BoneKEy Reports | BoneKEy Watch

Gα proteins, the Wnt/β-catenin pathway and fibrous dysplasia

DOI:10.1038/bonekey.2012.43

Fibrous dysplasia (FD), a complex bone disorder characterized by fibrosis in the bone marrow, is thought to be due to the abnormal differentiation of skeletal progenitor cells that occurs as a result of activation of the Gαs protein due to gain-of-function mutations in the GNAS gene. This leads to constitutive cAMP signaling and persistent proliferation of undifferentiated osteoblast precursors.

This study examined how the four main Gα protein families, including Gαs interact with Wnt/β-catenin signaling, both in tissues from FD patients and in vivo in a newly generated mouse model.

Activation of the Gαs protein in cells from FD patients primed bone marrow stem cells to respond to Wnt/β-catenin signaling, suggesting that this could be a causative mechanism in the disease. Activating Gαs in the mouse model increased the level of signaling in the Wnt/β-catenin pathway, whereas removing it had the opposite effect, reducing abnormal bone formation. While an FD-like phenotype was generated by activating Wnt/β-catenin signaling in osteoblast progenitor cells, lowering the levels of β-catenin was able to rescue the differentiation defects in stromal cells derived from FD patients.

Editor's comment: This seminal paper demonstrates a cross-talk between the G protein-mediated and β-catenin -mediated signaling pathways, providing a greater insight into the mechanism of FD. These observations may also lead to a better understanding of how parathyroid hormone activates β-catenins.

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