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

Abstract

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.

Aberrant activation of TGF-β1 induces high bone turnover via Rho GTPases-mediated cytoskeletal remodeling in Camurati-Engelmann disease

“…In the future, a treatment approach that modulates the TGF-β1 signaling pathway might be effective in patients with CED ( 5 ). In a recent study, the inhibition of RhoA/ROCK prevented aging-associated bone loss ( 44 ). Similarly, our findings raise the possibility of a treatment for diseases in which TGF-β1 is abnormally activated, including CED.…”

Morphometric Analysis of Rat Prostate Development: Roles of MEK/ERK and Rho Signaling Pathways in Prostatic Morphogenesis

“…Other studies have shown that Wnt signaling can activate Rho kinase through both canonical and non-canonical pathways [ 47 , 48 ]. Rho/Rho-kinase integrate Wnt-induced signals spatially and temporally to promote transcriptional and morphological changes in cells regulating multiple cellular processes, including cell polarity, proliferation, differentiation, and apoptosis [ 49 ]. Our findings in the current study suggest that activation of Rho signaling pathways by Wnt ligands may be an essential downstream mechanism of prostate branching morphogenesis.…”

Tumor Microenvironment in Acute Myeloid Leukemia: Adjusting Niches

“…This alteration might also explain the well-known increasingly reduced bone marrow cellularity in the course of life. The underlying change of MSC differentiation is achieved via different mechanisms, including altered cytokine levels, resulting in decreased Wnt-related signaling and intensified RhoA-related signaling ( 38 ) as well as reduced Runx2 signaling, which is important for osteoblastic differentiation ( 39 ). “Senescence” that can be attributed to (cumulative effects of) pro-inflammatory cytokines, and changes of the sympathetic nerve system during life affect MSC ( 40 ).…”