{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:07:02Z","timestamp":1790644022405,"version":"4.1.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T00:00:00Z","timestamp":1665964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31570906, 81671476"],"award-info":[{"award-number":["31570906, 81671476"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007128","name":"Natural Science Foundation of Shaanxi Province","doi-asserted-by":"publisher","award":["2019SF-059, 2020SF-204, 2021ZDLSF02-02"],"award-info":[{"award-number":["2019SF-059, 2020SF-204, 2021ZDLSF02-02"]}],"id":[{"id":"10.13039\/501100007128","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>In the adult skeleton, the bone remodeling process involves a dynamic coordination between osteoblasts and osteoclasts, which is disrupted in diseases with high bone turnover rates and dysregulated transforming growth factor beta 1 (TGF-\u03b21). However, little is known about how TGF-\u03b21 signaling mediates bone resorption. Here, we described a pedigree with a heterozygous variant in TGF-\u03b21 (R218C) that resulted in aberrant activation of TGF-\u03b21 through an activating mechanism that caused Camurati-Engelmann disease (CED). We showed that CED patients have high levels of active Rho GTPases and the migration-related proteins Integrin \u03b21 and Integrin \u03b23 in their peripheral blood. HEK293T cells transfected with a plasmid encoding this mutant expressed high levels of TGF-\u03b21 and active Rho GTPases. Furthermore, activation of Rho by TGF-\u03b21 increased osteoclast formation and bone resorption, with increased migration of pre-osteoclasts, as well as cytoskeletal remodeling of pre-osteoclasts and mature osteoclasts. Importantly, pharmacological inhibition of Rho GTPases effectively rescued hyperactive TGF-\u03b21-induced osteoclastogenesis <jats:italic>in vitro<\/jats:italic>. Overall, we propose that Rho GTPases mediate TGF-\u03b21-induced osteoclastogenesis and suggest that Rho-TGF-\u03b21 crosstalk is associated with high bone turnover in CED.<\/jats:p>","DOI":"10.3389\/fendo.2022.913979","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T06:46:53Z","timestamp":1665989213000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Aberrant activation of TGF-\u03b21 induces high bone turnover via Rho GTPases-mediated cytoskeletal remodeling in Camurati-Engelmann 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