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Overexpression of ubiquitin specific protease 25 suppresses osteoclastogenesis and alleviates bone loss in OVX mice

Qunhu Zhang^a,?, Huanhuan Chen^a,?, Shiyuan Yin^a, Yu Wang^a, Chengjuan Wang^a, Ce Shi^b,*, Chaoming Huang^a,*

 
ABSTRACT:      Ubiquitin specific protease 25 (USP25), a deubiquitinase, has been associated with inflammation, cancer, and immune response. However, the effect of USP25 on bone metabolism in postmenopausal osteoporosis (PMOP) is still unclear. Here, we examined the role of USP25 in the regulation of bone resorption and osteoclastogenesis in PMOP. The expression of USP25 was assessed in patients with PMOP and ovariectomy (OVX) mice. The role of USP25 on osteoclastogenesis was analyzed using osteoclastogenesis and bone resorption assays. The effect of USP25 inhibition was evaluated in a OVX mice model. The mechanism by which USP25 regulates osteoclastogenesis and bone resorption was explored through a series of in vitro studies. USP25 was downregulated in OVX miceandPMOPpatients. USP25 suppressed osteoclastogenesis and bone resorption in vitro, and it inhibited the expression of osteoclast-related genes. USP25 regulated osteoclastogenesis by promoting tumor necrosis factor receptor-associated factor 6 (TRAF6) deubiquitination. Moreover, AZ1, a selective small molecule blocker of USP25, could exacerbate pathological bone loss in OVX mice. In conclusion, these data unequivocally suggest that USP25 could suppress osteoclast differentiation and impede bone absorption by restraining TRAF6 polyubiquitination. USP25 overexpression could effectively alleviate pathological bone loss in OVX mice. Therefore, USP25 may be used as a new target for the treatment of bone loss in PMOP

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* Corresponding author, E-mail: shice99@126.com, huangao2019@163.com

Received 15 Jan 2025, Accepted 0 0000