Effects and mechanism of conditional osteoblast PHB1 knockout on bone metabolism in miceOA

Background:Postmenopausal osteoporosis(PMOP)is a highly prevalent metabolic bone disorder with limited effective clinical therapies.To verify prohibitin 1(PHB1)as a potential therapeutic target for PMOP,we generated an osteoblast-specific PHB1 conditional knockout(CKO)mouse model.This strategy is based on our preliminary results that Huangqi Sanxian Decoction enhances osteogenesis by inhibiting PHB1 expression,indicating that PHB1 may serve as a critical negative regulator of bone formation.Methods:An osteoblast-specific PHB1 conditional knockout(CKO)mouse model was established for in vivo experiments.In vitro assays were conducted to evaluate the biological functions of PHB1 knockout on osteoblasts,including assessments of cell proliferation,differentiation,and survival.Molecular analyses were performed to detect the expression of osteogenic markers and the activity of the PI3K/Akt signaling pathway.Results:Compared to controls,CKO mice exhibited significantly increased bone mineral density(BMD),elevated bone formation marker(PINP),and reduced bone resorption marker(CTX-1)and osteoclast number.In vitro,PHB1 knockout enhanced osteoblast proliferation,differentiation(increased ALP activity and mineralization),and survival(elevated Bcl-2/Bax ratio,decreased caspase-3),while upregulating osteogenic markers(OPN,Runx2).Mechanistically,the PI3K/Akt pathway was activated,as indicated by an increased p-Akt/Akt ratio.Conclusion:These findings demonstrate that osteoblast-specific PHB1 deletion promotes bone formation and inhibits resorption via the PI3K/Akt pathway,offering a mechanistic foundation for PHB1-targeted therapies in PMOP.