MST4 as a Key Driver of Osteoclast Activation in Osteoporosis

Osteoporosis, characterized by excessive bone resorption driven by heightened osteoclast activity, remains a major health concern with molecular mechanisms that are not fully understood. This study explores the role of mammalian Sterile 20-like kinase 4 (MST4), a member of the Sterile 20 (Ste20) kinase family, in osteoclast differentiation and function. Analysis of blood samples from osteoporosis patients revealed a significant increase in MST4 expression compared to healthy controls, with a negative correlation to bone mineral density (BMD). In vitro experiments using stem cell-derived osteoclast models showed that MST4 knockdown reduced osteoclast differentiation and bone resorption activity, whereas MST4 overexpression enhanced these processes. In vivo studies with ovariectomized (OVX) mouse models further corroborated these findings. Mechanistically, MST4 was found to promote tumor necrosis factor receptor-associated factor 6 (TRAF6) autoubiquitination through phosphorylation, a critical event for osteoclast activation. Collectively, these results identify MST4 as a key regulator of osteoclast-mediated bone resorption in osteoporosis, suggesting that targeting the MST4–TRAF6 signaling axis may offer a novel therapeutic strategy to prevent bone loss.