03/07/2023] [Indexed: 03/16/2023] Open
Abstract
Manufacturing three-dimensional (3D) objects with polymers/bioceramic composite materials has been investigated in recent years. In this study, we manufactured and evaluated solvent-free polycaprolactone (PCL) and beta-tricalcium phosphate (β-TCP) composite fiber as a scaffold material for 3D printing. To investigate the optimal ratio of feedstock material for 3D printing, the physical and biological characteristics of four different ratios of β-TCP compounds mixed with PCL were investigated. PCL/β-TCP ratios of 0 wt.%, 10 wt.%, 20 wt.%, and 30 wt.% were fabricated, with PCL melted at 65 °C and blended with β-TCP with no solvent added during the fabrication process. Electron microscopy revealed an even distribution of β-TCP in the PCL fibers, while Fourier transform infrared spectroscopy demonstrated that the biomaterial compounds remained intact after the heating and manufacturing process. In addition, adding 20% β-TCP into the PCL/β-TCP mixture significantly increased hardness and Young’s Modulus by 10% and 26.5%, respectively, suggesting that PCL-20 has better resistance to deformation under load. Cell viability, alkaline phosphatase (ALPase) activity, osteogenic gene expression, and mineralization were also observed to increase according to the amount of β-TCP added. Cell viability and ALPase activity were 20% higher with PCL-30, while upregulation for osteoblast-related gene expression was better with PCL-20. In conclusion, PCL-20 and PCL-30 fibers fabricated without solvent exhibited excellent mechanical properties, high biocompatibility, and high osteogenic ability, making them promising materials for 3D printing customized bone scaffolds promptly, sustainably, and cost-effectively.
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Affiliation(s)
- Sin Ting Ngo
- Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
| | - Wei-Fang Lee
- School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Yi-Fan Wu
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Eisner Salamanca
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Lwin Moe Aung
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Yan-Qiao Chao
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Ting-Chia Tsao
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Hao-Wen Hseuh
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Yi-Huan Lee
- Department of Molecular Science and Engineering, National Taipei University of Technology, Taipei 106, Taiwan
- Correspondence: (Y.-H.L.); (C.-C.W.); (W.-J.C.)
| | - Ching-Chiung Wang
- Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
- Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan
- Correspondence: (Y.-H.L.); (C.-C.W.); (W.-J.C.)
| | - Wei-Jen Chang
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan
- Dental Department, Taipei Medical University, Shuang Ho Hospital, New Taipei 235, Taiwan
- Correspondence: (Y.-H.L.); (C.-C.W.); (W.-J.C.)
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18
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Nishimura R. Bone and Cartilage Biology. Int J Mol Sci 2023; 24:ijms24065264. [PMID: 36982339 PMCID: PMC10049210 DOI: 10.3390/ijms24065264] [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: 02/27/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
Recent technical and conceptual advances in molecular and cellular biology have dramatically advanced bone and cartilage biology [...]
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Affiliation(s)
- Riko Nishimura
- Department of Molecular & Cellular Biochemistry, Osaka University Graduate School of Dentistry, 1-8 Yamdaoka, Suita, Osaka 565-0871, Japan
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19
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Hendrickx G, Boudin E, Steenackers E, Collet C, Mortier GR, Geneviève D, Van Hul W. A recessive form of craniodiaphyseal dysplasia caused by a homozygous missense variant in SP7/Osterix. Bone 2023; 167:116633. [PMID: 36436818 DOI: 10.1016/j.bone.2022.116633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 10/28/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022]
Affiliation(s)
- Gretl Hendrickx
- Department of Medical Genetics, Antwerp University Hospital and University of Antwerp, 2650 Edegem, Belgium; Laboratory for Skeletal Dysplasia Research, Department of Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Eveline Boudin
- Department of Medical Genetics, Antwerp University Hospital and University of Antwerp, 2650 Edegem, Belgium
| | - Ellen Steenackers
- Department of Medical Genetics, Antwerp University Hospital and University of Antwerp, 2650 Edegem, Belgium
| | - Corinne Collet
- INSERM U1132 and Université de Paris, Reference Centre for Rare Bone Diseases, Hospital Robert Debré, F-75010 Paris, France
| | - Geert R Mortier
- Department of Medical Genetics, Antwerp University Hospital and University of Antwerp, 2650 Edegem, Belgium; Laboratory for Skeletal Dysplasia Research, Department of Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Center for Human Genetics, University Hospital Leuven, Leuven, Belgium
| | - David Geneviève
- Montpellier University and INSERM U1183, Montpellier, France; Competence Center for Bone Diseases, Clinical Genetics Unit, Montpellier University Hospital, Montpellier, France
| | - Wim Van Hul
- Department of Medical Genetics, Antwerp University Hospital and University of Antwerp, 2650 Edegem, Belgium.
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Xiong J, Bao J, Hu W, Shang M, Zhang L. Whole-genome resequencing reveals genetic diversity and selection characteristics of dairy goat. Front Genet 2023; 13:1044017. [PMID: 36685859 PMCID: PMC9852865 DOI: 10.3389/fgene.2022.1044017] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 12/13/2022] [Indexed: 01/09/2023] Open
Abstract
The dairy goat is one of the earliest dairy livestock species, which plays an important role in the economic development, especially for developing countries. With the development of agricultural civilization, dairy goats have been widely distributed across the world. However, few studies have been conducted on the specific characteristics of dairy goat. In this study, we collected the whole-genome data of 89 goat individuals by sequencing 48 goats and employing 41 publicly available goats, including five dairy goat breeds (Saanen, Nubian, Alpine, Toggenburg, and Guanzhong dairy goat; n = 24, 15, 11, 6, 6), and three goat breeds (Guishan goat, Longlin goat, Yunshang Black goat; n = 6, 15, 6). Through compared the genomes of dairy goat and non-dairy goat to analyze genetic diversity and selection characteristics of dairy goat. The results show that the eight goats could be divided into three subgroups of European, African, and Chinese indigenous goat populations, and we also found that Australian Nubian, Toggenburg, and Australian Alpine had the highest linkage disequilibrium, the lowest level of nucleotide diversity, and a higher inbreeding coefficient, indicating that they were strongly artificially selected. In addition, we identified several candidate genes related to the specificity of dairy goat, particularly genes associated with milk production traits (GHR, DGAT2, ELF5, GLYCAM1, ACSBG2, ACSS2), reproduction traits (TSHR, TSHB, PTGS2, ESR2), immunity traits (JAK1, POU2F2, LRRC66). Our results provide not only insights into the evolutionary history and breed characteristics of dairy goat, but also valuable information for the implementation and improvement of dairy goat cross breeding program.
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Could BMPs Therapy Be Improved if BMPs Were Used in Composition Acting during Bone Formation in Endochondral Ossification? Int J Mol Sci 2022; 23:ijms231810327. [PMID: 36142232 PMCID: PMC9499665 DOI: 10.3390/ijms231810327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/01/2022] [Accepted: 09/04/2022] [Indexed: 11/28/2022] Open
Abstract
The discovery of bone morphogenetic proteins (BMPs) inspired hope for the successful treatment of bone disorders, but side effects worsening the clinical effects were eventually observed. BMPs exert a synergistic effect, stimulating osteogenesis; however, predicting the best composition of growth factors for use in humans is difficult. Chondrocytes present within the growth plate produce growth factors stored in calcified cartilage adhering to metaphysis. These factors stimulate initial bone formation in metaphysis. We have previously determined the growth factors present in bovine calcified cartilage and produced by rat epiphyseal chondrocytes. The results suggest that growth factors stimulating physiological ossification are species dependent. The collection of human calcified cartilage for growth factors determination does not appear feasible, but chondrocytes for mRNA determination could be obtained. Their collection from young recipients, in view of the Academy of Medical Royal Colleges Recommendation, would be ethical. The authors of this review do not have facilities to conduct such a study and can only appeal to competent institutions to undertake the task. The results could help to formulate a better recipe for the stimulation of bone formation and improve clinical results.
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Sun P, Huang T, Huang C, Wang Y, Tang D. Role of histone modification in the occurrence and development of osteoporosis. Front Endocrinol (Lausanne) 2022; 13:964103. [PMID: 36093077 PMCID: PMC9458911 DOI: 10.3389/fendo.2022.964103] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/09/2022] [Indexed: 11/13/2022] Open
Abstract
Osteoporosis is a systemic degenerative bone disease characterized by low bone mass and damage to bone microarchitecture, which increases bone fragility and susceptibility to fracture. The risk of osteoporosis increases with age; with the aging of the global population, osteoporosis is becoming more prevalent, adding to the societal healthcare burden. Histone modifications such as methylation, acetylation, ubiquitination, and ADP-ribosylation are closely related to the occurrence and development of osteoporosis. This article reviews recent studies on the role of histone modifications in osteoporosis. The existing evidence indicates that therapeutic targeting of these modifications to promote osteogenic differentiation and bone formation may be an effective treatment for this disease.
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Affiliation(s)
- Pan Sun
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tingrui Huang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chen Huang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yongjun Wang
- Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Yongjun Wang, ; Dezhi Tang,
| | - Dezhi Tang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Yongjun Wang, ; Dezhi Tang,
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