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

ABSTRACT: The Wnt/?-catenin signaling pathway appears to be particularly important for bone homeostasis, whereas nuclear accumulation of ?-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/?-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 Gsk3? at Tyr216, resulting in Gsk3? activation and subsequent ?-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 ?-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 Gsk3? activities but inversely correlates with ?-catenin signaling activity in bone marrow mesenchymal stromal cells from elderly male humans and mice, whereas systemic inhibition of Rock therefore activates the ?-catenin signaling to antagonize aging-associated bone loss. Taken together, these results identify RhoA/Rock-dependent Gsk3? activation and subsequent ?-catenin destabilization as a hitherto uncharacterized mechanism controlling limb outgrowth and bone homeostasis.

SUBMITTER: Shi W

PROVIDER: S-EPMC7925793 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Shi Wei W Shi Wei W Xu Chengyun C Gong Ying Y Wang Jirong J Ren Qianlei Q Yan Ziyi Z Mei Liu L Tang Chao C Ji Xing X Hu Xinhua X Qv Meiyu M Hussain Musaddique M Zeng Ling-Hui LH Wu Ximei X

Cell regeneration (London, England) 20210303 1

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 phosphorylat ...[more]

PMID: 33655459

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Project description:BackgroundForkhead box protein f1 (Foxf1) is associated with cell differentiation, and may be a key player in bone homoeostasis. However, the effect of Foxf1 on osteogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) and ovariectomy-induced bone loss, as well as its clinical implications, is unknown.MethodsBy quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blotting, we assayed Foxf1 expression in bone tissue, BMSCs, and bone marrow-derived macrophages (BMMs), derived from ovariectomised (OVX) mice, and during osteogenic differentiation and osteoclast differentiation. Using a loss-of-function approach (small interfering RNA [siRNA]-mediated knockdown) in vitro, we examined whether Foxf1 regulates osteoblast differentiation of BMSCs via the Wnt/β-catenin signalling pathway. Furthermore, we assessed the anabolic effect of Foxf1 knockdown (siFoxf1) in OVX mice in vivo. We also assayed the expression of Foxf1 in bone tissue derived from postmenopausal osteoporosis (PMOP) patients and its link with bone mineral density (BMD). Finally, we examined the effect of Foxf1 knockdown on the osteoblastic differentiation of human BMSCs.FindingsFoxf1 expression was significantly increased in bone extract and BMSCs from OVX mice and gradually decreased during osteoblastic differentiation of BMSCs but did not differ significantly in OVX mouse-derived BMMs or during osteoclast differentiation. In vitro, Foxf1 knockdown markedly increased the expression of osteoblast specific genes, alkaline phosphatase (ALP) activity, and mineralisation. Moreover, siFoxf1 activated the Wnt/β-catenin signalling pathway. The siFoxf1-induced increase in osteogenic differentiation was partly rescued by inhibitor of Wnt signalling (DKK1). In OVX mice, Foxf1 siRNA significantly reduced bone loss by enhancing bone formation. Foxf1 expression levels negatively correlated with reduced bone mass and bone formation in bone tissue from PMOP patients. Finally, Foxf1 knockdown significantly promoted osteogenesis by human BMSCs.InterpretationOur findings indicate that Foxf1 knockdown promotes BMSC osteogenesis and prevents OVX-induced bone loss. Therefore, Foxf1 has potential as a biomarker of osteogenesis and may be a therapeutic target for PMOP.

Dataset Information

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

Publications

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

Similar Datasets

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