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Currently the precise treatment strategies of disuse OP remain largely unexplored. Piezo1, a mechanosensitive calcium (Ca<jats:sup>2+<\/jats:sup>) ion channel, is a key force sensor mediating mechanotransduction and it is demonstrated to regulate bone homeostasis and osteogenesis in response to mechanical forces. Using structure\u2010based drug design, a novel small\u2010molecule Piezo1 agonist, MCB\u201022\u2010174, which can effectively activate Piezo1 and initiate Ca<jats:sup>2+<\/jats:sup> influx, is developed and is more potent than the canonical Piezo1 agonist, Yoda1. Moreover, MCB\u201022\u2010174 is found as a safe Piezo1 agonist without any signs of serious toxicity. Mechanistically, Piezo1 activation promotes the proliferation of bone marrow mesenchymal stem cells by activating the Ca<jats:sup>2+<\/jats:sup>\u2010related extracellular signal\u2010related kinases and calcium\u2013calmodulin (CaM)\u2010dependent protein kinase II (CaMKII) pathway. Importantly, MCB\u201022\u2010174 could effectively promote osteogenesis and attenuate disuse OP in\u2009vivo. Overall, the findings provide a promising therapeutic strategy for disuse OP by chemical activation of Piezo1.<\/jats:p>","DOI":"10.1002\/smsc.202400061","type":"journal-article","created":{"date-parts":[[2024,6,30]],"date-time":"2024-06-30T14:58:31Z","timestamp":1719759511000},"source":"Crossref","is-referenced-by-count":15,"title":["A Novel Piezo1 Agonist Promoting Mesenchymal Stem Cell Proliferation and Osteogenesis to Attenuate Disuse Osteoporosis"],"prefix":"10.1002","author":[{"given":"Ruihan","family":"Hao","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)  Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hairong","family":"Tang","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of Targeted Drugs School of Pharmaceutical Sciences Shanghai Jiao Tong University  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyong","family":"Ding","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of Targeted Drugs School of Pharmaceutical Sciences Shanghai Jiao Tong University  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhavana","family":"Rajbanshi","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venereology Tongji University School of Medicine  Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)  Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ding","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)  Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhouyi","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)  Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Qi","sequence":"additional","affiliation":[{"name":"Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co\u2010constructed by the Province and Ministry Guangxi Medical University  Nanning Guangxi 530021 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liming","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)  Shanghai 200092 China"},{"name":"National Facility for Translational Medicine (Shanghai)  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6149-7095","authenticated-orcid":false,"given":"Bingjun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)  Shanghai 200092 China"},{"name":"National Facility for Translational Medicine (Shanghai)  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7205-9202","authenticated-orcid":false,"given":"Ao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of Targeted Drugs School of Pharmaceutical Sciences Shanghai Jiao Tong University  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0134-1347","authenticated-orcid":false,"given":"Xiaoling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM)  Shanghai 200092 China"},{"name":"National Facility for Translational Medicine (Shanghai)  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,30]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1007\/s00223-021-00836-1","volume":"110","author":"Rolvien T.","year":"2022","journal-title":"Calcif. 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