Author:
Chen Qi,Yao Yan,Chen Kun,Chen Xihui,Li Bowen,Li Rui,Mo Lidangzhi,Hu Weihong,Zhang Mengjie,Wang Zhen,Wu Yaoping,Wu Yuanming,Liu Fangfang
Abstract
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-β1). However, little is known about how TGF-β1 signaling mediates bone resorption. Here, we described a pedigree with a heterozygous variant in TGF-β1 (R218C) that resulted in aberrant activation of TGF-β1 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 β1 and Integrin β3 in their peripheral blood. HEK293T cells transfected with a plasmid encoding this mutant expressed high levels of TGF-β1 and active Rho GTPases. Furthermore, activation of Rho by TGF-β1 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-β1-induced osteoclastogenesis in vitro. Overall, we propose that Rho GTPases mediate TGF-β1-induced osteoclastogenesis and suggest that Rho-TGF-β1 crosstalk is associated with high bone turnover in CED.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Shaanxi Province
Subject
Endocrinology, Diabetes and Metabolism
Cited by
1 articles.
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