Tomatidine suppresses osteoclastogenesis and mitigates estrogen deficiency‐induced bone mass loss by modulating TRAF6‐mediated signaling

摘要

Postmenopausal osteoporosis is initiated by estrogen withdrawal and is characterized mainly by over‐activated osteoclastic bone resorption. Targeting TNF receptor‐associated factor 6 (TRAF6) or its downstream signaling pathways to modulate osteoclast formation and function is an appealing strategy for osteoclast‐related disorders. In the present study, we determined the effect of tomatidine, a steroidal alkaloid derived from Solanaceae, on the formation and function of receptor activator of NF‐κB (RANK) ligand‐induced osteoclasts and the underlying mechanism. Tomatidine inhibited osteoclast formation in a dose‐dependent manner and decreased the expression of osteoclast marker genes. Actin ring formation and osteoclastic bone resorption were attenuated in the presence of tomatidine in vitro . Eight weeks after ovariectomy, tomatidine prevented estrogen deficiency‐induced bone loss and restored the mechanical properties of the femur. At the molecular level, tomatidine abrogated phosphorylation of c‐Jun N‐terminal kinase (JNK)/p38, NF‐κB, and protein kinase B (Akt) pathway proteins by suppressing RANK expression, inhibiting the binding of TRAF6 to RANK, and downregulating the osteoclastogenesis marker‐related protein expression. In summary, these data demonstrated that tomatidine attenuated osteoclast formation and function by modulating multiple TRAF6‐mediated pathways. Therefore, tomatidine could be a novel candidate for the treatment of osteoclast‐related disorders, including osteoporosis.—Hu, B., Sun, X., Yang, Y., Ying, Z., Meng, J., Zhou, C., Jiang, G., Li, S., Wu, F., Zhao, X., Zhu, H., Wu, H., Cai, X., Shi, Z., Yan, S. Tomatidine suppresses osteoclastogenesis and mitigates estrogen deficiency‐induced bone mass loss by modulating TRAF6‐mediated signaling. FASEB J. 33,2574–2586 (2019). www.fasebj.org

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