Induced Gnas R201H expression from the endogenous Gnas locus causes fibrous dysplasia by up-regulating Wnt/β-catenin signaling

Significance Understanding molecular and cellular mechanisms of rare genetic diseases provides invaluable insights into the human biology and pathology of both rare and related common diseases. Fibrous dysplasia (FD) is a mosaic disease resulting from postzygotic activating mutations of GNAS . The mouse models we created allowed us to precisely model FD by expressing the FD Gα s mutation under the control of its endogenous genetic locus. We found in our FD mouse models that up-regulated Wnt/β-catenin signaling resulted in impaired differentiation and proliferation of bone marrow stem cells, which in turn caused marrow fibrosis. Our work provides a solid new foundation for therapeutic development of FD and understanding the principles whereby Gα s signaling governs bone formation and maintenance and bone marrow stromal cell differentiation.