Yuhe Wang, Shipei Yang, Yulu Yuan, Danping Fan, Hongyan Zhao, Meijie Liu
Collectively, these findings suggest that the protective effects of estrogen against osteoclast-mediated bone resorption are associated with modulation of the RhoA-Pkn3-c-Src signaling pathway, providing additional insight into the mechanisms underlying PMOP.
Postmenopausal osteoporosis (PMOP) is characterized by excessive bone resorption caused by increased osteoclast activity. Estrogen remains an effective therapeutic option for preventing bone loss; however, its regulatory effects on osteoclast cytoskeletal remodeling have not been fully clarified. In this study, an ovariectomized (OVX) rat model and RANKL-induced RAW264.7 osteoclasts were used to investigate the role of the RhoA-Pkn3-c-Src signaling pathway in the anti-resorptive effects of estrogen. Bone microarchitecture was evaluated by micro-computed tomography, while osteoclast activity and pathway-related proteins were assessed using histological staining and immunofluorescence. In vitro, osteoclast differentiation, bone resorption, actin ring formation, and protein interactions were analyzed, with additional validation using a RhoA agonist. Estrogen treatment markedly alleviated OVX-induced bone loss, reduced osteoclast number and activity, and improved trabecular bone microarchitecture. These changes were accompanied by decreased expression of RhoA, Pkn3, c-Src, and Pyk2 in osteoclasts. Consistently, estrogen suppressed RANKL-induced osteoclast differentiation, bone resorption, and cytoskeletal remodeling in vitro, whereas activation of RhoA partially attenuated these effects. Collectively, these findings suggest that the protective effects of estrogen against osteoclast-mediated bone resorption are associated with modulation of the RhoA-Pkn3-c-Src signaling pathway, providing additional insight into the mechanisms underlying PMOP.