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Previously, we demonstrated that an antioxidant, resveratrol, substantially reduces the intracellular accumulation of mutant\u2010COMP, dampens cellular stress, and lowers the level of growth plate chondrocyte death. In addition, we showed that resveratrol reduces mammalian target of rapamycin complex 1 (mTORC1) signaling, suggesting a potential mechanism. In this work, we investigate the role of autophagy in treatment of COMPopathies. In cultured chondrocytes expressing wild\u2010type COMP or mutant\u2010COMP, resveratrol significantly increased the number of Microtubule\u2010associated protein 1A\/1B\u2010light chain 3 (LC3) vesicles, directly demonstrating that resveratrol\u2010stimulated autophagy is an important component of the resveratrol\u2010driven mechanism responsible for the degradation of mutant\u2010COMP. Moreover, pharmacological inhibitors of autophagy suppressed degradation of mutant\u2010COMP in our established mouse model of PSACH. In contrast, blockage of the proteasome did not substantially alter resveratrol clearance of mutant\u2010COMP from growth plate chondrocytes. Mechanistically, resveratrol increased SIRT1 and PP2A expression and reduced MID1 expression and activation of phosphorylated protein kinase B (pAKT) and mTORC1 signaling in growth plate chondrocytes, allowing clearance of mutant\u2010COMP by autophagy. Importantly, we show that optimal reduction in growth plate pathology, including decreased mutant\u2010COMP retention, decreased mTORC1 signaling, and restoration of chondrocyte proliferation was attained when treatment was initiated between birth to 1 week of age in MT\u2010COMP mice, translating to birth to approximately 2\u2009years of age in children with PSACH. These results clearly demonstrate that resveratrol stimulates clearance of mutant\u2010COMP by an autophagy\u2010centric mechanism. \u00a9 2020 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10456","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T17:20:10Z","timestamp":1608312010000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Resveratrol Reduces\n                    <scp>COMPopathy<\/scp>\n                    in Mice Through Activation of Autophagy"],"prefix":"10.1093","volume":"5","author":[{"given":"Jacqueline T","family":"Hecht","sequence":"first","affiliation":[{"name":"Department of Pediatrics, McGovern Medical School The University of Texas Health Science Center at Houston 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