MYC promotes fibroblast osteogenesis by regulating ALP and BMP2 to participate in ectopic ossification of ankylosing spondylitis

Arthritis Research & Therapy

Research

Xingzhu Wen¹  Ziqiang Chen²  Yaoyang Liu³  Xin Wu³  Qianmei Jin³  Zhiguo Zhang³  Zijian Kang³  Huji Xu⁴  Haijun Tian⁵ 

[1] Department of General Surgery, 72nd Group Army Hospital, Huzhou University, 313000, Huzhou, Zhejiang, China;Department of Orthopaedics, Changhai Hospital, Naval Medical University, 200433, Shanghai, China;Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Naval Medical University, 200003, Shanghai, China;Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Naval Medical University, 200003, Shanghai, China;School of Medicine, Tsinghua University, 100084, Beijing, China;Peking-Tsinghua Center for Life Sciences, Tsinghua University, 100084, Beijing, China;Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China;

关键词: Ankylosing spondylitis;    Inflammation;    Ligaments;    Ectopic ossification;    MYC;   

DOI  :  10.1186/s13075-023-03011-z

 received in 2022-08-23, accepted in 2023-02-09,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundEctopic ossification is an important cause of disability in patients with ankylosing spondylitis (AS). Whether fibroblasts can transdifferentiate into osteoblasts and contribute to ossification remains unknown. This study aims to investigate the role of stem cell transcription factors (POU5F1, SOX2, KLF4, MYC, etc.) of fibroblasts in ectopic ossification in patients with AS.MethodsPrimary fibroblasts were isolated from the ligaments of patients with AS or osteoarthritis (OA). In an in vitro study, primary fibroblasts were cultured in osteogenic differentiation medium (ODM) to induce ossification. The level of mineralization was assessed by mineralization assay. The mRNA and protein levels of stem cell transcription factors were measured by real-time quantitative PCR (q-PCR) and western blotting. MYC was knocked down by infecting primary fibroblasts with lentivirus. The interactions between stem cell transcription factors and osteogenic genes were analysed by chromatin immunoprecipitation (ChIP). Recombinant human cytokines were added to the osteogenic model in vitro to evaluate their role in ossification.ResultsWe found that MYC was elevated significantly in the process of inducing primary fibroblasts to differentiate into osteoblasts. In addition, the level of MYC was remarkably higher in AS ligaments than in OA ligaments. When MYC was knocked down, the expression of the osteogenic genes alkaline phosphatase (ALP) and bone morphogenic protein 2 (BMP2) was decreased, and the level of mineralization was reduced significantly. In addition, the ALP and BMP2 were confirmed to be the direct target genes of MYC. Furthermore, interferon-γ (IFN-γ), which showed high expression in AS ligaments, was found to promote the expression of MYC in fibroblasts in the process of ossification in vitro.ConclusionsThis study demonstrates the role of MYC in ectopic ossification. MYC may act as the critical bridge that links inflammation with ossification in AS, thus providing new insights into the molecular mechanisms of ectopic ossification in AS.

【 授权许可】

CC BY   
© The Author(s) 2023

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