BMP9 reduces age-related bone loss in mice by inhibiting osteoblast senescence through Smad1-Stat1-P21 axis

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.

STAT1 negatively regulates human glioma U251 cell proliferation Huang et al: Role of STAT1 in glioma

“…Research has shown that Bmp9 treatment inhibits osteoblast senescence through activating Smad1, which suppresses the transcriptional activity of Stat1, thereby inhibits P21 expression and SASPs production. 29 Sun Y et al showed that 82% (82/100) of pancreatic adenocarcinoma cases expressed Stat1 protein, whereas 72% (72/100) of PA cases expressed p21 protein. The expression of these 2 proteins was positively correlated (co-expressed in tumor cells), whereas the loss of expression of Stat1 and p21 proteins was associated with tumor dedifferentiation, advanced clinical stages, and LN metastasis of pancreatic cancer.…”

Single-Cell RNA-Sequencing Reveals the Skeletal Cellular Dynamics in Bone Repair and Osteoporosis

“…Alterations in the number and function of BMSCs are an important cause of senile osteoporosis [ 80 , 81 , 82 ]. The proportion of senescent BMSCs in the skeletal microenvironment increases with age, thereby leading to a decrease in the osteogenic capacity of osteoblasts [ 81 , 83 ]. Notably, only a small fraction of cells undergo senescence even at advanced ages.…”

The roles of hepatokine and osteokine in liver-bone crosstalk: Advance in basic and clinical aspects

“…proved that overexpression of BMP9 led to not only elevated BMP9 levels in the liver and serum but also suppressed bone resorption activity, improved cortical and trabecular volumetric BMD, and ameliorated bone strength in an ovariectomy mouse model ( 21 , 60 ). BMP9 increased bone mass in aged mice by preventing osteoblast senescence and stimulating osteoblast differentiation, improved bone biomechanical properties, and ameliorated the bone microenvironment ( 61 ). Aside from directly influencing bone resorption and bone formation, BMP9 upregulated the endogenous expression of RUNX3 in mesenchymal stem cells ( 62 ), which are undifferentiated stem cells with the potential to differentiate into multiple lineages, including osteoblasts ( 63 ).…”