Epoxymicheliolide inhibits osteoclastogenesis and resists OVX-induced osteoporosis by suppressing ERK1/2 and NFATc1 signaling.

Feng Long, Runfeng Chen, Yuangang Su, Jiamin Liang, Yansi Xian, Fan Yang, Haoyu Lian, Jiake Xu, Jinmin Zhao, Qian Liu

International immunopharmacology 2022 Jun

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The hyperactivity of osteoclasts caused by postmenopausal estrogen deficiency plays an imperative role in the progression of osteoporosis. Although osteoporosis-related drugs have been widely used to alleviate this disorder, there is an urgent need for drugs with fewer side effects. In this study, we found that epoxymicheliolide (EMCL), a derivative of parthenolide, has a high affinity to ERK1/2, but the treatment and mechanism of osteoporosis using EMCL have not been explored. Therefore, we intended to figure out the effects and potential mechanisms of EMCL on RANKL-stimulated osteoclast formation and function in vitro, construct an OVX murine model to simulate the therapeutic effects of EMCL on estrogen-deficient bone loss subsequently. EMCL restrained the phosphorylation of ERK1/2 in the RANKL-stimulated MAPK pathway, which in sequence inhibited the transcription and expression of the main osteoclast transcription factor NFATc1, resulting in the suppression of osteoclastogenesis and bone resorption. However, the same concentration of EMCL did not affect the proliferation and differentiation of osteoblasts. In vivo experiments showed that EMCL can significantly resist osteoporosis caused by estrogen deficiency, alleviate bone loss, and reduce the number of osteoclasts. These results suggest that EMCL can reduce osteoclast production and bone resorption by inhibiting ERK1/2 phosphorylation and NFATc1 entering the nucleus, and could be used in the treatment of osteoporosis caused by estrogen deficiency and hyperactivity of osteoclasts. Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Citation

Feng Long, Runfeng Chen, Yuangang Su, Jiamin Liang, Yansi Xian, Fan Yang, Haoyu Lian, Jiake Xu, Jinmin Zhao, Qian Liu. Epoxymicheliolide inhibits osteoclastogenesis and resists OVX-induced osteoporosis by suppressing ERK1/2 and NFATc1 signaling. International immunopharmacology. 2022 Jun;107:108632