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Restrained Mitf-associated autophagy by Mulberroside A ameliorates osteoclastogenesis and counteracts OVX-Induced osteoporosis in mice
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  • Hong Xue,
  • Zhenhua Feng,
  • Putao Yuan,
  • Li Qiao,
  • Qiliang Lou,
  • Xiangde Zhao,
  • Qingliang Ma,
  • Shiyu Wang,
  • Huali Ye,
  • Jiao Cheng,
  • Jiying Wang,
  • Peihua Shi,
  • Xuewu Sun
Hong Xue
Zhejiang University
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Zhenhua Feng
Zhejiang University
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Putao Yuan
Zhejiang University
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Li Qiao
Zhejiang University
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Qiliang Lou
Zhejiang University
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Xiangde Zhao
Zhejiang University
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Qingliang Ma
Zhejiang University
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Shiyu Wang
Zhejiang University
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Huali Ye
Zhejiang University
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Jiao Cheng
Zhejiang University
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Jiying Wang
Zhejiang University
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Peihua Shi
Zhejiang University
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Xuewu Sun
Zhejiang University

Corresponding Author:[email protected]

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Abstract

Background and Purpose: Overactivated osteoclasts disrupt the mineral homeostasis of bone, inducing osteoporosis. Despite the rapid development of pharmacological therapy in osteoporosis, a safer and more effective treatment remains to be explored. Recently, the connection between osteoporosis and autophagy has gained more attention. Autophagy activation promotes osteoclastogenesis and the development of osteoporosis. Mulberroside A (Mul-A), a natural component extracted from mulberry bark and branches, has various pharmacological functions. Nevertheless, the role of Mulberroside A on osteoporosis and autophagy is unknown. Here, we aimed to investigate the changes in osteoclastogenesis and autophagy occurrence in response to Mulberroside A. Experimental and Approach: TRAP staining and bone resorption assay were used to confirm the inhibitory effect of Mul-A on osteoclastogenesis and function. Western blot, Quantitative real-time PCR, transmission electron microscope and confocal microscope were performed to explore the mechanism. Ovariectomy(OVX) was employed to verify the therapeutic effect of Mul-A on osteoporosis in vivo. Key Results: Mul-A effectively suppresses osteoclastogenesis in vitro and counteracts the bone loss caused by ovariectomy(OVX). Mechanically, Mul-A represses the occurrence of autophagy flux during osteoclastogenesis, which can be attributed to the restrained expression of microphthalmia-related transcription factor(Mitf) and its nuclear translocation. Moreover, the application of two autophagy agonists, rapamycin and Torin 1, attenuates the osteoclastogenic regulatory role of Mul-A as well. Conclusions and Implications: Our study demonstrates that Mul-A damages the differentiation of osteoclasts and ameliorates osteoporosis caused by estrogen deficiency through modulation of Mitf-associated autophagy, suggesting its therapeutic potential against osteoporosis.