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Tumor necrosis factor α (TNF-α)-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-α 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-α increasing Semaphorin3D expression contributes to estrogen deficiency-induced osteoporosis. In this study, we found that Semaphorin3D expression was upregulated by TNF-α during the process of RANKL-induced osteoclast differentiation. Inhibition of Semaphorin3D in pre-osteoclasts could attenuate the stimulatory effects of TNF-α on osteoclast proliferation and differentiation. Mechanistically, blocking of the Jun N-terminal kinase (JNK) signaling markedly rescued TNF-α-induced Semaphorin3D expression, suggesting that JNK signaling was involved in the regulation of Semaphorin3D expression by TNF-α. In addition, silencing of Semaphorin3D in vivo could alleviate estrogen deficiency-induced osteoporosis. Our results revealed a novel function for Semaphorin3D and suggested that increased Semaphorin3D may contribute to enhanced bone loss by increased TNF-α in estrogen deficiency-induced osteoporosis. Thus, Semaphorin3D may provide a potential therapeutic target for the treatment of estrogen-deficiency induced osteoporosis. [ABSTRACT FROM AUTHOR]

Background: Calcium ion (Ca2+) signals are required for osteoclast differentiation. Previous study showed that transient receptor potential vanilloid 5 (TRPV5) is an essential Ca2+ transporter in osteoclastogenesis and bone resorption. TRPV5 and TRPV6 represent two highly homologous members within the transient receptor potential (TRP) superfamily. However, the role of TRPV6 in bone metabolism is still controversial and little is known about the involvement of TRPV6 in receptor activator of nuclear factor κ-B ligand (RANKL)-induced osteoclastogenesis. Methods: In our study, gene knockout mice, RNA interference, western blot, quantitative real-time PCR, tartrate-resistant acid phosphatase (TRAP) staining, pit formation assay, histomorphometry and measurement of serum parameters were employed to investigate the role of TRPV6 in bone homeostasis, osteoclastogenesis and bone resorption. Results: We found that TRPV6 depletion results in noticeable destruction of bone microarchitecture in TRPV6 knockout mice (TRPV6-/-), suggesting that TRPV6 is a critical regulator in bone homeostasis. Inactivation of Trpv6 had no effect on osteoblastic bone formation. However, quantification of the TRAP staining showed a significantly increased osteoclast number and surface area in the metaphyseal area of femurs bone sections derived from TRPV6-/- mice. In agreement with our observations from TRPV6-/- mice, TRPV6 depletion in vitro significantly increased osteoclasts differentiation and bone resorption activity. Conclusion: Based on these results above, we can draw conclusions that TRPV6 plays an essential role in bone metabolism and is a critical regulator in osteoclasts differentiation and bone resorption. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]