TY - JOUR AU - Shi, Wei AU - Xu, Chengyun AU - Gong, Ying AU - Wang, Jirong AU - Ren, Qianlei AU - Yan, Ziyi AU - Mei, Liu AU - Tang, Chao AU - Ji, Xing AU - Hu, Xinhua AU - Qv, Meiyu AU - Hussain, Musaddique AU - Zeng, Ling-Hui AU - Wu, Ximei PY - 2021 DA - 2021/03/03 TI - RhoA/Rock activation represents a new mechanism for inactivating Wnt/β-catenin signaling in the aging-associated bone loss JO - Cell Regeneration SP - 8 VL - 10 IS - 1 AB - The Wnt/β-catenin signaling pathway appears to be particularly important for bone homeostasis, whereas nuclear accumulation of β-catenin requires the activation of Rac1, a member of the Rho small GTPase family. The aim of the present study was to investigate the role of RhoA/Rho kinase (Rock)-mediated Wnt/β-catenin signaling in the regulation of aging-associated bone loss. We find that Lrp5/6-dependent and Lrp5/6-independent RhoA/Rock activation by Wnt3a activates Jak1/2 to directly phosphorylate Gsk3β at Tyr216, resulting in Gsk3β activation and subsequent β-catenin destabilization. In line with these molecular events, RhoA loss- or gain-of-function in mouse embryonic limb bud ectoderms interacts genetically with Dkk1 gain-of-function to rescue the severe limb truncation phenotypes or to phenocopy the deletion of β-catenin, respectively. Likewise, RhoA loss-of-function in pre-osteoblasts robustly increases bone formation while gain-of-function decreases it. Importantly, high RhoA/Rock activity closely correlates with Jak and Gsk3β activities but inversely correlates with β-catenin signaling activity in bone marrow mesenchymal stromal cells from elderly male humans and mice, whereas systemic inhibition of Rock therefore activates the β-catenin signaling to antagonize aging-associated bone loss. Taken together, these results identify RhoA/Rock-dependent Gsk3β activation and subsequent β-catenin destabilization as a hitherto uncharacterized mechanism controlling limb outgrowth and bone homeostasis. SN - 2045-9769 UR - https://doi.org/10.1186/s13619-020-00071-3 DO - 10.1186/s13619-020-00071-3 ID - Shi2021 ER -