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RhoA/Rock activation represents a new mechanism for inactivating Wnt/β-catenin signaling in the aging-associated bone loss

引用

Cell Regeneration 2021年第1期10卷 76-94页

作者： Wei Shi Chengyun Xu Ying Gong Jirong Wang Qianlei Ren Ziyi Yan Liu Mei Chao Tang Xing Ji Xinhua Hu Meiyu Qv musaddique hussain Ling-Hui Zeng Ximei Wu Department of Pharmacology Zhejiang University School of Medicine866 Yuhangtang RoadHangzhou 310058China Department of Biology and Genetics University of North Carolina-Chapel HillChapel HillNC 27599USA Department of Orthopeadic Surgery of Sir Run Run Shaw Hospital Zhejiang University School of MedicineHangzhou 310016China Department of Pharmacology Zhejiang University City College51 Huzhou StreetHangzhou 310015China Translational Research Program in Pediatric Orthopaedics The Children’s Hospital of PhiladelphiaPhiladelphiaPA 19104USA

The Wnt/β-catenin signaling pathway appears to be particularly important for bone homeostasis,whereas nuclear accumulation ofβ-catenin requires the activation of Rac1,a member of the Rho small GTPase *** 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 *** find that Lrp5/6-dependent and Lrp5/6-independent RhoA/Rock activation by Wnt3a activates Jak1/2 to directly phosphorylate Gsk3βat Tyr216,resulting in Gsk3βactivation and subsequentβ-catenin *** 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 ofβ-catenin,***,RhoA loss-of-function in pre-osteoblasts robustly increases bone formation while gain-of-function decreases ***,high RhoA/Rock activity closely correlates with Jak and Gsk3βactivities but inversely correlates withβ-catenin signaling activity in bone marrow mesenchymal stromal cells from elderly male humans and mice,whereas systemic inhibition of Rock therefore activates theβ-catenin signaling to antagonize aging-associated bone *** together,these results identify RhoA/Rock-dependent Gsk3βactivation and subsequentβ-catenin destabilization as a hitherto uncharacterized mechanism controlling limb outgrowth and bone homeostasis.

关键词： RhoA Rock Wnt β-Catenin Limb bud Bone

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