Wnt/β-catenin signaling is differentially regulated by Gα proteins and contributes to fibrous dysplasia

Regard, Jean B.; Cherman, Natasha; Palmer, Daniel; Kuznetsov, Sergei A.; Celi, Francesco S.; Guettier, Jean‐Marc; Chen, Min; Bhattacharyya, Nisan; Wess, Jürgen; Coughlin, Shaun R.; Weinstein, Lee S.; Collins, Michael T.; Robey, Pamela Gehron; Yang, Yingzi

doi:10.1073/pnas.1114656108

Cited by 94 publications

(107 citation statements)

References 51 publications

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“…This raises the possibility that Vegfa might require one or more co-factors to exert its effect on osteoblast differentiation; alternatively, Vegfa functions via intracrine rather than paracrine mechanisms, as described in adult mice (Liu et al, 2012). We also tested the possible involvement of Gαs (Gnas -Mouse Genome Informatics), which is a modulator of Wnt/β-catenin and Hh signaling activities in mesenchymal progenitors (Regard et al, 2011(Regard et al, , 2013. In hindlimb lysates, Gαs expression was not affected in Vegfa fl/fl ; Osx-Cre:GFP mice (supplementary material Fig.…”

Section: Vegfa Stimulates Ihh Expression and Represses Notch2 Levelsmentioning

confidence: 99%

Vegfa regulates perichondrial vascularity and osteoblast differentiation in bone development

Duan

Murata

et al. 2015

Development

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Vascular endothelial growth factor A (Vegfa) has important roles in endochondral bone formation. Osteoblast precursors, endothelial cells and osteoclasts migrate from perichondrium into primary ossification centers of cartilage templates of future bones in response to Vegfa secreted by ( pre)hypertrophic chondrocytes. Perichondrial osteolineage cells also produce Vegfa, but its function is not well understood. By deleting Vegfa in osteolineage cells in vivo, we demonstrate that progenitor-derived Vegfa is required for blood vessel recruitment in perichondrium and the differentiation of osteoblast precursors in mice. Conditional deletion of Vegfa receptors indicates that Vegfa-dependent effects on osteoblast differentiation are mediated by Vegf receptor 2 (Vegfr2). In addition, Vegfa/Vegfr2 signaling stimulates the expression and activity of Indian hedgehog, increases the expression of β-catenin and inhibits Notch2. Our findings identify Vegfa as a regulator of perichondrial vascularity and osteoblast differentiation at early stages of bone development.

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Section: Vegfa Stimulates Ihh Expression and Represses Notch2 Levelsmentioning

confidence: 99%

Vegfa regulates perichondrial vascularity and osteoblast differentiation in bone development

Duan

Murata

et al. 2015

Development

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“…However, the effect of Wnt/b-catenin signaling on osteoblast formation appears to Tcf1 KO Reduced bone mass, increased osteoclastogenesis Glass et al 2005 depend on the developmental stage of the cells. In vitro activation of the Wnt/b-catenin signaling pathway in MSCs promotes their proliferation and inhibits osteoblastic differentiation (Boland et al 2004;de Boer et al 2004;Cho et al 2006;Regard et al 2011 Eijken et al 2008). This stage-dependent function of Wnt/b-catenin signaling in bone development is also manifested in human diseases.…”

Section: Wnt/b-catenin Signaling In Osteoblast Differentiation and Mamentioning

confidence: 99%

“…This stage-dependent function of Wnt/b-catenin signaling in bone development is also manifested in human diseases. For instance, fibrous dysplasia (FD) caused by activated Gas protein is due to inhibition of osteoblast differentiation, and maturation resulted from up-regulated Wnt/b-catenin signaling in MSCs and/or early osteoblasts (Regard et al 2011). …”

Section: Wnt/b-catenin Signaling In Osteoblast Differentiation and Mamentioning

confidence: 99%

Wnt Signaling in Bone Development and Disease: Making Stronger Bone with Wnts

Regard

Zhong

Williams

et al. 2012

Cold Spring Harbor Perspectives in Biology

173

147

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The skeleton as an organ is widely distributed throughout the entire vertebrate body. Wnt signaling has emerged to play major roles in almost all aspects of skeletal development and homeostasis. Because abnormal Wnt signaling causes various human skeletal diseases, Wnt signaling has become a focal point of intensive studies in skeletal development and disease. As a result, promising effective therapeutic agents for bone diseases are being developed by targeting the Wnt signaling pathway. Understanding the functional mechanisms of Wnt signaling in skeletal biology and diseases highlights how basic and clinical studies can stimulate each other to push a quick and productive advancement of the entire field. Here we review the current understanding of Wnt signaling in critical aspects of skeletal biology such as bone development, remodeling, mechanotransduction, and fracture healing. We took special efforts to place fundamentally important discoveries in the context of human skeletal diseases.T he skeleton has many important functions related to human health. Aside from the classical functions of the skeleton in structural support and movement, the bone matrix forms a major reservoir of calcium and other inorganic ions, and bone cells are active regulators of calcium homeostasis. Recent data suggest that bone cells can secrete hormones (e.g., FGF23 and osteocalcin) and likely play a physiologically significant role in regulating phosphate and energy homeostasis. It has emerged that Wnt signaling plays a major role controlling multiple aspects of skeletal development and maintenance. Thus, understanding how the Wnt pathway controls skeletal growth and homeostasis has broad implications for human health and disease.Cartilage and bone define the skeleton and are produced by chondrocytes and osteoblasts, respectively. During embryonic development, bones are formed by two distinct processes: intramembranous and endochondral ossification (Fig. 1A). A number of cranial bones and the lateral portion of the clavicles are formed by intramembranous ossification. In this process, mesenchymal progenitor cells condense and differentiate directly into bone-forming osteoblasts. The majority of bones in our body are formed by endochondral ossification, during which mesenchymal progenitor cells condense and differentiate first into cartilage-forming chondrocytes to generate an avascular template of the future bone. Chondrocytes in these

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“…We also examined the expression of Wnt pathway genes because the Wnt pathway is important in fracture healing and bone formation (25)(26)(27)(28) and because the Wnt/b-catenin pathway can be differentially regulated by GPCRs. (29) The Col1(2.3) þ /PTX þ mice had higher expression of Lef1 and lower expression of the Wnt pathway inhibitor Dkk1, but no difference in SOST (not shown), in the fracture callus at day 28 (Fig. 3D).…”

Section: Resultsmentioning

confidence: 89%

“…(29) Dkk1, an inhibitor of the Wnt pathway, is implicated in regulating bone mass, (45) fractures can induce high expression of Dkk1 mRNA within calluses during healing, and antibody blockade of Dkk1 significantly increases bone density and maximum load at fracture callus. (46) Moreover, PTH suppresses Dkk1 expression, induces PKA-mediated phosphorylation of b-catenin, and increases Lef1 expression in osteoblast cell culture.…”

Section: Discussionmentioning

confidence: 99%

Loss of Gi G-Protein-Coupled Receptor Signaling in Osteoblasts Accelerates Bone Fracture Healing

Wang

Hsiao

Lieu

et al. 2015

Journal of Bone and Mineral Research

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G-protein-coupled receptors (GPCRs) are key regulators of skeletal homeostasis and are likely important in fracture healing. Because GPCRs can activate multiple signaling pathways simultaneously, we used targeted disruption of G i -GPCR or activation of G s -GPCR pathways to test how each pathway functions in the skeleton. We previously demonstrated that blockade of G i signaling by pertussis toxin (PTX) transgene expression in maturing osteoblastic cells enhanced cortical and trabecular bone formation and prevented agerelated bone loss in female mice. In addition, activation of G s signaling by expressing the G s -coupled engineered receptor Rs1 in maturing osteoblastic cells induced massive trabecular bone formation but cortical bone loss. Here, we test our hypothesis that the G i and G s pathways also have distinct functions in fracture repair. We applied closed, nonstabilized tibial fractures to mice in which endogenous G i signaling was inhibited by PTX, or to mice with activated G s signaling mediated by Rs1. Blockade of endogenous G i resulted in a smaller callus but increased bone formation in both young and old mice. PTX treatment decreased expression of Dkk1 and increased Lef1 mRNAs during fracture healing, suggesting a role for endogenous G i signaling in maintaining Dkk1 expression and suppressing Wnt signaling. In contrast, adult mice with activated G s signaling showed a slight increase in the initial callus size with increased callus bone formation. These results show that G i blockade and G s activation of the same osteoblastic lineage cell can induce different biological responses during fracture healing. Our findings also show that manipulating the GPCR/cAMP signaling pathway by selective timing of G s and G i -GPCR activation may be important for optimizing fracture repair.

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Wnt/β-catenin signaling is differentially regulated by Gα proteins and contributes to fibrous dysplasia

Cited by 94 publications

References 51 publications

Vegfa regulates perichondrial vascularity and osteoblast differentiation in bone development

Vegfa regulates perichondrial vascularity and osteoblast differentiation in bone development

Wnt Signaling in Bone Development and Disease: Making Stronger Bone with Wnts

Loss of Gi G-Protein-Coupled Receptor Signaling in Osteoblasts Accelerates Bone Fracture Healing

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