{'fraction_non_alphanumeric': 0.019813084112149534, 'fraction_numerical': 0.00485981308411215, 'mean_word_length': 5.326241134751773, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Induced GnasR201H 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 Gαs 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 Gαs signaling governs bone formation and maintenance and bone marrow stromal cell differentiation. Fibrous dysplasia (FD; Online Mendelian Inheritance in Man no. 174800) is a crippling skeletal disease caused by activating mutations of the GNAS gene, which encodes the stimulatory G protein Gαs. FD can lead to severe adverse conditions such as bone deformity, fracture, and severe pain, leading to functional impairment and wheelchair confinement. So far there is no cure, as the underlying molecular and cellular mechanisms remain largely unknown and the lack of appropriate animal models has severely hampered FD research. Here we have investigated the cellular and molecular mechanisms underlying FD and tested its potential treatment by establishing a mouse model in which the human FD mutation (R201H) has been conditionally knocked into the corresponding mouse Gnas locus. We found that the germ-line FD mutant was embryonic lethal, and Cre-induced Gnas FD mutant expression in early osteochondral progenitors, osteoblast cells, or bone marrow stromal cells (BMSCs) recapitulated FD features. In addition, mosaic expression of FD mutant Gαs in BMSCs induced bone marrow fibrosis both cell autonomously and non-cell autonomously. Furthermore, Wnt/β-catenin signaling was up-regulated in FD mutant mouse bone and BMSCs undergoing osteogenic differentiation, as we have found in FD human tissue previously. Reduction of Wnt/β-catenin signaling by removing one Lrp6 copy in an FD mutant line significantly rescued the phenotypes. We demonstrate that induced expression of the FD Gαs mutant from the mouse endogenous Gnas locus exhibits human FD phenotypes in vivo, and that inhibitors of Wnt/β-catenin signaling may be repurposed for treating FD and other bone diseases caused by Gαs activation.