Xu Jing-Zun, Zhou Yan-Man, Zhang Lin-Lin, Chen Xiao-Jing, Yang Yu-Ying, Zhang Deng, Zhu Ke-Cheng, Kong Xiao-Ke, Sun Li-Hao, Tao Bei, Zhao Hong-Yan, Liu Jian-Min
Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Death Discov. 2022 May 6;8(1):254. doi: 10.1038/s41420-022-01048-8.
Age-related osteoporosis is characterized by the accumulation of senescent osteoblastic cells in bone microenvironment and significantly reduced osteogenic differentiation. Clearing of the senescent cells is helpful to improve bone formation in aged mice. Bone morphogenetic protein 9 (BMP9), a multifunctional protein produced and secreted by liver, was reported to improve osteoporosis caused by estrogen withdrawal. However, the mechanism of BMP9 has not been fully elucidated, and its effect on senile osteoporosis has not been reported. This study reveals that BMP9 significantly increases bone mass and improves bone biomechanical properties in aged mice. Furthermore, BMP9 reduces expression of senescent genes in bone microenvironment, accompanied by decreased senescence-associated secretory phenotypes (SASPs) such as Ccl5, Mmp9, Hmgb1, Nfkb1, and Vcam1. In vitro, Bmp9 treatment inhibits osteoblast senescence through activating Smad1, which suppresses the transcriptional activity of Stat1, thereby inhibits P21 expression and SASPs production. Furthermore, inhibiting the Smad1 signal in vivo can reverse the inhibitory effect of BMP9 on Stat1 and downstream senescent genes, which eliminates the protection of BMP9 on age-related osteoporosis. These findings highlight the critical role of BMP9 on reducing age-related bone loss by inhibiting osteoblast senescence through Smad1-Stat1-P21 axis.
年龄相关性骨质疏松症的特征是衰老的成骨细胞在骨微环境中积累，成骨分化显著降低。清除衰老细胞有助于改善老年小鼠的骨形成。骨形态发生蛋白9（BMP9）是一种由肝脏产生和分泌的多功能蛋白质，据报道可改善雌激素缺乏引起的骨质疏松症。然而，BMP9的作用机制尚未完全阐明，其对老年性骨质疏松症的影响也未见报道。本研究表明，BMP9可显著增加老年小鼠的骨量并改善骨生物力学性能。此外，BMP9可降低骨微环境中衰老基因的表达，同时伴随着衰老相关分泌表型（SASPs）如Ccl5、Mmp9、Hmgb1、Nfkb1和Vcam1的减少。在体外，Bmp9处理通过激活Smad1抑制成骨细胞衰老，Smad1抑制Stat1的转录活性，从而抑制P21表达和SASPs产生。此外，在体内抑制Smad1信号可逆转BMP9对Stat1和下游衰老基因的抑制作用，从而消除BMP9对年龄相关性骨质疏松症的保护作用。这些发现突出了BMP9通过Smad1-Stat1-P21轴抑制成骨细胞衰老在减少年龄相关性骨质流失中的关键作用。
