BMP9 reduces age-related bone loss in mice by inhibiting osteoblast senescence through Smad1-Stat1-P21 axis.
BMP9 reduces age-related bone loss in mice by inhibiting osteoblast senescence through Smad1-Stat1-P21 axis.
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BMP9通过Smad1-Stat1-P21轴抑制成骨细胞衰老，从而减少小鼠年龄相关性骨质流失。
DOI：
10.1038/s41420-022-01048-8
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发表时间：
2022-05-06
影响因子：
7
通讯作者：
Liu, Jian-min
中科院分区：
文献类型：
--
作者：
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
老年性骨质疏松症的特征是衰老的成骨细胞在骨微环境中积聚，成骨分化明显降低。清除衰老细胞有助于改善衰老小鼠的骨形成。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，有报道可改善雌激素停用引起的骨质疏松症。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作用也未见报道。本研究表明，BMP9可显著增加老年小鼠的骨量，改善骨生物力学性能。此外，BMP9减少了骨骼微环境中衰老基因的表达，并伴随着CCL5、Mmp9、HMGB1、Nfkb1和Vcam1等衰老相关分泌表型(SASP)的减少。在体外，BMP9通过激活Smad1抑制STAT1的转录活性，从而抑制P21表达和SASPs的产生，从而抑制成骨细胞的衰老。此外，在体内抑制Smad1信号可以逆转BMP9对STAT1及其下游衰老基因的抑制作用，从而消除BMP9对老年性骨质疏松的保护作用。这些发现强调了BMP9通过Smad1-STAT1-P21轴抑制成骨细胞衰老，从而减少与年龄相关的骨丢失的关键作用。BMP9通过激活Smad1抑制STAT1的转录，从而抑制成骨细胞中P21的表达和SASPs的产生，从而抑制细胞的衰老。BMP9的抗衰老作用有利于改善老年性骨质疏松症。
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. BMP9 inhibits cellular senescence by activation of Smad1, which suppresses the transcription of Stat1, resulting in decreased P21 expression and SASPs production in osteoblast. The anti-aging effect of BMP9 is benefit to improving age-related osteoporosis.
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影响因子：
82.9
作者：
Farr JN;Xu M;Weivoda MM;Monroe DG;Fraser DG;Onken JL;Negley BA;Sfeir JG;Ogrodnik MB;Hachfeld CM;LeBrasseur NK;Drake MT;Pignolo RJ;Pirtskhalava T;Tchkonia T;Oursler MJ;Kirkland JL;Khosla S
通讯作者：
Khosla S
影响因子：
3.7
作者：
Chen, Xiaojing;Zhang, Shuang;Gao, Yanhong
通讯作者：
Gao, Yanhong
影响因子：
4.1
作者：
Farr, Joshua N.;Khosla, Sundeep
通讯作者：
Khosla, Sundeep
影响因子：
7.5
作者：
Choi, Da Hyeon;Oh, Se-Young;Park, Yoon Shin
通讯作者：
Park, Yoon Shin
影响因子：
6.2
作者：
Colaianni, Graziana;Errede, Mariella;Grano, Maria
通讯作者：
Grano, Maria