C-Jun NH2-terminal kinase inhibitor bentamapimod prevents RANKL-mediated osteoclastogenesis and ovariectomy-induced...

Over the past five decades, numerous treatment approaches have been developed to target either the inhibition of bone resorption or the promotion of bone formation. However, therapeutic strategies for osteoporosis still face limitations and safety concerns. Bentamapimod, initially designed for neurological disorders, is a novel JNK inhibitor that has demonstrated anti-tumor and immunomodulatory properties. In this study, we aim to investigate the protective role of bentamapimod against bone loss in mice suffering from estrogen deficiency. In vivo, we investigated that bentamapimod alleviated bone loss in mice suffering from estrogen deficiency. According to the micro-CT and histomorphometry assays, bentamapimod inhibits bone resorption as well as bone formation, but the effect of bentamapimod on bone resorption is better than that of bone formation, which ultimately results in ameliorating bone loss caused by ovariectomy. Moreover, we confirmed that bentamapimod can attenuate receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclast differentiation via inactivating the JNK, while anisomycin (a JNK agonist) partially confronts this effect. Our study demonstrated that bentamapimod would be able to be used as a promising new drug strategy for osteoporosis via inhibiting osteoclast differentiation both in vitro and in vivo.