TNF-α promotes osteoclastogenesis through JNK signaling-dependent induction of Semaphorin3D expression in estrogen-deficiency induced osteoporosis

Tumor necrosis factor a (TNF-alpha)-induced osteoclast formation have been demonstrated to play an important role in the pathogenesis of estrogen deficiency-mediated bone loss, but the exact mechanisms by which TNF-alpha enhanced osteoclast differentiation were not fully elucidated. The class III semaphorins members were critical to regulate bone homeostasis. Here, we identified a novel mechanism whereby TNF-alpha increasing Semaphorin 3D expression contributes to estrogen deficiency-induced osteoporosis. In this study, we found that Semaphorin 3D expression was upregulated by TNF-alpha during the process of RANKL-induced osteoclast differentiation. Inhibition of Semaphorin 3D in pre-osteoclasts could attenuate the stimulatory effects of TNF-alpha on osteoclast proliferation and differentiation. Mechanistically, blocking of the Jun N-terminal kinase (JNK) signaling markedly rescued TNF-alpha-induced Semaphorin 3D expression, suggesting that JNK signaling was involved in the regulation of Semaphorin 3D expression by TNF-alpha. In addition, silencing of Semaphorin 3D in vivo could alleviate estrogen deficiency-induced osteoporosis. Our results revealed a novel function for Semaphorin 3D and suggested that increased Semaphorin 3D may contribute to enhanced bone loss by increased TNF-alpha in estrogen deficiency-induced osteoporosis. Thus, Semaphorin 3D may provide a potential therapeutic target for the treatment of estrogen-deficiency induced osteoporosis.