HDAC6 inactivates Runx2 promoter to block osteogenesis of bone marrow stromal cells in age-related bone loss of mice

Stem Cell Research & Therapy

Jun Liang¹  Juan Gao²  Sen Huang³  Long Xu³  Zhenfei Wang³  Guangwang Liu³  Weixiang Dai³  Chao Ma³  Mengjiao Xia³  Tao Chen³  Jian Na³  Shiming Feng³  Kerong Dai⁴ 

[1] Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou Clinical Medical College of Nanjing University of Chinese Medicine, 221009, Xuzhou, Jiangsu, China;Department of Gynaecology and Obstetrics, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou Clinical Medical College of Nanjing University of Chinese Medicine, 221009, Xuzhou, Jiangsu, China;Department of Orthopedic Surgery, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou Clinical Medical College of Nanjing University of Chinese Medicine, 221009, Xuzhou, Jiangsu, China;Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, 200011, Shanghai, China;

关键词: Aging;    Osteoporosis;    Bone marrow stromal cells;    Runx2;    Histone deacetylases 6;    Androgen receptor;   

DOI  :  10.1186/s13287-021-02545-w

来源: Springer

【 摘 要 】

BackgroundSenile osteoporosis can cause bone fragility and increased risk for fractures and has been one of the most prevalent and severe diseases affecting the elderly population worldwidely. The underlying mechanisms are currently intensive areas of investigation. In age-related bone loss, decreased bone formation overweighs increased bone resorption. The molecular mechanisms underlying defective bone formation in age-related bone loss are not completely understood. In particular, the specific role of histone acetylation in age-related bone loss has not been examined thoroughly.MethodsWe employed 6- and 18-month-old mice to investigate the mechanisms of defective bone formation in age-related bone loss. Bone marrow stromal cells (BMSCs) were induced to undergo in vitro osteogenic differentiation. Chromatin immunoprecipitation (ChIP) was used to investigate the binding of histone deacetylases (HDACs) on Runx2 promoter in BMSCs. Luciferase reporter and transient transfection assay were employed to study Runx2 gene expression modulation by HDAC and androgen receptor (AR). siRNA and HDAC6 inhibitor, Tubastatin A, were used to inhibit HDAC6 in vitro. And systemic administration of Tubastatin A was used to block HDAC6 in vivo.ResultsAge-related trabecular bone loss was observed in 18-month-old mice compared with 6-month-old mice. In vitro osteogenic differentiation potential of BMSCs from 18-month-old mice was weaker than 6-month-old mice, in which there was Runx2 expression inactivation in BMSCs of 18-month-old mice compared with 6-month-old mice, which was attributable to HDAC6-mediated histone hypoacetylation in Runx2 promoter. There was competitive binding of HDAC6 and AR on Runx2 promoter to modulate Runx2 expression in BMSCs. More importantly, through siRNA- or specific inhibitor-mediated HDAC6 inhibition, we could activate Runx2 expression, rescue in vitro osteogenesis potential of BMSCs, and alleviate in vivo age-related bone loss of mice.ConclusionHDAC6 accumulation and histone hypoacetylation on Runx2 promoter contributed to the attenuation of in vitro osteogenic differentiation potential of BMSCs from aged mice. Through HDAC6 inhibition, we could activate Runx2 expression and osteogenic differentiation potential of BMSCs from aged mice and alleviate the age-related bone loss of aged mice. Our study will benefit not only for understanding the age-related bone loss, but also for finding new therapies to treat senile osteoporosis.

【 授权许可】

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