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Guo H, Chen X, Li J, Mo G, Li Y, Tang Y, Kai Y, Zhang S. β-Sitosterol inhibits osteoclast activity and reduces ovariectomy-induced bone loss by regulating the cAMP and NF-κB signaling pathways. Cell Signal 2025; 130:111672. [PMID: 39983806 DOI: 10.1016/j.cellsig.2025.111672] [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: 12/05/2024] [Revised: 01/23/2025] [Accepted: 02/14/2025] [Indexed: 02/23/2025]
Abstract
BACKGROUND β-Sitosterol, a prominent phytosterol present in numerous plant species, has been extensively studied for its potential health benefits, such as lipid-lowering, anxiolytic, and anti-inflammatory properties. Recently, the benefit of β-sitosterol on bone metabolism has been noted. The objective of the current study was to examine the impact of β-sitosterol on the skeletal system. METHODS Network pharmacology and molecular docking were used to predict how β-sitosterol may be used to treat osteoporosis. Cytotoxicity tests were conducted with different concentrations of β-sitosterol. The ability of β-sitosterol to inhibit osteoclast formation and function was evaluated, along with its potential molecular mechanism. An ovariectomized mouse model was used to assess the preventive effect of β-sitosterol on bone loss. RESULTS Network pharmacology analysis suggested that β-sitosterol could be a potential therapeutic treatment for osteoporosis by regulating the cAMP signaling pathway. β-sitosterol dose-dependently inhibited osteoclast differentiation and function without obvious cytotoxicity. Specifically, 20 μM β-sitosterol could obviously repress the number and size of osteoclasts, decrease the formation of F-actin belts, and reduce the bone-resorbing activity of osteoclasts. Some key signaling mediators, including PKA, c-Jun, NFATc1, p-CREB, and NF-κB, were downregulated by β-sitosterol. β-sitosterol acted by attenuating the cAMP and NF-κB signaling pathways. In vivo experiments confirmed β-sitosterol protected ovariectomy-induced bone loss though suppressing osteoclastic bone resorption. CONCLUSION β-sitosterol could inhibit the production and function of osteoclasts in vitro and reverse ovariectomy-induced bone loss. Thus, β-sitosterol could be a potential supplement for diseases with active bone resorption such as osteoporosis.
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Affiliation(s)
- Huizhi Guo
- Spine Surgery Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaojun Chen
- School of Biomedical Sciences, University of Western Australia, Perth, WA 6009, Australia
| | - Jinglan Li
- Spine Surgery Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Guoye Mo
- Spine Surgery Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yongxian Li
- Spine Surgery Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yongchao Tang
- Spine Surgery Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuan Kai
- Spine Surgery Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shuncong Zhang
- Spine Surgery Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
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Zhang J, Wu S, Xing F, Kong N, Zhao Y, Duan X, Li Y, Wang K, Tian R, Yang P. Unveiling the role of melatonin-related gene CSNK1D in osteoclastogenesis and its implications for osteoporosis treatment. Exp Physiol 2025; 110:261-276. [PMID: 39612374 PMCID: PMC11782177 DOI: 10.1113/ep092189] [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: 07/23/2024] [Accepted: 10/07/2024] [Indexed: 12/01/2024]
Abstract
Osteoporosis (OP) is a prevalent bone disease characterized by reduced bone density and quality, increasing fragility and fracture risk. Osteoclast (OC) activity and circadian rhythm play a role in the pathogenesis of OP. Melatonin is a circadian regulator that affects bone metabolism, but its molecular mechanism has not been studied in detail. This study aimed to identify the relationship between melatonin-related genes and OP through bioinformatics methods and to verify it experimentally.We analysed microarray data from the GSE35959 dataset, identifying differentially expressed genes in OP patients. Circadian rhythm-related genes and melatonin-related genes intersect with these differentially expressed genes, highlighting that CSNK1D is a central gene. Functional enrichment, correlation and protein-protein interaction analyses were conducted. Experimental validation involved in vitro differentiation assays using RAW264.7 cells and in vivo studies with an ovariectomy-induced rat model of OP to evaluate the role of CSNK1D in osteoclastogenesis to verify its effect on OP. Differential expression analysis revealed 272 significant genes, with CSNK1D identified as central to the circadian rhythm and to melatonin and OP interplay. Functional analyses showed involvement of CSNK1D in OC differentiation and inflammatory pathways. in vitro experiments confirmed CSNK1D upregulation during OC differentiation, and small interfering RNA-mediated knockdown reduced OC marker expression and TRAP+ cell formation. in vivo, CSNK1D expression is associated with bone loss in OP rats. Melatonin-related CSNK1D promotes OC differentiation and promotes the development of OP. These findings suggest CSNK1D as a potential therapeutic target for OP, offering insights into new treatment strategies integrating circadian rhythm regulation.
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Affiliation(s)
- Jiewen Zhang
- Joint & Ankle SectionThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Shaobo Wu
- Department of Spinal Surgery, Honghui HospitalXi'an Jiaotong UniversityXi'anChina
| | - Fangze Xing
- Joint & Ankle SectionThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Ning Kong
- Joint & Ankle SectionThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Yiwei Zhao
- Joint & Ankle SectionThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Xudong Duan
- Joint & Ankle SectionThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Yiyang Li
- Joint & Ankle SectionThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Kunzheng Wang
- Joint & Ankle SectionThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Run Tian
- Joint & Ankle SectionThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Pei Yang
- Joint & Ankle SectionThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
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Lin B, Liu H, Liu H, Su L, Sun K, Feng H, Liu Y, Yu M, Han D. A novel WNT10A variant impairs the homeostasis of alveolar bone mesenchymal stem cells. Oral Dis 2025; 31:168-180. [PMID: 38852166 DOI: 10.1111/odi.15032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 05/15/2024] [Accepted: 05/22/2024] [Indexed: 06/11/2024]
Abstract
OBJECTIVES To explore the influence of a novel WNT10A variant on bone mineral density, proliferation, and osteogenic differentiation capacities of alveolar bone mesenchymal stem cells in humans. SUBJECTS AND METHODS Whole-exome sequencing and Sanger sequencing were utilized to detect gene variants in a family with non-syndromic tooth agenesis (NSTA). The panoramic mandibular index was calculated on the proband with WNT10A variant and normal controls to evaluate bone mineral density. Alveolar bone mesenchymal stem cells from the proband with a novel WNT10A variant and normal controls were isolated and cultured, then proliferation and osteogenic differentiation capacities were evaluated and compared. RESULTS We identified a novel WNT10A pathogenic missense variant (c.353A > G/p. Tyr118Cys) in a family with NSTA. The panoramic mandibular index of the proband implied a reduction in bone mineral density. Moreover, the proliferation and osteogenic differentiation capacities of alveolar bone mesenchymal stem cells from the proband with WNT10A Tyr118Cys variant were significantly decreased. CONCLUSIONS Our findings broaden the spectrum of WNT10A variants in patients with non-syndromic oligodontia, suggest an association between WNT10A and the proliferation and osteogenic differentiation of alveolar bone mesenchymal stem cells, and demonstrate that WNT10A is involved in maintaining jaw bone homeostasis.
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Affiliation(s)
- Bichen Lin
- Frist Clinical Division, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Haochen Liu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Hangbo Liu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Lanxin Su
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Kai Sun
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Hailan Feng
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Yang Liu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Miao Yu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Dong Han
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
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Abhishek Shah A, Chand D, Ahamad S, Porwal K, Chourasia MK, Mohanan K, Srivastava KR, Chattopadhyay N. Therapeutic targeting of Wnt antagonists by small molecules for treatment of osteoporosis. Biochem Pharmacol 2024; 230:116587. [PMID: 39447984 DOI: 10.1016/j.bcp.2024.116587] [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: 06/05/2024] [Revised: 09/11/2024] [Accepted: 10/21/2024] [Indexed: 10/26/2024]
Abstract
Wnt signaling is one of the key regulators of bone development and homeostasis. Wnt signaling regulates key biological events, including stem cell fate and osteoblast and osteoclast activity, leading to the maintenance of bone mass and strength. Wnt ligands are secreted glycoproteins that bind to Frizzled (FZD) receptors and their coreceptors, lipoprotein receptor-related proteins-5/6 (LRP5/6). Binding of Wnts to FZD triggers canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) pathways. In canonical Wnt signaling, stabilized β-catenin translocates to the nucleus, where it promotes osteoblast differentiation by activating target genes, including Runx2 and Osterix. The negative regulators of Wnt or so-called Wnt antagonists, including CXXC5, sFRP, sclerostin, DKK1, and Notum, compete for Fzd binding, attenuating Wnt signaling. The critical roles of Wnt signaling in bone homeostasis have been established by various bone diseases caused by mutations in Wnt signaling pathways. Loss-of-function mutations in the LRP5 gene cause osteoporosis-pseudoglioma syndrome, whereas gain-of-function mutations are linked to osteopetrosis characterized by high bone density. Sclerosteosis and Van Buchem disease are caused by mutations affecting the SOST gene, which encodes sclerostin, a natural inhibitor of Wnt signalling. Loss-of-function mutations in SOST result in excessive bone growth, markedly increased bone density, and other skeletal abnormalities due to uncontrolled Wnt activity. Considering the clinical relevance of Wnt signaling, targeting Wnt inhibitors is being intensely pursued using small molecules that act by inhibiting endogenous Wnt agonists. We used a computational biology approach to review current data on pharmacophores of Wnt antagonists, assessing their potential as therapeutic candidates for postmenopausal osteoporosis.
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Affiliation(s)
- Aarti Abhishek Shah
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Diwan Chand
- Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Shakir Ahamad
- Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Konica Porwal
- Division of Endocrinology and Center for Research on Anabolic Skeletal Targets for Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Manish K Chourasia
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Kishor Mohanan
- Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Kinshuk R Srivastava
- Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
| | - Naibedya Chattopadhyay
- Division of Endocrinology and Center for Research on Anabolic Skeletal Targets for Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Wang X, Qu Z, Zhao S, Luo L, Yan L. Wnt/β-catenin signaling pathway: proteins' roles in osteoporosis and cancer diseases and the regulatory effects of natural compounds on osteoporosis. Mol Med 2024; 30:193. [PMID: 39468464 PMCID: PMC11520425 DOI: 10.1186/s10020-024-00957-x] [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: 05/17/2024] [Accepted: 10/09/2024] [Indexed: 10/30/2024] Open
Abstract
Osteoblasts are mainly derived from mesenchymal stem cells in the bone marrow. These stem cells can differentiate into osteoblasts, which have the functions of secreting bone matrix, promoting bone formation, and participating in bone remodeling. The abnormality of osteoblasts can cause a variety of bone-related diseases, including osteoporosis, delayed fracture healing, and skeletal deformities. In recent years, with the side effects caused by the application of PTH drugs, biphosphonate drugs, and calmodulin drugs, people have carried out more in-depth research on the mechanism of osteoblast differentiation, and are actively looking for natural compounds for the treatment of osteoporosis. The Wnt/β-catenin signaling pathway is considered to be one of the important pathways of osteoblast differentiation, and has become an important target for the treatment of osteoporosis. The Wnt/β-catenin signaling pathway, whether its activation is enhanced or its expression is weakened, will cause a variety of diseases including tumors. This review will summarize the effect of Wnt/β-catenin signaling pathway on osteoblast differentiation and the correlation between the related proteins in the pathway and human diseases. At the same time, the latest research progress of natural compounds targeting Wnt/β-catenin signaling pathway against osteoporosis is summarized.
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Affiliation(s)
- Xiaohao Wang
- Department of Spinal Surgery, Honghui Hospital of Xi'an Jiaotong University, Xi'an, China
- Xi'an Medical University, Xi'an, China
| | - Zechao Qu
- Department of Spinal Surgery, Honghui Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Songchuan Zhao
- Department of Spinal Surgery, Honghui Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lei Luo
- Department of Spinal Surgery, Honghui Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Liang Yan
- Department of Spinal Surgery, Honghui Hospital of Xi'an Jiaotong University, Xi'an, China.
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Koroth J, Karkache IY, Vu EK, Mansky KC, Bradley EW. CD11B+CD36+ cells are bone anabolic macrophages that limit age-associated bone loss. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.13.612932. [PMID: 39314303 PMCID: PMC11419144 DOI: 10.1101/2024.09.13.612932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Disruptions in the bone remodeling cycle that occur with increasing age lead to degeneration of the skeleton and increased risk of fragility fractures. Our understanding of how bone remodeling within cortical bone is controlled and altered with age in males and females is limited. Here, we generated bone marrow chimeric mice to understand the impacts of age and sex on bone remodeling. We demonstrate that transplantation of aged male or female bone marrow into young, lethally irradiated male hosts unexpectedly enhances cortical bone mass without impacting cancellous bone. Our single cell RNA-sequencing data show that mice reconstituted with aged bone marrow exhibited subsets of cells marked by CD11B/CD36 expression that demonstrate enhanced production of anabolic cytokines as compared to young counterparts, and that these myeloid subsets exist under conditions of normal physiology in aged mice. Importantly, CD11B+CD36+ cells do not differentiate into osteoclasts in vitro, and CD36 does not mark TRAP+ cells in vivo. Instead, CD36+ cells localize to resorption sites, including within cortical bone defects, suggesting their involvement in cortical bone remodeling and healing. CD11B+CD36+ cells also express elevated levels of bone anabolic WNT ligands, especially Wnt6. In functional assays, we demonstrate that soluble factors produced by CD11B+CD36+ cells enhance osteoblast progenitor commitment, mineralization, and activation of WNT signaling in vitro. Moreover, CD11B/CD36 exquisitely mark a subset of anabolic myeloid cells within human bone marrow. In conclusion, our studies identified a novel population of aged macrophages that limit cortical bone loss.
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Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, Zhang C, Gao J. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduct Target Ther 2024; 9:234. [PMID: 39289339 PMCID: PMC11408715 DOI: 10.1038/s41392-024-01931-z] [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: 02/18/2024] [Revised: 06/17/2024] [Accepted: 07/16/2024] [Indexed: 09/19/2024] Open
Abstract
The glucagon-like peptide-1 (GLP-1) receptor, known as GLP-1R, is a vital component of the G protein-coupled receptor (GPCR) family and is found primarily on the surfaces of various cell types within the human body. This receptor specifically interacts with GLP-1, a key hormone that plays an integral role in regulating blood glucose levels, lipid metabolism, and several other crucial biological functions. In recent years, GLP-1 medications have become a focal point in the medical community due to their innovative treatment mechanisms, significant therapeutic efficacy, and broad development prospects. This article thoroughly traces the developmental milestones of GLP-1 drugs, from their initial discovery to their clinical application, detailing the evolution of diverse GLP-1 medications along with their distinct pharmacological properties. Additionally, this paper explores the potential applications of GLP-1 receptor agonists (GLP-1RAs) in fields such as neuroprotection, anti-infection measures, the reduction of various types of inflammation, and the enhancement of cardiovascular function. It provides an in-depth assessment of the effectiveness of GLP-1RAs across multiple body systems-including the nervous, cardiovascular, musculoskeletal, and digestive systems. This includes integrating the latest clinical trial data and delving into potential signaling pathways and pharmacological mechanisms. The primary goal of this article is to emphasize the extensive benefits of using GLP-1RAs in treating a broad spectrum of diseases, such as obesity, cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases, musculoskeletal inflammation, and various forms of cancer. The ongoing development of new indications for GLP-1 drugs offers promising prospects for further expanding therapeutic interventions, showcasing their significant potential in the medical field.
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Affiliation(s)
- Zhikai Zheng
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yao Zong
- Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia
| | - Yiyang Ma
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yucheng Tian
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yidan Pang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Changqing Zhang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
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Tan Z, Chen P, Zhang J, Shek HT, Li Z, Zhou X, Zhou Y, Yin S, Dong L, Feng L, Wong JSH, Gao B, To MKT. Multi-omics analyses reveal aberrant differentiation trajectory with WNT1 loss-of-function in type XV osteogenesis imperfecta. J Bone Miner Res 2024; 39:1253-1267. [PMID: 39126373 PMCID: PMC11371906 DOI: 10.1093/jbmr/zjae123] [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: 04/10/2024] [Revised: 07/07/2024] [Accepted: 07/17/2024] [Indexed: 08/12/2024]
Abstract
Osteogenesis imperfecta (OI) is a group of severe genetic bone disorders characterized by congenital low bone mass, deformity, and frequent fractures. Type XV OI is a moderate to severe form of skeletal dysplasia caused by WNT1 variants. In this cohort study from southern China, we summarized the clinical phenotypes of patients with WNT1 variants and found that the proportion of type XV patients was around 10.3% (25 out of 243) with a diverse spectrum of phenotypes. Functional assays indicated that variants of WNT1 significantly impaired its secretion and effective activity, leading to moderate to severe clinical manifestations, porous bone structure, and enhanced osteoclastic activities. Analysis of proteomic data from human skeleton indicated that the expression of SOST (sclerostin) was dramatically reduced in type XV patients compared to patients with COL1A1 quantitative variants. Single-cell transcriptome data generated from human tibia samples of patients diagnosed with type XV OI and leg-length discrepancy, respectively, revealed aberrant differentiation trajectories of skeletal progenitors and impaired maturation of osteocytes with loss of WNT1, resulting in excessive CXCL12+ progenitors, fewer mature osteocytes, and the existence of abnormal cell populations with adipogenic characteristics. The integration of multi-omics data from human skeleton delineates how WNT1 regulates the differentiation and maturation of skeletal progenitors, which will provide a new direction for the treatment strategy of type XV OI and relative low bone mass diseases such as early onset osteoporosis.
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Affiliation(s)
- Zhijia Tan
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
- Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China
- Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Peikai Chen
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
- Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- The AI and Big Data Lab, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
| | - Jianan Zhang
- Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Hiu Tung Shek
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
- Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China
| | - Zeluan Li
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
- Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China
| | - Xinlin Zhou
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
| | - Yapeng Zhou
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
- Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China
| | - Shijie Yin
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
- Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China
| | - Lina Dong
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
- Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China
| | - Lin Feng
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
- Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China
| | - Janus Siu Him Wong
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
- Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China
- Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Bo Gao
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
- Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Michael Kai Tsun To
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
- Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518083, China
- Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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Chen J, Ying Y, Li H, Sha Z, Lin J, Wu Y, Wu Y, Zhang Y, Chen X, Zhang W. Abnormal dental follicle cells: A crucial determinant in tooth eruption disorders (Review). Mol Med Rep 2024; 30:168. [PMID: 39027997 DOI: 10.3892/mmr.2024.13292] [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: 05/16/2024] [Accepted: 06/20/2024] [Indexed: 07/20/2024] Open
Abstract
The dental follicle (DF) plays an indispensable role in tooth eruption by regulating bone remodeling through their influence on osteoblast and osteoclast activity. The process of tooth eruption involves a series of intricate regulatory mechanisms and signaling pathways. Disruption of the parathyroid hormone‑related protein (PTHrP) in the PTHrP‑PTHrP receptor signaling pathway inhibits osteoclast differentiation by DF cells (DFCs), thus resulting in obstructed tooth eruption. Furthermore, parathyroid hormone receptor‑1 mutations are linked to primary tooth eruption failure. Additionally, the Wnt/β‑catenin, TGF‑β, bone morphogenetic protein and Hedgehog signaling pathways have crucial roles in DFC involvement in tooth eruption. DFC signal loss or alteration inhibits osteoclast differentiation, affects osteoblast and cementoblast differentiation, and suppresses DFC proliferation, thus resulting in failed tooth eruptions. Abnormal tooth eruption is also associated with a range of systemic syndromes and genetic diseases, predominantly resulting from pathogenic gene mutations. Among these conditions, the following disorders arise due to genetic mutations that disrupt DFCs and impede proper tooth eruption: Cleidocranial dysplasia associated with Runt‑related gene 2 gene mutations; osteosclerosis caused by CLCN7 gene mutations; mucopolysaccharidosis type VI resulting from arylsulfatase B gene mutations; enamel renal syndrome due to FAM20A gene mutations; and dentin dysplasia caused by mutations in the VPS4B gene. In addition, regional odontodysplasia and multiple calcific hyperplastic DFs are involved in tooth eruption failure; however, they are not related to gene mutations. The specific mechanism for this effect requires further investigation. To the best of our knowledge, previous reviews have not comprehensively summarized the syndromes associated with DF abnormalities manifesting as abnormal tooth eruption. Therefore, the present review aims to consolidate the current knowledge on DFC signaling pathways implicated in abnormal tooth eruption, and their association with disorders of tooth eruption in genetic diseases and syndromes, thereby providing a valuable reference for future related research.
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Affiliation(s)
- Jiahao Chen
- Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Ying Ying
- Department of Child Health, Yongkang Women and Children's Health Hospital, Yongkang, Zhejiang 321300, P.R. China
| | - Huimin Li
- Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Zhuomin Sha
- Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Jiaqi Lin
- Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Yongjia Wu
- Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Yange Wu
- Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Yun Zhang
- Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Xuepeng Chen
- Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Weifang Zhang
- Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
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10
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Iwamoto N, Sato S, Furukawa K, Michitsuji T, Shiraishi K, Watanabe K, Chiba K, Osaki M, Kawakami A. Association of denosumab with serum cytokines, chemokines, and bone-related factors in patients with rheumatoid arthritis: A post hoc analysis of a multicentre, open-label, randomised, parallel-group study. Mod Rheumatol 2024; 34:936-946. [PMID: 38226481 DOI: 10.1093/mr/roae002] [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: 10/25/2023] [Revised: 12/12/2023] [Accepted: 12/26/2023] [Indexed: 01/17/2024]
Abstract
OBJECTIVES To clarify changes in serum cytokines, chemokines, and bone-related factors during denosumab treatment in rheumatoid arthritis (RA) patients. METHODS This was a post hoc analysis of a multicentre, open-label, randomised, parallel-group study. Patients were randomly assigned to continue treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) plus receive treatment with denosumab (csDMARDs plus denosumab group) or to continue treatment with csDMARD therapy alone for 12 months. Serum biomarker levels were measured at baseline and at 6 and 12 months. RESULTS Baseline and 6-month data from the csDMARDs plus denosumab (n = 22) and csDMARD therapy alone (n = 22) groups were analysed. Statistically significant changes from baseline were seen: Dickkopf-related protein 1 decreased at 6 and 12 months (both groups); osteopontin decreased at 6 months in the csDMARDs plus denosumab group; osteopontin and soluble CD40 ligand increased at 6 and 12 months in the csDMARD therapy alone group; osteocalcin decreased at 6 and 12 months, epidermal growth factor decreased at 12 months, and macrophage-derived chemokine decreased at 6 months in the csDMARDs plus denosumab group; and interferon gamma-induced protein-10 increased at 12 months in the csDMARD therapy alone group. CONCLUSIONS Denosumab may inhibit bone destruction by suppressing bone-related factors/chemokines.
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Affiliation(s)
- Naoki Iwamoto
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Shuntaro Sato
- Clinical Research Center, Nagasaki University Hospital, Nagasaki, Japan
| | - Kaori Furukawa
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Toru Michitsuji
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kazuteru Shiraishi
- Department of Orthopedic Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kounosuke Watanabe
- Department of Orthopedic Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Ko Chiba
- Department of Orthopedic Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Makoto Osaki
- Department of Orthopedic Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Atsushi Kawakami
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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11
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Hu L, Chen W, Qian A, Li YP. Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and disease. Bone Res 2024; 12:39. [PMID: 38987555 PMCID: PMC11237130 DOI: 10.1038/s41413-024-00342-8] [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: 12/10/2023] [Revised: 04/27/2024] [Accepted: 05/12/2024] [Indexed: 07/12/2024] Open
Abstract
Wnts are secreted, lipid-modified proteins that bind to different receptors on the cell surface to activate canonical or non-canonical Wnt signaling pathways, which control various biological processes throughout embryonic development and adult life. Aberrant Wnt signaling pathway underlies a wide range of human disease pathogeneses. In this review, we provide an update of Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and diseases. The Wnt proteins, receptors, activators, inhibitors, and the crosstalk of Wnt signaling pathways with other signaling pathways are summarized and discussed. We mainly review Wnt signaling functions in bone formation, homeostasis, and related diseases, and summarize mouse models carrying genetic modifications of Wnt signaling components. Moreover, the therapeutic strategies for treating bone diseases by targeting Wnt signaling, including the extracellular molecules, cytosol components, and nuclear components of Wnt signaling are reviewed. In summary, this paper reviews our current understanding of the mechanisms by which Wnt signaling regulates bone formation, homeostasis, and the efforts targeting Wnt signaling for treating bone diseases. Finally, the paper evaluates the important questions in Wnt signaling to be further explored based on the progress of new biological analytical technologies.
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Affiliation(s)
- Lifang Hu
- Laboratory for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Laboratory for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China
| | - Wei Chen
- Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, LA, 70112, USA
| | - Airong Qian
- Laboratory for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Laboratory for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China.
| | - Yi-Ping Li
- Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, LA, 70112, USA.
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12
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Caviness PC, Lazarenko OP, Blackburn ML, Chen JF, Randolph CE, Zabaleta J, Zhan F, Chen JR. Phenolic acids prevent sex-steroid deficiency-induced bone loss and bone marrow adipogenesis in mice. J Nutr Biochem 2024; 127:109601. [PMID: 38367948 DOI: 10.1016/j.jnutbio.2024.109601] [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: 09/20/2023] [Revised: 01/19/2024] [Accepted: 02/12/2024] [Indexed: 02/19/2024]
Abstract
Phenolic acids, such as hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3-PPA), can be produced from microbiome digestion of polyphenols. Previously it was found that HA and 3-3-PPA facilitate bone formation and suppress bone resorption. However, the mechanism of action by which HA and 3-3-PPA protect bone from degeneration is currently unknown. In this report, we present that HA and 3-3-PPA suppression of bone resorption is able to ameliorate bone loss in an ovariectomy (OVX) osteopenic mouse model though not to the extent of Zoledronic acid (ZA). HA and 3-3-PPA treatments were shown to significantly decrease bone marrow adipocyte-like cell formation and inhibited gene expression of key adipogenesis regulator peroxisome proliferator activated receptor gamma (PPARγ) and lipoprotein lipase (Lpl) in bone from OVX mice. In addition, ChIP experiments showed that the association between PPARγ and Lpl promoter region in preadipocyte-like cells was significantly suppressed following HA or 3-3-PPA treatment. Contrasting HA and 3-3-PPA, ZA significantly increased TRAP activity in the area close to growth plate and significantly suppressed bone cell proliferation. These data suggest that phenolics acids such as HA or 3-3-PPA may prevent bone degeneration after OVX through suppression of inflammatory milieu in the bone.
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Affiliation(s)
- Perry C Caviness
- Arkansas Children's Nutrition Center, Little Rock, Arkansas 72205, USA; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
| | - Oxana P Lazarenko
- Arkansas Children's Nutrition Center, Little Rock, Arkansas 72205, USA; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
| | - Michael L Blackburn
- Arkansas Children's Nutrition Center, Little Rock, Arkansas 72205, USA; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
| | - Jennifer F Chen
- Undergraduate Pre-Medical Program, University of Arkansas at Fayetteville, Fayetteville, Arkansas 72701, USA
| | - Christopher E Randolph
- Center for Translational Pediatric Research, Arkansas Children's Research Institute, Little Rock, Arkansas 72202, USA
| | - Jovanny Zabaleta
- Department of Interdisciplinary Oncology, Louisiana State University Health Sciences Center, New Orleans, Los Angeles 70112, USA
| | - Fenghuang Zhan
- Myeloma Center, Winthrop P. Rockefeller Cancer Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Jin-Ran Chen
- Arkansas Children's Nutrition Center, Little Rock, Arkansas 72205, USA; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
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13
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Zhang L, Guan Q, Wang Z, Feng J, Zou J, Gao B. Consequences of Aging on Bone. Aging Dis 2023; 15:2417-2452. [PMID: 38029404 PMCID: PMC11567267 DOI: 10.14336/ad.2023.1115] [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: 09/21/2023] [Accepted: 11/16/2023] [Indexed: 12/01/2023] Open
Abstract
With the aging of the global population, the incidence of musculoskeletal diseases has been increasing, seriously affecting people's health. As people age, the microenvironment within skeleton favors bone resorption and inhibits bone formation, accompanied by bone marrow fat accumulation and multiple cellular senescence. Specifically, skeletal stem/stromal cells (SSCs) during aging tend to undergo adipogenesis rather than osteogenesis. Meanwhile, osteoblasts, as well as osteocytes, showed increased apoptosis, decreased quantity, and multiple functional limitations including impaired mechanical sensing, intercellular modulation, and exosome secretion. Also, the bone resorption function of macrophage-lineage cells (including osteoclasts and preosteoclasts) was significantly enhanced, as well as impaired vascularization and innervation. In this study, we systematically reviewed the effect of aging on bone and the within microenvironment (including skeletal cells as well as their intracellular structure variations, vascular structures, innervation, marrow fat distribution, and lymphatic system) caused by aging, and mechanisms of osteoimmune regulation of the bone environment in the aging state, and the causal relationship with multiple musculoskeletal diseases in addition with their potential therapeutic strategy.
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Affiliation(s)
- Lingli Zhang
- College of Athletic Performance, Shanghai University of Sport, Shanghai, China
| | - Qiao Guan
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Zhikun Wang
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Jie Feng
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Jun Zou
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Bo Gao
- Department of Orthopedic Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
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14
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Yamanouchi D, Igari K. The inhibition of Wnt signaling attenuates RANKL-induced osteoclastogenic macrophage activation. VASCULAR BIOLOGY (BRISTOL, ENGLAND) 2023; 5:e230007. [PMID: 37314315 PMCID: PMC10390850 DOI: 10.1530/vb-23-0007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 06/14/2023] [Indexed: 06/15/2023]
Abstract
Abdominal aortic aneurysms (AAAs) have been linked to the activation of osteoclastogenic macrophages. Reports have suggested that Wnt signaling has a dual effect of proliferation and differentiation during osteoclastogenesis. The Wnt/β-Catenin pathway is a critical regulator of cell pluripotency, cell survival, and cell fate decisions. It regulates cell proliferation and differentiation through transcriptional co-activators, CBP, and p300, respectively. The inhibition of β-catenin suppresses proliferation but induces differentiation of osteoclast precursor cells. This study aimed to examine the effect of ICG-001, a β-catenin/CBP-specific Wnt signaling inhibitor, on osteoclastogenesis by inhibiting proliferation without inducing differentiation. To induce osteoclastogenesis, RAW 264.7 macrophages were stimulated with a soluble receptor activator of NF-κB ligand (RANKL). The effect of Wnt signaling inhibition was examined by treating macrophages with or without ICG-001 during RANKL stimulation. The activation and differentiation of macrophages were examined through western blotting, quantitative PCR, and tartrate-resistant acid phosphate (TRAP) staining in vitro. The relative expression level of the nuclear factor of activated T-cells cytoplasmic 1 protein was significantly suppressed by ICG-001 treatment. The relative expression levels of mRNA of TRAP, cathepsin K, and matrix metalloproteinase-9 were significantly lower in the ICG-001-treated group. The number of TRAP-positive cells decreased in the ICG-001-treated group relative to the non-treated group. The inhibition of Wnt signaling pathway via ICG-001 suppressed osteoclastogenic macrophage activation. Our previous studies have shown the importance of osteoclastogenic macrophage activation in AAA. Further research to examine the therapeutic potential of ICG-001 on AAA is warranted.
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Affiliation(s)
- Dai Yamanouchi
- Department of Surgery, Division of Vascular Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
- Department of Vascular Surgery, Fujita Health University, Toyoake City, Japan
| | - Kimihiro Igari
- Department of Surgery, Division of Vascular Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
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15
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Simic MK, Mohanty ST, Xiao Y, Cheng TL, Taylor VE, Charlat O, Croucher PI, McDonald MM. Multi-Targeting DKK1 and LRP6 Prevents Bone Loss and Improves Fracture Resistance in Multiple Myeloma. J Bone Miner Res 2023; 38:814-828. [PMID: 36987921 PMCID: PMC10947379 DOI: 10.1002/jbmr.4809] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 03/01/2023] [Accepted: 03/21/2023] [Indexed: 03/30/2023]
Abstract
An imbalance between bone resorption and bone formation underlies the devastating osteolytic lesions and subsequent fractures seen in more than 90% of multiple myeloma (MM) patients. Currently, Wnt-targeted therapeutic agents that prevent soluble antagonists of the Wnt signaling pathway, sclerostin (SOST) and dickkopf-1 (DKK1), have been shown to prevent bone loss and improve bone strength in preclinical models of MM. In this study, we show increasing Wnt signaling via a novel anti-low-density lipoprotein receptor-related protein 6 (LRP6) antibody, which potentiates Wnt1-class ligand signaling through binding the Wnt receptor LRP6, prevented the development of myeloma-induced bone loss primarily through preventing bone resorption. When combined with an agent targeting the soluble Wnt antagonist DKK1, we showed more robust improvements in bone structure than anti-LRP6 treatment alone. Micro-computed tomography (μCT) analysis demonstrated substantial increases in trabecular bone volume in naïve mice given the anti-LRP6/DKK1 combination treatment strategy compared to control agents. Mice injected with 5TGM1eGFP murine myeloma cells had significant reductions in trabecular bone volume compared to naïve controls. The anti-LRP6/DKK1 combination strategy significantly improved bone volume in 5TGM1-bearing mice by 111%, which was also superior to anti-LRP6 single treatment; with similar bone structural changes observed within L4 lumbar vertebrae. Consequently, this combination strategy significantly improved resistance to fracture in lumbar vertebrae in 5TGM1-bearing mice compared to their controls, providing greater protection against fracture compared to anti-LRP6 antibody alone. Interestingly, these improvements in bone volume were primarily due to reduced bone resorption, with significant reductions in osteoclast numbers and osteoclast surface per bone surface demonstrated in 5TGM1-bearing mice treated with the anti-LRP6/DKK1 combination strategy. Importantly, Wnt stimulation with either single or combined Wnt-targeted agents did not exacerbate tumor activity. This work provides a novel approach of targeting both membrane-bound and soluble Wnt pathway components to provide superior skeletal outcomes in patients with multiple myeloma and other bone destructive cancers. © 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)
- Marija K. Simic
- Skeletal Diseases ProgramGarvan Institute of Medical ResearchDarlinghurstNSWAustralia
- St Vincent's Clinical Campus, School of Clinical MedicineUniversity of New South WalesKensingtonNSWAustralia
| | - Sindhu T. Mohanty
- Skeletal Diseases ProgramGarvan Institute of Medical ResearchDarlinghurstNSWAustralia
| | - Ya Xiao
- Skeletal Diseases ProgramGarvan Institute of Medical ResearchDarlinghurstNSWAustralia
| | - Tegan L. Cheng
- Centre for Children's Bone and Musculoskeletal HealthThe Children's Hospital at WestmeadWestmeadNSWAustralia
| | - Victoria E. Taylor
- Skeletal Diseases ProgramGarvan Institute of Medical ResearchDarlinghurstNSWAustralia
| | - Olga Charlat
- Novartis Institutes for Biomedical ResearchCambridgeMAUSA
| | - Peter I. Croucher
- Skeletal Diseases ProgramGarvan Institute of Medical ResearchDarlinghurstNSWAustralia
- St Vincent's Clinical Campus, School of Clinical MedicineUniversity of New South WalesKensingtonNSWAustralia
| | - Michelle M. McDonald
- Skeletal Diseases ProgramGarvan Institute of Medical ResearchDarlinghurstNSWAustralia
- St Vincent's Clinical Campus, School of Clinical MedicineUniversity of New South WalesKensingtonNSWAustralia
- School of Medical Science, Faculty of Medicine and HealthThe University of SydneySydneyNSWAustralia
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16
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Messina OD, Vidal M, Adami G, Vidal LF, Clark P, Torres JAM, Lems W, Zerbini C, Arguissain C, Reginster JY, Lane NE. Chronic arthritides and bone structure: focus on rheumatoid arthritis-an update. Aging Clin Exp Res 2023:10.1007/s40520-023-02432-9. [PMID: 37222927 DOI: 10.1007/s40520-023-02432-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 05/01/2023] [Indexed: 05/25/2023]
Abstract
Normal bone remodeling depends of a balance between bone forming cells, osteoblasts and bone resorbing cells, the osteoclasts. In chronic arthritides and some inflammatory and autoimmune diseases such as rheumatoid arthritis, there is a great constellation of cytokines produced by pannus that impair bone formation and stimulate bone resorption by inducing osteoclast differentiation and inhibiting osteoblast maturation. Patients with chronic inflammation have multiple causes that lead to low bone mineral density, osteoporosis and a high risk of fracture including circulating cytokines, impaired mobility, chronic administration of glucocorticoids, low vitamin D levels and post-menopausal status in women, among others. Biologic agents and other therapeutic measures to reach prompt remission might ameliorate these deleterious effects. In many cases, bone acting agents need to be added to conventional treatment to reduce the risk of fractures and to preserve articular integrity and independency for daily living activities. A limited number of studies related to fractures in chronic arthritides were published, and future investigation is needed to determine the risk of fractures and the protective effects of different treatments to reduce this risk.
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Affiliation(s)
- Osvaldo Daniel Messina
- Collaborating Centre WHO, Investigaciones Reumatológicas y Osteológicas (IRO), Buenos Aires, Argentina
- International Osteoporosis Foundation (IOF), Buenos Aires, Argentina
| | - Maritza Vidal
- Centro de Diagnóstico de Osteoporosis y Enfermedades Reumáticas (CEDOR), Lima, Peru.
| | - Giovanni Adami
- Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy
| | - Luis Fernando Vidal
- Centro de Diagnóstico de Osteoporosis y Enfermedades Reumáticas (CEDOR), Lima, Peru
- Regional Advisory Council for Latin America - International Osteoporosis Foundation (IOF), Lima, Peru
| | - Patricia Clark
- International Osteoporosis Foundation (IOF), Buenos Aires, Argentina
- Chief of Clinical Epidemiology Unit-Hospital Federico Gomez School of Medicine UNAM, Mexico City, Mexico
| | | | - William Lems
- Department of Rheumatology, Amsterdam UMC, Location VU University Medical Centre Amsterdam, Amsterdam, North-Holland, The Netherlands
| | | | - Constanza Arguissain
- Collaborating Centre WHO, Investigaciones Reumatológicas y Osteológicas (IRO), Buenos Aires, Argentina
| | - Jean-Yves Reginster
- Division of Public Health, Epidemiology and Health Economics, WHO Collaborating Centre for Public Health, Aspects of Musculoskeletal Health and Ageing, University of Liege, Liege, Belgium
| | - Nancy E Lane
- Center for Musculoskeletal Health, University of California at Davis School of Medicine, Sacramento, CA, 95817, USA
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17
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Bao K, Jiao Y, Xing L, Zhang F, Tian F. The role of wnt signaling in diabetes-induced osteoporosis. Diabetol Metab Syndr 2023; 15:84. [PMID: 37106471 PMCID: PMC10141960 DOI: 10.1186/s13098-023-01067-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 04/24/2023] [Indexed: 04/29/2023] Open
Abstract
Osteoporosis, a chronic complication of diabetes mellitus, is characterized by a reduction in bone mass, destruction of bone microarchitecture, decreased bone strength, and increased bone fragility. Because of its insidious onset, osteoporosis renders patients highly susceptible to pathological fractures, leading to increased disability and mortality rates. However, the specific pathogenesis of osteoporosis induced by chronic hyperglycemia has not yet been fully elucidated. But it is currently known that the disruption of Wnt signaling triggered by chronic hyperglycemia is involved in the pathogenesis of diabetic osteoporosis. There are two main types of Wnt signaling pathways, the canonical Wnt signaling pathway (β-catenin-dependent) and the non-canonical Wnt signaling pathway (non-β-catenin-dependent), both of which play an important role in regulating the balance between bone formation and bone resorption. Therefore, this review systematically describes the effects of abnormal Wnt pathway signaling on bone homeostasis under hyperglycemia, hoping to reveal the relationship between Wnt signaling and diabetic osteoporosis to further improve understanding of this disease.
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Affiliation(s)
- Kairan Bao
- Department of Integrated Traditional & Western Medicine, Affiliated hospital of North, China University of Science and Technology, Jianshe South Road 73, Tangshan, 063000, Hebei, People's Republic of China.
| | - Yinghua Jiao
- Department of Integrated Traditional & Western Medicine, Affiliated hospital of North, China University of Science and Technology, Jianshe South Road 73, Tangshan, 063000, Hebei, People's Republic of China
- North China University of Science and Technology, Bohai Road 21, Caofeidian Dis, Tangshan, 063210, Hebei, People's Republic of China
| | - Lei Xing
- Department of Integrated Traditional & Western Medicine, Affiliated hospital of North, China University of Science and Technology, Jianshe South Road 73, Tangshan, 063000, Hebei, People's Republic of China
| | - Fang Zhang
- Department of Integrated Traditional & Western Medicine, Affiliated hospital of North, China University of Science and Technology, Jianshe South Road 73, Tangshan, 063000, Hebei, People's Republic of China
| | - Faming Tian
- Department of Integrated Traditional & Western Medicine, Affiliated hospital of North, China University of Science and Technology, Jianshe South Road 73, Tangshan, 063000, Hebei, People's Republic of China
- North China University of Science and Technology, Bohai Road 21, Caofeidian Dis, Tangshan, 063210, Hebei, People's Republic of China
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Chen J, Xu W, Song K, Da LT, Zhang X, Lin M, Hong X, Zhang S, Guo F. Legumain inhibitor prevents breast cancer bone metastasis by attenuating osteoclast differentiation and function. Bone 2023; 169:116680. [PMID: 36702335 DOI: 10.1016/j.bone.2023.116680] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 12/16/2022] [Accepted: 01/20/2023] [Indexed: 01/26/2023]
Abstract
Breast cancer is the main lethal disease among females, and metastasis to lung and bone poses a serious threat to patients' life. Therefore, identification of novel molecular mediators that can potentially be exploited as therapeutic targets for treating osteolytic bone metastases is needed. A murine model of breast cancer bone metastasis was developed by injection of 4 T1.2 cells into the left ventricle and hence directly into the arterial system leading to bone. AEP (Asparagine endopeptidase) inhibitor combined with epirubicin or epirubicin alone was administered by intraperitoneal injection into animal model. The presence of bone metastatic and osteolytic lesions in bone were assessed by bioluminescent imaging and X-rays analysis. The expression of EMT (Epithelial-Mesenchymal Transition) relevant genes were examined by Western blotting. Cell migration and invasion were investigated with a transwell assay. Compound BIC-113, small molecule inhibitors of AEP, inhibited AEP enzymatic activity in breast cancer cell lines, and affected invasion and migration of cancer cells, but had no effect on cell growth. In animal model of breast cancer bone metastasis, compound BIC-113 combined with epirubicin inhibited breast cancer bone metastasis and attenuated breast cancer osteolytic lesions in bone by inhibiting osteoclast differentiation and EMT. These results indicate that compound BIC-113 combined with epirubicin has the potential to be used in breast cancer therapy by preventing bone metastasis via improving E-cadherin expression and inhibition of osteoclast formation.
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Affiliation(s)
- Junsong Chen
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Wenke Xu
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Kaiyuan Song
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Lin-Tai Da
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Xin Zhang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Mengyao Lin
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Xiaowu Hong
- Department of Immunology, School of basic medical sciences, Fudan University, No.138, Yixueyuan Road, Xuhui District, Shanghai 200032, China
| | - Sheng Zhang
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Chazhong Road, Fuzhou 350000, China.
| | - Fang Guo
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
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19
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Gill AK, McCormick PJ, Sochart D, Nalesso G. Wnt signalling in the articular cartilage: A matter of balance. Int J Exp Pathol 2023; 104:56-63. [PMID: 36843204 PMCID: PMC10009303 DOI: 10.1111/iep.12472] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 01/30/2023] [Accepted: 02/04/2023] [Indexed: 02/28/2023] Open
Abstract
Degradation of the articular cartilage is a hallmark of osteoarthritis, a progressive and chronic musculoskeletal condition, affecting millions of people worldwide. The activation of several signalling cascades is altered during disease development: among them, the Wnt signalling plays a pivotal role in the maintenance of tissue homeostasis. Increasing evidence is showing that its activation needs to be maintained within a certain range to avoid the triggering of degenerative mechanisms. In this review, we summarise our current knowledge about how a balanced activation of the Wnt signalling is maintained in the articular cartilage, with a particular focus on receptor-mediated mechanisms.
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Affiliation(s)
- Amandeep Kaur Gill
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary, University of London, London, UK
| | - Peter J McCormick
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary, University of London, London, UK
| | - David Sochart
- South West London Elective Orthopaedic Centre, Epsom, UK
| | - Giovanna Nalesso
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, University of Surrey, Guildford, UK
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20
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Wang Y, Gan Y, Dong Y, Zhou J, Zhu E, Yuan H, Li X, Wang B. Tax1 binding protein 3 regulates osteogenic and adipogenic differentiation through inactivating Wnt/β-catenin signalling. J Cell Mol Med 2023; 27:950-961. [PMID: 36892460 PMCID: PMC10064035 DOI: 10.1111/jcmm.17702] [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: 09/21/2021] [Revised: 02/09/2023] [Accepted: 02/15/2023] [Indexed: 03/10/2023] Open
Abstract
Tax1 binding protein 3 (Tax1bp3) is a PDZ domain-containing protein that is overexpressed in cancer. Previous studies recognized Tax1bp3 as an inhibitor of β-catenin. Till now it is not known whether Tax1bp3 regulates osteogenic and adipogenic differentiation of mesenchymal progenitor cells. In the current study, the data showed that Tax1bp3 was expressed in bone and was increased in the progenitor cells when induced toward osteoblast and adipocyte differentiation. The overexpression of Tax1bp3 in the progenitor cells inhibited osteogenic differentiation and conversely stimulated adipogenic differentiation, and the knockdown of Tax1bp3 affected the differentiation of the progenitor cells oppositely. Ex vivo experiments using the primary calvarial osteoblasts from osteoblast-specific Tax1bp3 knock-in mice also demonstrated the anti-osteogenic and pro-adipogenic function of Tax1bp3. Mechanistic investigations revealed that Tax1bp3 inhibited the activation of canonical Wnt/β-catenin and bone morphogenetic proteins (BMPs)/Smads signalling pathways. Taken together, the current study has provided evidences demonstrating that Tax1bp3 inactivates Wnt/β-catenin and BMPs/Smads signalling pathways and reciprocally regulates osteogenic and adipogenic differentiation from mesenchymal progenitor cells. The inactivation of Wnt/β-catenin signalling may be involved in the reciprocal role of Tax1bp3.
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Affiliation(s)
- Yi Wang
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien‐I Memorial Hospital & Institute of EndocrinologyTianjin Medical UniversityTianjinChina
| | - Ying Gan
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien‐I Memorial Hospital & Institute of EndocrinologyTianjin Medical UniversityTianjinChina
| | - Yuan Dong
- College of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Jie Zhou
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien‐I Memorial Hospital & Institute of EndocrinologyTianjin Medical UniversityTianjinChina
| | - Endong Zhu
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien‐I Memorial Hospital & Institute of EndocrinologyTianjin Medical UniversityTianjinChina
| | - Hairui Yuan
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien‐I Memorial Hospital & Institute of EndocrinologyTianjin Medical UniversityTianjinChina
| | - Xiaoxia Li
- College of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Baoli Wang
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien‐I Memorial Hospital & Institute of EndocrinologyTianjin Medical UniversityTianjinChina
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21
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Choi H, Yang L, Liu Y, Jeong JK, Cho ES. Inactivation of Sufu in cementoblasts accelerates external tooth root resorption. J Cell Physiol 2023; 238:447-458. [PMID: 36598878 DOI: 10.1002/jcp.30943] [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: 09/28/2022] [Revised: 12/20/2022] [Accepted: 12/24/2022] [Indexed: 01/05/2023]
Abstract
Cementum has been empirically regarded as an antiresorptive barrier against tooth roots. However, little is known about the factors of homeostasis and resistant mechanisms of tooth roots against resorption. Here, we investigated cementum factors and their interaction against resorption using transgenic mice exhibiting external cervical root resorption (ECRR). Ectopically thickened cervical cementum caused by functional inactivation of ectonucleotide pyrophosphotase/phosphodiesterase 1 (Enpp1) was susceptible to ECRR with aging. In addition, the inactivation of the suppressor of fused (Sufu), a Hedgehog signaling inhibitor, in cementoblasts led to ECRR. Interestingly, concurrent inactivation of Sufu and Enpp1 in cementoblasts remarkably exacerbated ECRR with higher Rankl expression. Cellular and molecular analyses using cementoblasts and bone marrow-derived macrophages indicated that Dickkopf-related protein 1 (Dkk1) induced by the inactivation of Sufu in cementoblasts has roles in the acceleration of ECRR triggered by Enpp1 inactivation. Using compound mutant mice for concurrent Wntless and Enpp1 inactivation, this synergistic cooperation of Dkk1 and Npp1 for resorption found in double mutant Sufu and Enpp1 mice was confirmed by the reproduction of amplified ECRR. On the basis of these findings, we conclude that proper Npp1 function and sustained Wnt activity in the cervical cementum are essential for the homeostasis of tooth roots against resorption in a physiological state.
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Affiliation(s)
- Hwajung Choi
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju, South Korea
| | - Liu Yang
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju, South Korea
| | - Yudong Liu
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju, South Korea
| | - Ju-Kyung Jeong
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju, South Korea
| | - Eui-Sic Cho
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju, South Korea
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22
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Abstract
Changes in bone architecture and metabolism with aging increase the likelihood of osteoporosis and fracture. Age-onset osteoporosis is multifactorial, with contributory extrinsic and intrinsic factors including certain medical problems, specific prescription drugs, estrogen loss, secondary hyperparathyroidism, microenvironmental and cellular alterations in bone tissue, and mechanical unloading or immobilization. At the histological level, there are changes in trabecular and cortical bone as well as marrow cellularity, lineage switching of mesenchymal stem cells to an adipogenic fate, inadequate transduction of signals during skeletal loading, and predisposition toward senescent cell accumulation with production of a senescence-associated secretory phenotype. Cumulatively, these changes result in bone remodeling abnormalities that over time cause net bone loss typically seen in older adults. Age-related osteoporosis is a geriatric syndrome due to the multiple etiologies that converge upon the skeleton to produce the ultimate phenotypic changes that manifest as bone fragility. Bone tissue is dynamic but with tendencies toward poor osteoblastic bone formation and relative osteoclastic bone resorption with aging. Interactions with other aging physiologic systems, such as muscle, may also confer detrimental effects on the aging skeleton. Conversely, individuals who maintain their BMD experience a lower risk of fractures, disability, and mortality, suggesting that this phenotype may be a marker of successful aging. © 2023 American Physiological Society. Compr Physiol 13:4355-4386, 2023.
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Affiliation(s)
- Robert J Pignolo
- Department of Medicine, Divisions of Geriatric Medicine and Gerontology, Endocrinology, and Hospital Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.,The Department of Physiology and Biomedical Engineering, and the Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA
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23
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Suzuki T, Mizobuchi M, Yoshida S, Terado N, Aoki S, Sato N, Honda H. Romosozumab successfully regulated progressive osteoporosis in a patient with autosomal dominant polycystic kidney disease undergoing hemodialysis. Osteoporos Int 2022; 33:2649-2652. [PMID: 35980440 DOI: 10.1007/s00198-022-06534-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 08/13/2022] [Indexed: 10/15/2022]
Abstract
Osteoporosis is a crucial complication in patients with chronic kidney disease (CKD), similar to that in the general population. Although romosozumab, a monoclonal antibody targeting sclerostin, has been administered for patients with CKD, its clinical effectiveness in these patients, especially in patients on hemodialysis (HD), remains to be studied. Herein, we report the case of a 42-year-old man on HD who developed severe osteoporosis. Serum calcium levels were extremely high, bone metabolic markers were abnormal, and the patient had pathological fractures. The bone biopsy indicated a bone metabolism disorder and high bone turnover. We administered romosozumab once a month as an intervention for bone alteration. Through the 10-month usage, bone metabolic markers improved, and the decrease in bone mineral density was ameliorated. We hypothesized that romosozumab could be a therapeutic option for osteoporosis in patients undergoing HD, especially in those with bone mineralization disorders.
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Affiliation(s)
- Taihei Suzuki
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan.
| | - Masahide Mizobuchi
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan
| | - Shunsuke Yoshida
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan
| | - Narumi Terado
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan
| | - Shugo Aoki
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan
| | - Nozomi Sato
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan
| | - Hirokazu Honda
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan
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24
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Niu Q, Gao J, Wang L, Liu J, Zhang L. Regulation of differentiation and generation of osteoclasts in rheumatoid arthritis. Front Immunol 2022; 13:1034050. [PMID: 36466887 PMCID: PMC9716075 DOI: 10.3389/fimmu.2022.1034050] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 10/31/2022] [Indexed: 09/25/2023] Open
Abstract
INTRODUCTION Rheumatoid arthritis (RA), which affects nearly 1% of the world's population, is a debilitating autoimmune disease. Bone erosion caused by periarticular osteopenia and synovial pannus formation is the most destructive pathological changes of RA, also leads to joint deformity and loss of function,and ultimately affects the quality of life of patients. Osteoclasts (OCs) are the only known bone resorption cells and their abnormal differentiation and production play an important role in the occurrence and development of RA bone destruction; this remains the main culprit behind RA. METHOD Based on the latest published literature and research progress at home and abroad, this paper reviews the abnormal regulation mechanism of OC generation and differentiation in RA and the possible targeted therapy. RESULT OC-mediated bone destruction is achieved through the regulation of a variety of cytokines and cell-to-cell interactions, including gene transcription, epigenetics and environmental factors. At present, most methods for the treatment of RA are based on the regulation of inflammation, the inhibition of bone injury and joint deformities remains unexplored. DISCUSSION This article will review the mechanism of abnormal differentiation of OC in RA, and summarise the current treatment oftargeting cytokines in the process of OC generation and differentiation to reduce bone destruction in patients with RA, which isexpected to become a valuable treatment choice to inhibit bone destruction in RA.
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Affiliation(s)
- Qing Niu
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Jinfang Gao
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Lei Wang
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Jiaxi Liu
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Liyun Zhang
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
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25
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Wu M, Chen F, Liu H, Wu P, Yang Z, Zhang Z, Su J, Cai L, Zhang Y. Bioinspired sandwich-like hybrid surface functionalized scaffold capable of regulating osteogenesis, angiogenesis, and osteoclastogenesis for robust bone regeneration. Mater Today Bio 2022; 17:100458. [PMID: 36278143 PMCID: PMC9583582 DOI: 10.1016/j.mtbio.2022.100458] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/27/2022] [Accepted: 10/08/2022] [Indexed: 11/05/2022]
Abstract
Recently, strategies that focus on biofunctionalized implant surfaces to enhance bone defect healing through the synergistic regulation of osteogenesis, angiogenesis, and osteoclastogenesis have attracted increasing attention in the bone tissue engineering field. Studies have shown that the Wnt/β-catenin signaling pathway has an imperative effect of promoting osteogenesis and angiogenesis while reducing osteoclastogenesis. However, how to prepare biofunctionalized bone implants with balanced osteogenesis, angiogenesis, and osteoclastogenesis by activating the Wnt/β-catenin pathway has seldom been investigated. Herein, through a bioinspired dopamine chemistry and self-assembly method, BML-284 (BML), a potent and highly selective Wnt signaling activator, was loaded on a mussel-inspired polydopamine (PDA) layer that had been immobilized on the porous beta-tricalcium calcium phosphate (β-TCP) scaffold surface and subsequently modified by a biocompatible carboxymethyl chitosan hydrogel to form a sandwich-like hybrid surface. β-TCP provides a biomimetic three-dimensional porous microenvironment similar to that of natural cancellous bone, and the BML-loaded sandwich-like hybrid surface endows the scaffold with multifunctional properties for potential application in bone regeneration. The results show that the sustained release of BML from the sandwich-like hybrid surface significantly facilitates the adhesion, migration, proliferation, spreading, and osteogenic differentiation of MC3T3-E1 cells as well as the angiogenic activity of human umbilical vein endothelial cells. In addition to osteogenesis and angiogenesis, the hybrid surface also exerts critical roles in suppressing osteoclastic activity. Remarkably, in a critical-sized cranial defect model, the biofunctionalized β-TCP scaffold could potentially trigger a chain of biological events: stimulating the polarization of M2 macrophages, recruiting endogenous stem cells and endothelial cells at the injury site to enable a favorable microenvironment for greatly accelerating bone ingrowth and angiogenesis while compromising osteoclastogenesis, thereby promoting bone healing. Therefore, these surface-biofunctionalized β-TCP implants, which regulate the synergies of osteogenesis, angiogenesis, and anti-osteoclastogenesis, indicate strong potential for clinical application as advanced orthopedic implants.
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Affiliation(s)
- Minhao Wu
- Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, 168 Donghu Street, Wuchang District, Wuhan, 430071, Hubei, China
| | - Feixiang Chen
- Department of Biomedical Engineering and Hubei Province Key Laboratory of Allergy and Immune Related Diseases, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Huifan Liu
- Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, 168 Donghu Street, Wuchang District, Wuhan, 430071, Hubei, China
| | - Ping Wu
- College of Life Science and Technology Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Zhiqiang Yang
- Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, 168 Donghu Street, Wuchang District, Wuhan, 430071, Hubei, China
| | - Zhe Zhang
- National Demonstration Center for Experimental General Medicine Education, Xianning Medical College, Hubei University of Science and Technology, China
| | - Jiajia Su
- Department of Radiology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Corresponding author.
| | - Lin Cai
- Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, 168 Donghu Street, Wuchang District, Wuhan, 430071, Hubei, China,Corresponding author.
| | - Yufeng Zhang
- Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, 168 Donghu Street, Wuchang District, Wuhan, 430071, Hubei, China,Corresponding author.
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26
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Solorzano E, Alejo AL, Ball HC, Magoline J, Khalil Y, Kelly M, Safadi FF. Osteopathy in Complex Lymphatic Anomalies. Int J Mol Sci 2022; 23:ijms23158258. [PMID: 35897834 PMCID: PMC9332568 DOI: 10.3390/ijms23158258] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/07/2022] [Accepted: 07/16/2022] [Indexed: 11/16/2022] Open
Abstract
Complex Lymphatic Anomalies (CLA) are lymphatic malformations with idiopathic bone and soft tissue involvement. The extent of the abnormal lymphatic presentation and boney invasion varies between subtypes of CLA. The etiology of these diseases has proven to be extremely elusive due to their rarity and irregular progression. In this review, we compiled literature on each of the four primary CLA subtypes and discuss their clinical presentation, lymphatic invasion, osseous profile, and regulatory pathways associated with abnormal bone loss caused by the lymphatic invasion. We highlight key proliferation and differentiation pathways shared between lymphatics and bone and how these systems may interact with each other to stimulate lymphangiogenesis and cause bone loss.
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Affiliation(s)
- Ernesto Solorzano
- Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), Rootstown, OH 44272, USA; (E.S.); (A.L.A.); (H.C.B.); (J.M.); (Y.K.); (M.K.)
- Musculoskeletal Research Group, Northeast Ohio Medical University (NEOMED), Rootstown, OH 44272, USA
| | - Andrew L. Alejo
- Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), Rootstown, OH 44272, USA; (E.S.); (A.L.A.); (H.C.B.); (J.M.); (Y.K.); (M.K.)
- Musculoskeletal Research Group, Northeast Ohio Medical University (NEOMED), Rootstown, OH 44272, USA
| | - Hope C. Ball
- Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), Rootstown, OH 44272, USA; (E.S.); (A.L.A.); (H.C.B.); (J.M.); (Y.K.); (M.K.)
- Musculoskeletal Research Group, Northeast Ohio Medical University (NEOMED), Rootstown, OH 44272, USA
| | - Joseph Magoline
- Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), Rootstown, OH 44272, USA; (E.S.); (A.L.A.); (H.C.B.); (J.M.); (Y.K.); (M.K.)
- Musculoskeletal Research Group, Northeast Ohio Medical University (NEOMED), Rootstown, OH 44272, USA
| | - Yusuf Khalil
- Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), Rootstown, OH 44272, USA; (E.S.); (A.L.A.); (H.C.B.); (J.M.); (Y.K.); (M.K.)
- Musculoskeletal Research Group, Northeast Ohio Medical University (NEOMED), Rootstown, OH 44272, USA
| | - Michael Kelly
- Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), Rootstown, OH 44272, USA; (E.S.); (A.L.A.); (H.C.B.); (J.M.); (Y.K.); (M.K.)
- Department of Pediatric Hematology Oncology and Blood, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Fayez F. Safadi
- Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), Rootstown, OH 44272, USA; (E.S.); (A.L.A.); (H.C.B.); (J.M.); (Y.K.); (M.K.)
- Musculoskeletal Research Group, Northeast Ohio Medical University (NEOMED), Rootstown, OH 44272, USA
- Rebecca D. Considine Research Institute, Akron Children’s Hospital, Akron, OH 44308, USA
- School of Biomedical Sciences, Kent State University, Kent, OH 44243, USA
- Correspondence: ; Tel.: +1-330-325-6619
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27
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Deosthale P, Hong JM, Essex AL, Rodriguez W, Tariq D, Sidhu H, Marcial A, Bruzzaniti A, Plotkin LI. Sex-specific differences in direct osteoclastic versus indirect osteoblastic effects underlay the low bone mass of Pannexin1 deletion in TRAP-expressing cells in mice. Bone Rep 2022; 16:101164. [PMID: 35028339 PMCID: PMC8739454 DOI: 10.1016/j.bonr.2021.101164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/17/2021] [Accepted: 12/27/2021] [Indexed: 01/21/2023] Open
Abstract
Pannexin1 (Panx1) is a hemichannel-forming protein that participates in the communication of cells with the extracellular space. To characterize the role of osteoclastic Panx1 on bone, Panx1fl/fl;TRAP-Cre (Panx1ΔOc) mice were generated, and compared to Panx1fl/fl littermates at 6 weeks of age. Total and femoral BMD was ~20% lower in females and males whereas spinal BMD was lower only in female Panx1ΔOc mice. μCT analyses showed that cortical bone of the femoral mid-diaphysis was not altered in Panx1ΔOc mice. In contrast, cancellous bone in the distal femur and lumbar vertebra was significantly decreased in both female and male Panx1ΔOc mice compared to Panx1fl/fl controls and was associated with higher osteoclast activity in female Panx1ΔOc mice, with no changes in the males. On the other hand, vertebral bone formation was decreased for both sexes, resulting from lower mineral apposition rate in the females and lower mineralizing surface in the males. Consistent with an osteoclastic effect in female Panx1ΔOc mice, osteoclast differentiation with RANKL/M-CSF and osteoclast bone resorbing activity in vitro were higher in female, but not male, Panx1ΔOc mice, compared to Panx1fl/fl littermates. Surprisingly, although Panx1 expression was normal in bone marrow stromal-derived osteoblasts from male and female Panx1ΔOc mice, mineral deposition by male (but not female) Panx1ΔOc osteoblasts was lower than controls, and it was reduced in male Panx1fl/fl osteoblasts when conditioned media prepared from male Panx1ΔOc osteoclast cultures was added to the cell culture media. Thus, deletion of Panx1 in TRAP-expressing cells in female mice leads to low bone mass primarily through a cell autonomous effect in osteoclast activity. In contrast, our evidence suggests that changes in the osteoclast secretome drive reduced osteoblast function in male Panx1ΔOc mice, resulting in low bone mass.
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Affiliation(s)
- Padmini Deosthale
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, USA
- Roudebush Veterans Administration Medical Center, USA
| | - Jung Min Hong
- Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, USA
| | - Alyson L. Essex
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, USA
- Roudebush Veterans Administration Medical Center, USA
- Indiana Center for Musculoskeletal Health, Indianapolis, IN, USA
| | - Wilyaret Rodriguez
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, USA
| | - Dua Tariq
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, USA
| | - Harmandeep Sidhu
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, USA
| | - Alejandro Marcial
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, USA
| | - Angela Bruzzaniti
- Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, USA
- Indiana Center for Musculoskeletal Health, Indianapolis, IN, USA
| | - Lilian I. Plotkin
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, USA
- Roudebush Veterans Administration Medical Center, USA
- Indiana Center for Musculoskeletal Health, Indianapolis, IN, USA
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Effects of Biological/Targeted Therapies on Bone Mineral Density in Inflammatory Arthritis. Int J Mol Sci 2022; 23:ijms23084111. [PMID: 35456929 PMCID: PMC9029148 DOI: 10.3390/ijms23084111] [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: 03/02/2022] [Revised: 04/06/2022] [Accepted: 04/07/2022] [Indexed: 11/30/2022] Open
Abstract
Inflammatory arthritis has been reported to be associated with the development of osteoporosis. Recent research has investigated the mechanisms of bone metabolism in chronic inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis (SpA). Progress in both animal and clinical studies has provided a better understanding of the osteoclastogenesis-related pathways regarding the receptor activator of nuclear factor-κB ligand (RANKL), anti-citrullinated protein antibodies (ACPAs), and Wnt signaling and Dickkopf-related protein 1 (Dkk-1). The complex interplay between inflammatory cytokines and bone destruction has been elucidated, especially that in the interleukin-17/23 (IL-17/23) axis and Janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling. Moreover, advances in biological and targeted therapies have achieved essential modifications to the bone metabolism of these inflammatory arthritis types. In this narrative review, we discuss recent findings on the pathogenic effects on bone in RA and SpA. Proinflammatory cytokines, autoantibodies, and multiple signaling pathways play an essential role in bone destruction in RA and SpA patients. We also reviewed the underlying pathomechanisms of bone structure in biological and targeted therapies of RA and SpA. The clinical implications of tumor necrosis factor inhibitors, abatacept, rituximab, tocilizumab, Janus kinase inhibitors, and inhibitors of the IL-17/23 axis are discussed. Since these novel therapeutics provide new options for disease improvement and symptom control in patients with RA and SpA, further rigorous evidence is warranted to provide a clinical reference for physicians and patients.
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29
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Nam YS, Yang DW, Moon JS, Kang JH, Cho JH, Kim OS, Kim MS, Koh JT, Kim YJ, Kim SH. Sclerostin in Periodontal Ligament: Homeostatic Regulator in Biophysical Force-Induced Tooth Movement. J Clin Periodontol 2022; 49:932-944. [PMID: 35373367 DOI: 10.1111/jcpe.13624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 02/25/2022] [Accepted: 03/29/2022] [Indexed: 11/30/2022]
Abstract
AIM This study elucidates the role of sclerostin in periodontal ligament (PDL) as a homeostatic regulator in biophysical force-induced tooth movement (BFTM). MATERIALS AND METHODS BFTM was performed in rats, followed by microarray, immunofluorescence, in situ hybridization, and real-time PCR for detection and identification of the molecules. The periodontal space was analyzed via micro-computed tomography. Effects on osteoclastogenesis and bone resorption were evaluated in mouse bone marrow-derived cells. In vitro human PDL cells were subjected to biophysical forces. RESULTS In the absence of BFTM, sclerostin was hardly detected in the periodontium except the PDL and alveolar bone in the furcation region and apex of the molar roots. However, sclerostin was upregulated in the PDL in vivo by adaptable force, which induced typical transfiguration without changes in periodontal space as well as in vitro PDL cells under compression and tension. In contrast, the sclerostin level was unaffected by heavy force, which caused severe degeneration of the PDL and narrowed periodontal space. Sclerostin inhibited osteoclastogenesis and bone resorption, which corroborates the accelerated tooth movement by the heavy force. CONCLUSIONS Sclerostin in PDL may be a key homeostatic molecule in the periodontium and a biological target for the therapeutic modulation of BFTM. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Yoo-Sung Nam
- Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Korea
| | - Dong-Wook Yang
- Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Korea
| | - Jung-Sun Moon
- Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Korea
| | - Jee-Hae Kang
- Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Korea
| | - Jin-Hyoung Cho
- Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Korea
| | - Ok-Su Kim
- Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Korea
| | - Min-Seok Kim
- Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Korea
| | - Jeong-Tae Koh
- Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Korea
| | - Young-Jun Kim
- Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Korea
| | - Sun-Hun Kim
- Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Korea
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30
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Phoenix dactilyfera L. Pits Extract Restored Bone Homeostasis in Glucocorticoid-Induced Osteoporotic Animal Model through the Antioxidant Effect and Wnt5a Non-Canonical Signaling. Antioxidants (Basel) 2022; 11:antiox11030508. [PMID: 35326158 PMCID: PMC8944842 DOI: 10.3390/antiox11030508] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/01/2022] [Accepted: 03/04/2022] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress associated with long-term glucocorticoids administration is a route through which secondary osteoporosis can be developed. The therapeutic potential of Phoenix dactilyfera L. pits is offered by their balanced, valuable and diverse phytochemical composition providing protective potential against oxidative reactions, making it a good candidate to treat glucocorticoid-induced osteoporosis (GIO). This study evaluates the possible anti-osteoporotic effect of date pit extract (DPE) against dexamethasone (DEXA)-induced osteoporosis. Male rats were allocated into three control groups, which received saline, low and high doses of DPE (150 and 300 mg/kg/day), respectively. Osteoporosis-induced groups that received DEXA (1 mg/kg/day) were divided into DEXA only, DPE (2 doses) + DEXA, and ipriflavone + DEXA. Femoral bone minerals density and bone mineral content, bone oxidative stress markers, Wnt signaling, osteoblast and osteoclast differentiation markers, and femur histopathology were evaluated. DPE defeated the oxidative stress, resulting in ameliorative changes in Wnt signaling. DPE significantly reduced the adipogenicity and abolished the osteoclastogenic markers (RANKL/OPG ratio, ACP, TRAP) while enhancing the osteogenic differentiation markers (Runx2, Osx, COL1A1, OCN). In Conclusion DPE restored the balanced proliferation and differentiation of osteoclasts and osteoblasts precursors. DPE can be considered a promising remedy for GIO, especially at a low dose that had more potency.
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Abstract
Inflammation is among the major determinants of bone loss in chronic disease and aging. Bone metabolism is radically affected by inflammation with consequent bone loss and increased fracture risk. Various cytokines and mediators are involved in the pathogenesis of bone loss in inflammatory conditions. The present review has the aim of discussing the main pathways involved in the pathogenesis of bone loss in inflammatory diseases, focusing in particular on the Wnt system and its regulators. Literature review of studies published between inception to 2021 on osteoporosis and inflammation was conducted. I will discuss the epidemiology of osteoporosis and fractures in common inflammatory diseases. The molecular basis of bone loss related to inflammation will be discussed as well. Finally, the effects of various anti-inflammatory medications on bone metabolism will be reviewed.
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Affiliation(s)
- Giovanni Adami
- Rheumatology Unit, University of Verona, Pz Scuro 10, Verona, Italy.
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32
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McMullan P, Germain-Lee EL. Aberrant Bone Regulation in Albright Hereditary Osteodystrophy dueto Gnas Inactivation: Mechanisms and Translational Implications. Curr Osteoporos Rep 2022; 20:78-89. [PMID: 35226254 DOI: 10.1007/s11914-022-00719-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/06/2021] [Indexed: 11/03/2022]
Abstract
PURPOSE OF REVIEW This review highlights the impact of Gnas inactivation on both bone remodeling and the development of heterotopic subcutaneous ossifications in Albright hereditary osteodystrophy (AHO). Here we discuss recent advancements in understanding the pathophysiologic mechanisms of the aberrant bone development in AHO as well as potential translational implications. RECENT FINDINGS Gnas inactivation can regulate the differentiation and function of not only osteoblasts but also osteoclasts and osteocytes. Investigations utilizing a mouse model of AHO generated by targeted disruption of Gnas have revealed that bone formation and resorption are differentially affected based upon the parental origin of the Gnas mutation. Data suggest that Gnas inactivation leads to heterotopic bone formation within subcutaneous tissue by changing the connective tissue microenvironment, thereby promoting osteogenic differentiation of tissue-resident mesenchymal progenitors. Observed variations in bone formation and resorption based upon the parental origin of the Gnas mutation warrant future investigations and may have implications in the management and treatment of AHO and related conditions. Additionally, studies of heterotopic bone formation due to Gnas inactivation have identified an essential role of sonic hedgehog signaling, which could have therapeutic implications not only for AHO and related conditions but also for heterotopic bone formation in a wide variety of settings in which aberrant bone formation is a cause of significant morbidity.
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Affiliation(s)
- Patrick McMullan
- Department of Pediatrics, Division of Pediatric Endocrinology & Diabetes, University of Connecticut School of Medicine, 505 Farmington Ave, 2nd floor, Farmington, CT, 06032, USA
- Department of Reconstructive Sciences, Center for Regenerative Medicine and Skeletal Development, University of Connecticut School of Dental Medicine, Farmington, CT, USA
| | - Emily L Germain-Lee
- Department of Pediatrics, Division of Pediatric Endocrinology & Diabetes, University of Connecticut School of Medicine, 505 Farmington Ave, 2nd floor, Farmington, CT, 06032, USA.
- Department of Reconstructive Sciences, Center for Regenerative Medicine and Skeletal Development, University of Connecticut School of Dental Medicine, Farmington, CT, USA.
- Albright Center, Connecticut Children's, Farmington, CT, USA.
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33
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Katchkovsky S, Chatterjee B, Abramovitch-Dahan CV, Papo N, Levaot N. Competitive blocking of LRP4-sclerostin binding interface strongly promotes bone anabolic functions. Cell Mol Life Sci 2022; 79:113. [PMID: 35099616 PMCID: PMC11073160 DOI: 10.1007/s00018-022-04127-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 12/16/2021] [Accepted: 01/03/2022] [Indexed: 01/07/2023]
Abstract
Induction of bone formation by Wnt ligands is inhibited when sclerostin (Scl), an osteocyte-produced antagonist, binds to its receptors, the low-density lipoprotein receptor-related proteins 5 or 6 (LRP5/6). Recently, it was shown that enhanced inhibition is achieved by Scl binding to the co-receptor LRP4. However, it is not clear if the binding of Scl to LRP4 facilitates Scl binding to LRP5/6 or inhibits the Wnt pathway in an LRP5/6-independent manner. Here, using the yeast display system, we demonstrate that Scl exhibits a stronger binding affinity for LRP4 than for LRP6. Moreover, we found stronger Scl binding to LRP6 in the presence of LRP4. We further show that a Scl mutant (SclN93A), which tightly binds LRP4 but not LRP6, does not inhibit the Wnt pathway on its own. We demonstrate that SclN93A competes with Scl for a common binding site on LRP4 and antagonizes Scl inhibition of the Wnt signaling pathway in osteoblasts in vitro. Finally, we demonstrate that 2 weeks of bi-weekly subcutaneous injections of SclN93A fused to the fragment crystallizable (Fc) domain of immunoglobulin (SclN93AFc), which retains the antagonistic activity of the mutant, significantly increases bone formation rate and enhances trabecular volumetric bone fraction, trabecular number, and bone length in developing mice. Our data show that LRP4 serves as an anchor that facilitates Scl-LRP6 binding and that inhibition of the Wnt pathway by Scl depends on its prior binding to LRP4. We further provide evidence that compounds that inhibit Scl-LRP4 interactions offer a potential strategy to promote anabolic bone functions.
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Affiliation(s)
- Svetlana Katchkovsky
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, 8410501, Beer-Sheva, Israel
| | - Biplab Chatterjee
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, 8410501, Beer-Sheva, Israel
| | - Chen-Viki Abramovitch-Dahan
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, 8410501, Beer-Sheva, Israel
| | - Niv Papo
- Avram and Stella Goldstein-Goren Department of Biotechnology Engineering and the National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, 8410501, Beer-Sheva, Israel.
| | - Noam Levaot
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, 8410501, Beer-Sheva, Israel.
- Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, 8410501, Beer-Sheva, Israel.
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34
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Tripathi A, John AA, Kumar D, Kaushal SK, Singh DP, Husain N, Sarkar J, Singh D. MiR-539-3p impairs osteogenesis by suppressing Wnt interaction with LRP-6 co-receptor and subsequent inhibition of Akap-3 signaling pathway. Front Endocrinol (Lausanne) 2022; 13:977347. [PMID: 36267566 PMCID: PMC9577939 DOI: 10.3389/fendo.2022.977347] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 09/07/2022] [Indexed: 11/21/2022] Open
Abstract
X-linked hypophosphatemia (XLH), an inheritable form of rickets is caused due to mutation in Phex gene. Several factors are linked to the disease's aetiology, including non-coding RNA molecules (miRNAs), which are key post-transcriptional regulators of gene expression and play a significant role in osteoblast functions. MicroRNAs sequence analysis showed differentially regulated miRNAs in phex silenced osteoblast cells. In this article, we report miR-539-3p, an unidentified novel miRNA, in the functional regulation of osteoblast. MiR-539-3p overexpression impaired osteoblast differentiation. Target prediction algorithm and experimental confirmation by luciferase 3' UTR reporter assay identified LRP-6 as a direct target of miR-539-3p. Over expression of miR-539-3p in osteoblasts down regulated Wnt/beta catenin signaling components and deteriorated trabecular microarchitecture leading to decreased bone formation in ovariectomized (Ovx) mice. Additionally, biochemical bone resorption markers like CTx and Trap-5b were elevated in serum samples of mimic treated group, while, reverse effect was observed in anti-miR treated animals along with increased bone formation marker P1NP. Moreover, transcriptome analysis with miR-539-3p identified a novel uncharacterized Akap-3 gene in osteoblast cells, knock down of which resulted in downregulation of osteoblast differentiation markers at both transcriptional and translational level. Overall, our study for the first time reported the role of miR-539-3p in osteoblast functions and its downstream Akap-3 signalling in regulation of osteoblastogenesis.
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Affiliation(s)
- Alok Tripathi
- Division of Endocrinology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, India
| | - Aijaz A. John
- Division of Endocrinology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India
| | - Deepak Kumar
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, India
- Division of Cancer Biology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India
| | - Saurabh Kumar Kaushal
- Division of Endocrinology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, India
| | - Devendra Pratap Singh
- Division of Endocrinology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, India
| | - Nazim Husain
- Division of Endocrinology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India
| | - Jayanta Sarkar
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, India
- Division of Cancer Biology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India
| | - Divya Singh
- Division of Endocrinology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, India
- *Correspondence: Divya Singh,
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35
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Xiao M, Qian H, Lv J, Wang P. Advances in the Study of the Mechanisms of Physiological Root Resorption in Deciduous Teeth. Front Pediatr 2022; 10:850826. [PMID: 35433548 PMCID: PMC9005890 DOI: 10.3389/fped.2022.850826] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 02/23/2022] [Indexed: 11/15/2022] Open
Abstract
Physiological root resorption of deciduous teeth is a complex physiological process that is essential for the normal replacement of deciduous teeth and permanent teeth in clinical practice, but its importance is often overlooked due to the presence of permanent teeth. This physiological process includes not only the resorption of hard tissues of deciduous teeth, such as dentin and cementum, but also the elimination of soft tissues, such as pulp and periodontal ligament (PDL). However, the mechanisms of physiological root resorption are not yet clear. In this article, the advances of research on the mechanisms related to physiological root resorption will be reviewed in two main aspects: hard tissues and soft tissues of deciduous teeth, specifically in relation to the effects of inflammatory microenvironment and mechanical stress on the resorption of hard tissues, the repair of hard tissues, and the elimination and the histological events of soft tissues.
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Affiliation(s)
- Manxue Xiao
- Department of Pediatric Dentistry, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Hong Qian
- Department of Pediatric Dentistry, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Jingwen Lv
- Department of Pediatric Dentistry, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Peixuan Wang
- Department of Pediatric Dentistry, Stomatological Hospital, Southern Medical University, Guangzhou, China
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36
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Wu F, Li B, Hu X, Yu F, Shi Y, Ye L. Wnt7b Inhibits Osteoclastogenesis via AKT Activation and Glucose Metabolic Rewiring. Front Cell Dev Biol 2021; 9:771336. [PMID: 34881243 PMCID: PMC8645835 DOI: 10.3389/fcell.2021.771336] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 10/12/2021] [Indexed: 02/05/2023] Open
Abstract
The imbalance between bone formation and bone resorption causes osteoporosis, which leads to severe bone fractures. It is known that increases in osteoclast numbers and activities are the main reasons for increasing bone resorption. Although extensive studies have investigated the regulation of osteoclastogenesis of bone marrow macrophages (BMMs), new pharmacological avenues still need to be unveiled for clinical purpose. Wnt ligands have been widely demonstrated as stimulators of bone formation; however, the inhibitory effect of the Wnt pathway in osteoclastogenesis is largely unknown. Here, we demonstrate that Wnt7b, a potent Wnt ligand that enhances bone formation and increases bone mass, also abolishes osteoclastogenesis in vitro. Importantly, enforced expression of Wnt in bone marrow macrophage lineage cells significantly disrupts osteoclast formation and activity, which leads to a dramatic increase in bone mass. Mechanistically, Wnt7b impacts the glucose metabolic process and AKT activation during osteoclastogenesis. Thus, we demonstrate that Wnt7b diminishes osteoclast formation, which will be beneficial for osteoporosis therapy in the future.
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Affiliation(s)
- Fanzi Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Boer Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xuchen Hu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Fanyuan Yu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yu Shi
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ling Ye
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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37
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Shang X, Böker KO, Taheri S, Lehmann W, Schilling AF. Extracellular Vesicles Allow Epigenetic Mechanotransduction between Chondrocytes and Osteoblasts. Int J Mol Sci 2021; 22:ijms222413282. [PMID: 34948080 PMCID: PMC8703680 DOI: 10.3390/ijms222413282] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/03/2021] [Accepted: 12/07/2021] [Indexed: 01/21/2023] Open
Abstract
MicroRNAs (miRNAs) can be transported in extracellular vesicles (EVs) and are qualified as possible messengers for cell–cell communication. In the context of osteoarthritis (OA), miR-221-3p has been shown to have a mechanosensitive and a paracrine function inside cartilage. However, the question remains if EVs with miR-221-3p can act as molecular mechanotransducers between cells of different tissues. Here, we studied the effect of EV-mediated transport in the communication between chondrocytes and osteoblasts in vitro in a rat model. In silico analysis (Targetscan, miRWalk, miRDB) revealed putative targets of miRNA-221-3p (CDKN1B/p27, TIMP-3, Tcf7l2/TCF4, ARNT). Indeed, transfection of miRNA-221-3p in chondrocytes and osteoblasts resulted in regulation of these targets. Coculture experiments of transfected chondrocytes with untransfected osteoblasts not only showed regulation of these target genes in osteoblasts but also inhibition of their bone formation capacity. Direct treatment with chondrocyte-derived EVs validated that chondrocyte-produced extracellular miR-221-3p was responsible for this effect. Altogether, our study provides a novel perspective on a possible communication pathway of a mechanically induced epigenetic signal through EVs. This may be important for processes at the interface of bone and cartilage, such as OA development, physiologic joint homeostasis, growth or fracture healing, as well as for other tissue interfaces with differing biomechanical properties.
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38
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McMullan P, Maye P, Yang Q, Rowe DW, Germain‐Lee EL. Parental Origin of
Gsα
Inactivation Differentially Affects Bone Remodeling in a Mouse Model of Albright Hereditary Osteodystrophy. JBMR Plus 2021; 6:e10570. [PMID: 35079678 PMCID: PMC8771002 DOI: 10.1002/jbm4.10570] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 09/25/2021] [Accepted: 10/08/2021] [Indexed: 01/13/2023] Open
Abstract
Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivation of GNAS, a complex locus that encodes the alpha‐stimulatory subunit of heterotrimeric G proteins (Gsα) in addition to NESP55 and XLαs due to alternative first exons. AHO skeletal manifestations include brachydactyly, brachymetacarpia, compromised adult stature, and subcutaneous ossifications. AHO patients with maternally‐inherited GNAS mutations develop pseudohypoparathyroidism type 1A (PHP1A) with resistance to multiple hormones that mediate their actions through G protein‐coupled receptors (GPCRs) requiring Gsα (eg, parathyroid hormone [PTH], thyroid‐stimulating hormone [TSH], growth hormone–releasing hormone [GHRH], calcitonin) and severe obesity. Paternally‐inherited GNAS mutations cause pseudopseudohypoparathyroidism (PPHP), in which patients have AHO skeletal features but do not develop hormonal resistance or marked obesity. These differences between PHP1A and PPHP are caused by tissue‐specific reduction of paternal Gsα expression. Previous reports in mice have shown loss of Gsα causes osteopenia due to impaired osteoblast number and function and suggest that AHO patients could display evidence of reduced bone mineral density (BMD). However, we previously demonstrated PHP1A patients display normal‐increased BMD measurements without any correlation to body mass index or serum PTH. Due to these observed differences between PHP1A and PPHP, we utilized our laboratory's AHO mouse model to address whether Gsα heterozygous inactivation differentially affects bone remodeling based on the parental inheritance of the mutation. We identified fundamental distinctions in bone remodeling between mice with paternally‐inherited (GnasE1+/−p) versus maternally‐inherited (GnasE1+/−m) mutations, and these findings were observed predominantly in female mice. Specifically, GnasE1+/−p mice exhibited reduced bone parameters due to impaired bone formation and enhanced bone resorption. GnasE1+/−m mice, however, displayed enhanced bone parameters due to both increased osteoblast activity and normal bone resorption. These in vivo distinctions in bone remodeling between GnasE1+/−p and GnasE1+/−m mice could potentially be related to changes in the bone microenvironment driven by calcitonin‐resistance within GnasE1+/−m osteoclasts. Further studies are warranted to assess how Gsα influences osteoblast–osteoclast coupling. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Patrick McMullan
- Department of Pediatrics University of Connecticut School of Medicine Farmington CT USA
- Department of Reconstructive Sciences University of Connecticut School of Dental Medicine Farmington CT USA
- Center for Regenerative Medicine and Skeletal Development University of Connecticut School of Dental Medicine Farmington CT USA
| | - Peter Maye
- Department of Reconstructive Sciences University of Connecticut School of Dental Medicine Farmington CT USA
- Center for Regenerative Medicine and Skeletal Development University of Connecticut School of Dental Medicine Farmington CT USA
| | - Qingfen Yang
- Department of Pediatrics University of Connecticut School of Medicine Farmington CT USA
- Department of Reconstructive Sciences University of Connecticut School of Dental Medicine Farmington CT USA
- Center for Regenerative Medicine and Skeletal Development University of Connecticut School of Dental Medicine Farmington CT USA
| | - David W. Rowe
- Department of Reconstructive Sciences University of Connecticut School of Dental Medicine Farmington CT USA
- Center for Regenerative Medicine and Skeletal Development University of Connecticut School of Dental Medicine Farmington CT USA
| | - Emily L. Germain‐Lee
- Department of Pediatrics University of Connecticut School of Medicine Farmington CT USA
- Department of Reconstructive Sciences University of Connecticut School of Dental Medicine Farmington CT USA
- Center for Regenerative Medicine and Skeletal Development University of Connecticut School of Dental Medicine Farmington CT USA
- Albright Center, Division of Pediatric Endocrinology Connecticut Children's Farmington CT USA
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Tokavanich N, Wein MN, English JD, Ono N, Ono W. The Role of Wnt Signaling in Postnatal Tooth Root Development. FRONTIERS IN DENTAL MEDICINE 2021; 2:769134. [PMID: 35782525 PMCID: PMC9248717 DOI: 10.3389/fdmed.2021.769134] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Appropriate tooth root formation and tooth eruption are critical for achieving and maintaining good oral health and quality of life. Tooth eruption is the process through which teeth emerge from their intraosseous position to their functional position in the oral cavity. This temporospatial process occurs simultaneously with tooth root formation through a cascade of interactions between the epithelial and adjoining mesenchymal cells. Here, we will review the role of the Wnt system in postnatal tooth root development. This signaling pathway orchestrates the process of tooth root formation and tooth eruption in conjunction with several other major signaling pathways. The Wnt signaling pathway is comprised of the canonical, or Wnt/β-catenin, and the non-Canonical signaling pathway. The expression of multiple Wnt ligands and their downstream transcription factors including β-catenin is found in the cells in the epithelia and mesenchyme starting from the initiation stage of tooth development. The inhibition of canonical Wnt signaling in an early stage arrests odontogenesis. Wnt transcription factors continue to be present in dental follicle cells, the progenitor cells responsible for differentiation into cells constituting the tooth root and the periodontal tissue apparatus. This expression occurs concurrently with osteogenesis and cementogenesis. The conditional ablation of β-catenin in osteoblast and odontoblast causes the malformation of the root dentin and cementum. On the contrary, the overexpression of β-catenin led to shorter molar roots with thin and hypo-mineralized dentin, along with the failure of tooth eruption. Therefore, the proper expression of Wnt signaling during dental development is crucial for regulating the proliferation, differentiation, as well as epithelial-mesenchymal interaction essential for tooth root formation and tooth eruption.
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Affiliation(s)
- Nicha Tokavanich
- Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, United States
| | - Marc N. Wein
- Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Jeryl D. English
- Department of Orthodontics, University of Texas Health Science Center at Houston School of Dentistry, Houston, TX, United States
| | - Noriaki Ono
- Department of Diagnostic and Biomedical Sciences, University of Texas Health Science Center at Houston School of Dentistry, Houston, TX, United States
| | - Wanida Ono
- Department of Orthodontics, University of Texas Health Science Center at Houston School of Dentistry, Houston, TX, United States
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Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells. Cancers (Basel) 2021; 13:cancers13225593. [PMID: 34830748 PMCID: PMC8615769 DOI: 10.3390/cancers13225593] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 10/28/2021] [Accepted: 11/06/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Osteoclasts are bone-resorbing cells and, together with bone-forming osteoblasts, they are responsible for maintaining healthy bones. When cancer cells invade into the bone, however, osteoclasts assist in cancer progression and stimulate bone loss. In this study, we converted the bone-destructive action of osteoclasts by activating their Wnt signaling and generated an osteoclast-derived, bone-protective, tumor-suppressive conditioned medium. The conditioned medium was able to suppress tumor growth and bone loss in a mouse model of mammary tumors and bone metastasis. The described approach is expected to add a novel strategy to treat primary breast cancer as well as bone metastasis. Abstract Osteoclasts are a driver of a vicious bone-destructive cycle with breast cancer cells. Here, we examined whether this vicious cycle can be altered into a beneficial one by activating Wnt signaling with its activating agent, BML284. The conditioned medium, derived from Wnt-activated RAW264.7 pre-osteoclast cells (BM CM), reduced the proliferation, migration, and invasion of EO771 mammary tumor cells. The same inhibitory effect was obtained with BML284-treated primary human macrophages. In a mouse model, BM CM reduced the progression of mammary tumors and tumor-induced osteolysis and suppressed the tumor invasion to the lung. It also inhibited the differentiation of RANKL-stimulated osteoclasts and enhanced osteoblast differentiation. BM CM was enriched with atypical tumor-suppressing proteins such as Hsp90ab1 and enolase 1 (Eno1). Immunoprecipitation revealed that extracellular Hsp90ab1 interacted with latent TGFβ (LAP-TGFβ) as an inhibitor of TGFβ activation, while Hsp90ab1 and Eno1 interacted and suppressed tumor progression via CD44, a cell-adhesion receptor and a cancer stem cell marker. This study demonstrated that osteoclast-derived CM can be converted into a bone-protective, tumor-suppressing agent by activating Wnt signaling. The results shed a novel insight on the unexplored function of osteoclasts as a potential bone protector that may develop an unconventional strategy to combat bone metastasis.
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SETD2-mediated epigenetic regulation of noncanonical Wnt5A during osteoclastogenesis. Clin Epigenetics 2021; 13:192. [PMID: 34663428 PMCID: PMC8522097 DOI: 10.1186/s13148-021-01125-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/28/2021] [Indexed: 01/17/2023] Open
Abstract
To define the role of SETD2 in the WNT5a signaling in the context of osteoclastogenesis, we exploited two different models: in vitro osteoclast differentiation, and K/BxN serum-induced arthritis model. We found that SETD2 and WNT5a were upregulated during osteoclast differentiation and after induction of arthritis. Using gain- and loss-of-function approaches in the myeloid cell, we confirmed that SETD2 regulated the osteoclast markers, and WNT5a via modulating active histone marks by enriching H3K36me3, and by reducing repressive H3K27me3 mark. Additionally, during osteoclastic differentiation, the transcription of Wnt5a was also associated with the active histone H3K9 and H4K8 acetylations. Mechanistically, SETD2 directed induction of NF-κβ expression facilitated the recruitment of H3K9Ac and H4K8Ac around the TSS region of the Wnt5a gene, thereby, assisting osteoclast differentiation. Together these findings for the first time revealed that SETD2 mediated epigenetic regulation of Wnt5a plays a critical role in osteoclastogenesis and induced arthritis. Model for the Role of SETD2 dependent regulation of osteoclastic differentiation. A In monocyte cells SETD2-dependent H3K36 trimethylation help to create open chromatin region along with active enhancer mark, H3K27Ac. This chromatin state facilitated the loss of a suppressive H3K27me3 mark. B Additionally, SETD2 mediated induction of NF-κβ expression leads to the recruitment of histone acetyl transferases, P300/PCAF, to the Wnt5a gene and establish H3K9Ac and H4K8Ac marks. Along with other activation marks, these acetylation marks help in Wnt5a transcription which leads to osteoclastogenesis.
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Lojk J, Marc J. Roles of Non-Canonical Wnt Signalling Pathways in Bone Biology. Int J Mol Sci 2021; 22:10840. [PMID: 34639180 PMCID: PMC8509327 DOI: 10.3390/ijms221910840] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/01/2021] [Accepted: 10/05/2021] [Indexed: 01/15/2023] Open
Abstract
The Wnt signalling pathway is one of the central signalling pathways in bone development, homeostasis and regulation of bone mineral density. It consists of numerous Wnt ligands, receptors and co-receptors, which ensure tight spatiotemporal regulation of Wnt signalling pathway activity and thus tight regulation of bone tissue homeostasis. This enables maintenance of optimal mineral density, tissue healing and adaptation to changes in bone loading. While the role of the canonical/β-catenin Wnt signalling pathway in bone homeostasis is relatively well researched, Wnt ligands can also activate several non-canonical, β-catenin independent signalling pathways with important effects on bone tissue. In this review, we will provide a thorough overview of the current knowledge on different non-canonical Wnt signalling pathways involved in bone biology, focusing especially on the pathways that affect bone cell differentiation, maturation and function, processes involved in bone tissue structure regulation. We will describe the role of the two most known non-canonical pathways (Wnt/planar cell polarity pathways and Wnt/Ca2+ pathway), as well as other signalling pathways with a strong role in bone biology that communicate with the Wnt signalling pathway through non-canonical Wnt signalling. Our goal is to bring additional attention to these still not well researched but important pathways in the regulation of bone biology in the hope of prompting additional research in the area of non-canonical Wnt signalling pathways.
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Affiliation(s)
- Jasna Lojk
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia;
| | - Janja Marc
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia;
- University Clinical Center Ljubljana, Clinical Department of Clinical Chemistry and Biochemistry, 1000 Ljubljana, Slovenia
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Henning P, Movérare-Skrtic S, Westerlund A, Chaves de Souza PP, Floriano-Marcelino T, Nilsson KH, El Shahawy M, Ohlsson C, Lerner UH. WNT16 is Robustly Increased by Oncostatin M in Mouse Calvarial Osteoblasts and Acts as a Negative Feedback Regulator of Osteoclast Formation Induced by Oncostatin M. J Inflamm Res 2021; 14:4723-4741. [PMID: 34566421 PMCID: PMC8457865 DOI: 10.2147/jir.s323435] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 09/02/2021] [Indexed: 01/22/2023] Open
Abstract
Background Bone loss is often observed adjacent to inflammatory processes. The WNT signaling pathways have been implicated as novel regulators of both immune responses and bone metabolism. WNT16 is important for cortical bone mass by inhibiting osteoclast differentiation, and we have here investigated the regulation of WNT16 by several members of the pro-inflammatory gp130 cytokine family. Methods The expression and regulation of Wnt16 in primary murine cells were studied by qPCR, scRNAseq and in situ hybridization. Signaling pathways were studied by siRNA silencing. The importance of oncostatin M (OSM)-induced WNT16 expression for osteoclastogenesis was studied in cells from Wnt16-deficient and wild-type mice. Results We found that IL-6/sIL-6R and OSM induce the expression of Wnt16 in primary mouse calvarial osteoblasts, with OSM being the most robust stimulator. The induction of Wnt16 by OSM was dependent on gp130 and OSM receptor (OSMR), and downstream signaling by the SHC1/STAT3 pathway, but independent of ERK. Stimulation of the calvarial cells with OSM resulted in enhanced numbers of mature, oversized osteoclasts when cells were isolated from Wnt16 deficient mice compared to cells from wild-type mice. OSM did not affect Wnt16 mRNA expression in bone marrow cell cultures, explained by the finding that Wnt16 and Osmr are expressed in distinctly different cells in bone marrow, nor was osteoclast differentiation different in OSM-stimulated bone marrow cell cultures isolated from Wnt16−/- or wild-type mice. Furthermore, we found that Wnt16 expression is substantially lower in cells from bone marrow compared to calvarial osteoblasts. Conclusion These findings demonstrate that OSM is a robust stimulator of Wnt16 mRNA in calvarial osteoblasts and that WNT16 acts as a negative feedback regulator of OSM-induced osteoclast formation in the calvarial bone cells, but not in the bone marrow.
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Affiliation(s)
- Petra Henning
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Sofia Movérare-Skrtic
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anna Westerlund
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Pedro Paulo Chaves de Souza
- The Innovation in Biomaterials Laboratory, School of Dentistry, Federal University of Goiás, Goiânia, Brazil.,Department of Physiology and Pathology, São Paulo State University (UNESP), School of Dentistry, Araraquara, Brazil
| | - Thais Floriano-Marcelino
- Department of Physiology and Pathology, São Paulo State University (UNESP), School of Dentistry, Araraquara, Brazil
| | - Karin H Nilsson
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maha El Shahawy
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Oral Biology, Faculty of Dentistry, Minia University, Minia, 61511, Egypt
| | - Claes Ohlsson
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ulf H Lerner
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Lauterlein JJL, Gossiel F, Weigl M, Eastell R, Hackl M, Hermann P, Bollerslev J, Frost M. Development of the Bone Phenotype and microRNA Profile in Adults With Low-Density Lipoprotein Receptor-Related Protein 5-High Bone Mass (LRP5-HBM) Disease. JBMR Plus 2021; 5:e10534. [PMID: 34532618 PMCID: PMC8441296 DOI: 10.1002/jbm4.10534] [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: 01/27/2021] [Revised: 07/07/2021] [Accepted: 07/19/2021] [Indexed: 12/01/2022] Open
Abstract
Pathogenic variants in the Wnt‐pathway co‐receptor low‐density lipoprotein (LDL) receptor‐related protein 5 (LRP5) cause high bone mass (LRP5‐HBM) due to insensitivity to the endogenous antagonist of Wnt‐signaling. Although indicating incessant progression of BMD and biomarkers reflecting bone formation, this has not been confirmed in individuals with LRP5‐HBM. We investigated how the LRP5‐HBM bone phenotype changes with age in adults and is associated with quantitative changes of bone turnover markers and bone‐related microRNAs (miRNAs) in the circulation. Whole body, lumbar spine, total hip, and femoral neck areal BMD (aBMD) and radial and tibial bone microarchitecture and geometry were assessed using DXA and HR‐pQCT scans of 15 individuals with LRP5‐HBMT253I (11 women; median age 51 years; range, 19 to 85 years) with a time interval between scans of 5.8 years (range, 4.9 to 7.6 years). Fasting P1NP and CTX were measured in 14 LRP5‐HBMT253I individuals and age‐, sex‐, and body mass index (BMI)‐matched controls, and 187 preselected miRNAs were quantified using qPCR in 12 individuals and age‐, sex‐, and BMI‐matched controls. DXA and HR‐pQCT scans were assessed in subjects who had reached peak bone mass (aged >25 years, n = 12). Femoral neck aBMD decreased by 0.8%/year (p = 0.01) and total hip by 0.3%/year, and radial volumetric BMD (vBMD) increased 0.3%/year (p = 0.03). Differences in bone turnover markers at follow‐up were not observed. Compared to controls, 11 of the 178 detectable miRNAs were downregulated and none upregulated in LRP5‐HBM individuals, and five of the downregulated miRNAs are reported to be involved in Wnt‐signaling. Bone loss at the hip in LRP5‐HBM individuals demonstrates that the bone phenotype does not uniformly progress with age. Differentially expressed miRNAs may reflect changes in the regulation of bone turnover and balance in LRP5‐HBM individuals. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Jens-Jacob Lindegaard Lauterlein
- Department of Endocrinology and Metabolism Odense University Hospital Odense Denmark.,Department of Clinical Research University of Southern Denmark Odense Denmark
| | - Fatma Gossiel
- Department of Oncology and Metabolism University of Sheffield Sheffield UK
| | | | - Richard Eastell
- Department of Oncology and Metabolism University of Sheffield Sheffield UK
| | | | - Pernille Hermann
- Department of Endocrinology and Metabolism Odense University Hospital Odense Denmark.,Department of Clinical Research University of Southern Denmark Odense Denmark
| | - Jens Bollerslev
- Department of Endocrinology Rikshospitalet Oslo Norway.,Faculty of Medicine University of Oslo Oslo Norway
| | - Morten Frost
- Department of Endocrinology and Metabolism Odense University Hospital Odense Denmark.,Department of Clinical Research University of Southern Denmark Odense Denmark.,Steno Diabetes Centre Odense Odense University Hospital Odense Denmark
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Mandelli A, Tacconi E, Levinger I, Duque G, Hayes A. The role of estrogens in osteosarcopenia: from biology to potential dual therapeutic effects. Climacteric 2021; 25:81-87. [PMID: 34423690 DOI: 10.1080/13697137.2021.1965118] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Osteoporosis and sarcopenia are two conditions associated with aging and characterized by a simultaneous decline in bone and muscle mass, respectively. These conditions share common risk factors (genetic, endocrine, nutritional and lifestyle factors) and biological pathways that often co-exist in a syndrome known as osteosarcopenia. Among the endocrine causes, estrogens play a critical role, especially in women. Estrogens have been demonstrated to exert a positive effect on bone and muscle development and maintenance. For this reason, menopause is characterized by a loss in bone mineral density and skeletal muscle quality and quantity. To date, studies indicate a positive effect of hormonal therapy on the prevention and management of osteoporosis, to the point that estrogen is prescribed as a first-line treatment for osteoporosis by the major international authorities. While results on sarcopenia are still disputable, such that estrogens are not recommended to prevent muscle loss in postmenopausal women, increased response to anabolic stimuli with estrogen therapy suggests similar beneficial effects on muscle as seen with bone, particularly when combined with resistance exercise.
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Affiliation(s)
- A Mandelli
- Institute for Health and Sport, Victoria University, St Albans, VIC, Australia
| | - E Tacconi
- Explorer Training S.r.l. Massa and Cozzile, Tuscany, Italy
| | - I Levinger
- Institute for Health and Sport, Victoria University, St Albans, VIC, Australia.,Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne, St Albans, VIC, Australia.,Department of Medicine - Western Health, Melbourne Medical School, The University of Melbourne, St Albans, VIC, Australia
| | - G Duque
- Institute for Health and Sport, Victoria University, St Albans, VIC, Australia.,Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne, St Albans, VIC, Australia.,Department of Medicine - Western Health, Melbourne Medical School, The University of Melbourne, St Albans, VIC, Australia
| | - A Hayes
- Institute for Health and Sport, Victoria University, St Albans, VIC, Australia.,Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne, St Albans, VIC, Australia.,Department of Medicine - Western Health, Melbourne Medical School, The University of Melbourne, St Albans, VIC, Australia
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Tan W, Qiu Y, Chen N, Gao J, Liang J, Liu Y, Zhao D. The intervention of intestinal Wnt/β-catenin pathway alters inflammation and disease severity of CIA. Immunol Res 2021; 69:323-333. [PMID: 34037945 DOI: 10.1007/s12026-021-09190-8] [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: 02/11/2021] [Accepted: 03/30/2021] [Indexed: 10/21/2022]
Abstract
Autoreactive T cell is one of the leading causes of immunological tolerance defects in the chronic inflammatory lesions of rheumatoid arthritis (RA). There have been several extracellular signals and intracellular pathways reported in regulating this process but largely remain unknown yet. In this study, we explored the roles of intestinal Wnt/β-catenin on disease severity during collagen-induced arthritis model (CIA), an animal model of RA. We first testified the activity pattern Wnt/β-catenin shifted by intragastric administration of LiCl and DKK-1 in the intestine by real-time PCR and WB analysis. The arthritis scores showing the disease severity in the DKK-1 group was significantly ameliorated compared with the control group at the late stage of the disease, while in the LiCl group, the scores were significantly elevated which was consistent with pathology score analysis of H&E staining. Next, ELISA was performed and showed that TNF-α and IL-17 in the LiCl group were significantly higher than that of the control group. IL-10 in the DKK-1 group was significantly higher than that in the LiCl-1 group and control group, P < 0.05. Flow cytometry of spleen T cells differentiation ratio showed that: Th1 from the DKK-1 and LiCl groups and Th17 from the LiCl group was significantly different from that of the blank model group, P < 0.05. Finally, we explored the effects of intestinal Wnt/β-catenin on T cell differentiation regulator ROR-γt and TCF1 and found that both transcription factors were up-regulated in the LiCl group. Together, these data suggested the pro-information role of Wnt/β-catenin pathway from the intestine in the CIA mouse, implying its use as a potential therapeutic target for the treatment of inflammatory diseases such as RA.
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Affiliation(s)
- Weixing Tan
- Department of Rheumatology and Immunology, Changhai Hospital, The Second Military Medical University, Shanghai, China
- Air Force Health Care Center for Special Services, Hangzhou, China
| | - Yang Qiu
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Ning Chen
- Department of Rheumatology and Immunology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Jie Gao
- Department of Rheumatology and Immunology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Jingjing Liang
- Department of Endocrinology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Yu Liu
- Department of Rheumatology and Immunology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Dongbao Zhao
- Department of Rheumatology and Immunology, Changhai Hospital, The Second Military Medical University, Shanghai, China.
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Prednisolone induces osteocytes apoptosis by promoting Notum expression and inhibiting PI3K/AKT/GSK3β/β-catenin pathway. J Mol Histol 2021; 52:1081-1095. [PMID: 34297260 DOI: 10.1007/s10735-021-10006-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 07/16/2021] [Indexed: 12/15/2022]
Abstract
The apoptosis of mature osteocytes is the main factor causing damage to the microstructure of cortical bone in glucocorticoid-induced osteoporosis (GIOP). Our previous research found damaged areas and empty osteocytes lacunae in the tibial cortical bone of GIOP mice. However, the specific mechanism has not been clarified. Recently, a study showed that the quality of the cortical bone significantly increased by knocking out Notum, a gene encoding α/β hydrolase. However, it is not clear whether Notum affects cortical bone remodeling by participating in glucocorticoids (GCs)-induced apoptosis of osteocytes. The present study aimed to explore the correlation between Notum, osteocytes apoptosis, and cortical bone quality in GIOP. Prednisolone acetate was intragastrically administered to mice for two weeks. Histochemical staining was applied to evaluate changes in GIOP and Notum expression. Osteocytes were stimulated with prednisolone, and cell viability was assessed via CCK8. Hoechst 33342/PI staining, flow cytometry, RT-PCR, and western blot were used to detect osteocytes apoptosis, siRNA transfection efficiency, and expressions of pathway related factors. The results showed that the number of empty osteocytes lacunae increased in GIOP mice. TUNEL-stained apoptotic osteocytes and Notum immuno-positive osteocytes were also observed. Furthermore, prednisolone was found to promote Notum expression and osteocytes apoptosis in vitro. Knocking down Notum via siRNA partially restored osteocytes apoptosis and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β)/β-catenin pathway. These findings showed GCs-induced osteocytes apoptosis by promoting Notum expression and inhibiting PI3K/AKT/GSK3β/β-catenin pathway. Thus, Notum might be a potential therapeutic target for the treatment of GIOP.
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Johnson de Sousa Brito FM, Butcher A, Pisconti A, Poulet B, Prior A, Charlesworth G, Sperinck C, Scotto di Mase M, Liu K, Bou-Gharios G, Jurgen van 't Hof R, Daroszewska A. Syndecan-3 enhances anabolic bone formation through WNT signaling. FASEB J 2021; 35:e21246. [PMID: 33769615 PMCID: PMC8251628 DOI: 10.1096/fj.202002024r] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 11/17/2020] [Accepted: 11/23/2020] [Indexed: 12/25/2022]
Abstract
Osteoporosis is the most common age‐related metabolic bone disorder, which is characterized by low bone mass and deterioration in bone architecture, with a propensity to fragility fractures. The best treatment for osteoporosis relies on stimulation of osteoblasts to form new bone and restore bone structure, however, anabolic therapeutics are few and their use is time restricted. Here, we report that Syndecan‐3 increases new bone formation through enhancement of WNT signaling in osteoblasts. Young adult Sdc3−/− mice have low bone volume, reduced bone formation, increased bone marrow adipose tissue, increased bone fragility, and a blunted anabolic bone formation response to mechanical loading. This premature osteoporosis‐like phenotype of Sdc3−/− mice is due to delayed osteoblast maturation and impaired osteoblast function, with contributing increased osteoclast‐mediated bone resorption. Indeed, overexpressing Sdc3 in osteoblasts using the Col1a1 promoter rescues the low bone volume phenotype of the Sdc3−/− mice, and also increases bone volume in WT mice. Mechanistically, SDC3 enhances canonical WNT signaling in osteoblasts through stabilization of Frizzled 1, making SDC3 an attractive target for novel bone anabolic drug development.
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Affiliation(s)
- Francesca Manuela Johnson de Sousa Brito
- Department of Musculoskeletal and Ageing Science (formerly Department of Musculoskeletal Biology), Institute of Life Course and Medical Sciences (formerly Institute of Ageing and Chronic Disease), University of Liverpool, Liverpool, UK
| | - Andrew Butcher
- Department of Musculoskeletal and Ageing Science (formerly Department of Musculoskeletal Biology), Institute of Life Course and Medical Sciences (formerly Institute of Ageing and Chronic Disease), University of Liverpool, Liverpool, UK
| | - Addolorata Pisconti
- Department of Biochemistry, IIB, University of Liverpool, Liverpool, UK.,Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA
| | - Blandine Poulet
- Department of Musculoskeletal and Ageing Science (formerly Department of Musculoskeletal Biology), Institute of Life Course and Medical Sciences (formerly Institute of Ageing and Chronic Disease), University of Liverpool, Liverpool, UK
| | - Amanda Prior
- Department of Musculoskeletal and Ageing Science (formerly Department of Musculoskeletal Biology), Institute of Life Course and Medical Sciences (formerly Institute of Ageing and Chronic Disease), University of Liverpool, Liverpool, UK
| | - Gemma Charlesworth
- Department of Musculoskeletal and Ageing Science (formerly Department of Musculoskeletal Biology), Institute of Life Course and Medical Sciences (formerly Institute of Ageing and Chronic Disease), University of Liverpool, Liverpool, UK
| | - Catherine Sperinck
- Department of Musculoskeletal and Ageing Science (formerly Department of Musculoskeletal Biology), Institute of Life Course and Medical Sciences (formerly Institute of Ageing and Chronic Disease), University of Liverpool, Liverpool, UK
| | - Michele Scotto di Mase
- Department of Musculoskeletal and Ageing Science (formerly Department of Musculoskeletal Biology), Institute of Life Course and Medical Sciences (formerly Institute of Ageing and Chronic Disease), University of Liverpool, Liverpool, UK
| | - Ke Liu
- Department of Musculoskeletal and Ageing Science (formerly Department of Musculoskeletal Biology), Institute of Life Course and Medical Sciences (formerly Institute of Ageing and Chronic Disease), University of Liverpool, Liverpool, UK
| | - George Bou-Gharios
- Department of Musculoskeletal and Ageing Science (formerly Department of Musculoskeletal Biology), Institute of Life Course and Medical Sciences (formerly Institute of Ageing and Chronic Disease), University of Liverpool, Liverpool, UK
| | - Robert Jurgen van 't Hof
- Department of Musculoskeletal and Ageing Science (formerly Department of Musculoskeletal Biology), Institute of Life Course and Medical Sciences (formerly Institute of Ageing and Chronic Disease), University of Liverpool, Liverpool, UK
| | - Anna Daroszewska
- Department of Musculoskeletal and Ageing Science (formerly Department of Musculoskeletal Biology), Institute of Life Course and Medical Sciences (formerly Institute of Ageing and Chronic Disease), University of Liverpool, Liverpool, UK.,Department of Clinical Biochemistry and Metabolic Medicine, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.,Department of Rheumatology, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
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Zhong X, Zhang F, Yin X, Cao H, Wang X, Liu D, Chen J, Chen X. Bone Homeostasis and Gut Microbial-Dependent Signaling Pathways. J Microbiol Biotechnol 2021; 31:765-774. [PMID: 34176870 PMCID: PMC9705830 DOI: 10.4014/jmb.2104.04016] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/27/2021] [Accepted: 06/13/2021] [Indexed: 12/15/2022]
Abstract
Although research on the osteal signaling pathway has progressed, understanding of gut microbial-dependent signaling pathways for metabolic and immune bone homeostasis remains elusive. In recent years, the study of gut microbiota has shed light on our understanding of bone homeostasis. Here, we review microbiota-mediated gut-bone crosstalk via bone morphogenetic protein/SMADs, Wnt and OPG/receptor activator of nuclear factor-kappa B ligand signaling pathways in direct (translocation) and indirect (metabolite) manners. The mechanisms underlying gut microbiota involvement in these signaling pathways are relevant in immune responses, secretion of hormones, fate of osteoblasts and osteoclasts and absorption of calcium. Collectively, we propose a signaling network for maintaining a dynamic homeostasis between the skeletal system and the gut ecosystem. Additionally, the role of gut microbial improvement by dietary intervention in osteal signaling pathways has also been elucidated. This review provides unique resources from the gut microbial perspective for the discovery of new strategies for further improving treatment of bone diseases by increasing the abundance of targeted gut microbiota.
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Affiliation(s)
- Xiaohui Zhong
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, P.R. China
| | - Feng Zhang
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, P.R. China,Clinical Assessment Center of Functional Food, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R. China,Nutritional Department, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R. China
| | - Xinyao Yin
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, P.R. China
| | - Hong Cao
- Clinical Assessment Center of Functional Food, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R. China,Department of Endocrinology, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R. China,Nutritional Department, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R. China
| | - Xuesong Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, P.R. China,Department of Orthopedics, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R.China
| | - Dongsong Liu
- Department of Orthopedics, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R.China
| | - Jing Chen
- Department of Orthopedics, Affiliated Hospital of Jiangnan University, Wuxi 214125, P.R.China
| | - Xue Chen
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, P.R. China,Corresponding author Phone: +86-15861589177 E-mail:
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Daley EJ, Trackman PC. β-Catenin mediates glucose-dependent insulinotropic polypeptide increases in lysyl oxidase expression in osteoblasts. Bone Rep 2021; 14:101063. [PMID: 33981809 PMCID: PMC8081922 DOI: 10.1016/j.bonr.2021.101063] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023] Open
Abstract
Osteoblast lysyl oxidase (LOX) is a strongly up-regulated mRNA and protein by the glucose-dependent insulinotropic polypeptide (GIP). LOX is critically required for collagen maturation, and was shown to be dramatically down-regulated in a mouse model of type 1 diabetes, consistent with known low collagen cross-linking and poor bone quality in diabetic bone disease in humans and in mouse models. GIP is a gastric hormone released by the gut upon consumption of nutrients, which then stimulates insulin release from β-cells in the pancreas. GIP is directly anabolic to osteoblasts and to bone, while gut-derived dopamine attenuates effects of GIP on osteoblast anabolic pathways, including LOX expression. GIP-stimulation of LOX expression was shown to be dependent on increased cAMP levels and protein kinase A activity, consistent with the fact that GIP receptors are G protein coupled receptors. Downstream signaling events resulting in increased LOX expression remain, however, unexplored. Here we provide evidence for β-catenin mediation of signaling from GIP to increase LOX expression. Moreover, we have identified a TCF/LEF element in the Lox promoter that is required for GIP-upregulation of LOX. These findings will be of importance in designing potential therapeutic approaches to address deficient LOX production in diabetic bone disease by pointing to the importance of exploring strategies to stimulate β-catenin signaling in osteoblasts under diabetic conditions as potential therapeutic strategies.
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Affiliation(s)
| | - Philip C. Trackman
- Corresponding author at: Forsyth Institute, Department of Applied Oral Sciences, 250 First Street, Cambridge, MA 02118, United States of America.
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