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- Title
BMP9 reduces age-related bone loss in mice by inhibiting osteoblast senescence through Smad1-Stat1-P21 axis.
- Authors
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
- Abstract
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.
- Subjects
OSTEOPOROSIS; BONE morphogenetic proteins; CELLULAR aging; STAT proteins; MICE; AGING
- Publication
Cell Death Discovery, 2022, Vol 8, Issue 1, p1
- ISSN
2058-7716
- Publication type
Article
- DOI
10.1038/s41420-022-01048-8