| First Author | Regard JB | Year | 2011 |
| Journal | Proc Natl Acad Sci U S A | Volume | 108 |
| Issue | 50 | Pages | 20101-6 |
| PubMed ID | 22106277 | Mgi Jnum | J:180451 |
| Mgi Id | MGI:5306285 | Doi | 10.1073/pnas.1114656108 |
| Citation | Regard JB, et al. (2011) Wnt/beta-catenin signaling is differentially regulated by Galpha proteins and contributes to fibrous dysplasia. Proc Natl Acad Sci U S A 108(50):20101-6 |
| abstractText | Skeletal dysplasias are common disabling disorders characterized by aberrant growth of bone and cartilage leading to abnormal skeletal structures and functions, often attributable to defects in skeletal progenitor cells. The underlying molecular and cellular mechanisms of most skeletal dysplasias remain elusive. Although the Wnt/beta-catenin signaling pathway is required for skeletal progenitor cells to differentiate along the osteoblastic lineage, inappropriately elevated levels of signaling can also inhibit bone formation by suppressing osteoblast maturation. Here, we investigate interactions of the four major Galpha protein families (Galpha(s), Galpha(i/o), Galpha(q/11), and Galpha(12/13)) with the Wnt/beta-catenin signaling pathway and identify a causative role of Wnt/beta-catenin signaling in fibrous dysplasia (FD) of bone, a disease that exhibits abnormal differentiation of skeletal progenitor cells. The activating Galpha(s) mutations that cause FD potentiated Wnt/beta-catenin signaling, and removal of Galpha(s) led to reduced Wnt/beta-catenin signaling and decreased bone formation. We further show that activation of Wnt/beta-catenin signaling in osteoblast progenitors results in an FD-like phenotype and reduction of beta-catenin levels rescued differentiation defects of FD patient-derived stromal cells. Galpha proteins may act at the level of beta-catenin destruction complex assembly by binding Axin. Our results indicate that activated Galpha proteins differentially regulate Wnt/beta-catenin signaling but, importantly, are not required core components of Wnt/beta-catenin signaling. Our data suggest that activated Galpha proteins are playing physiologically significant roles during both skeletal development and disease by modulating Wnt/beta-catenin signaling strength. |
