Gα_s signaling controls intramembranous ossification during cranial bone development by regulating both Hedgehog and Wnt/β-catenin signaling

Abstract

How osteoblast cells are induced is a central question for understanding skeletal formation. Abnormal osteoblast differentiation leads to a broad range of devastating craniofacial diseases. Here we have investigated intramembranous ossification during cranial bone development in mouse models of skeletal genetic diseases that exhibit craniofacial bone defects. The GNAS gene encodes Gα_s that transduces GPCR signaling. GNAS activation or loss-of-function mutations in humans cause fibrous dysplasia (FD) or progressive osseous heteroplasia (POH) that shows craniofacial hyperostosis or craniosynostosis, respectively. We find here that, while Hh ligand-dependent Hh signaling is essential for endochondral ossification, it is dispensable for intramembranous ossification, where Gα_s regulates Hh signaling in a ligand-independent manner. We further show that Gα_s controls intramembranous ossification by regulating both Hh and Wnt/β-catenin signaling. In addition, Gα_s activation in the developing cranial bone leads to reduced ossification but increased cartilage presence due to reduced cartilage dissolution, not cell fate switch. Small molecule inhibitors of Hh and Wnt signaling can effectively ameliorate cranial bone phenotypes in mice caused by loss or gain of Gnas function mutations, respectively. Our work shows that studies of genetic diseases provide invaluable insights in both pathological bone defects and normal bone development, understanding both leads to better diagnosis and therapeutic treatment of bone diseases.

Skull formation: Finding new avenues

Investigating two genetic diseases of skull formation revealed underlying similarities that may help improve treatments. During skull development, growth of too much or too little bone leads to deformation of the head or face, with potentially devastating medical consequences. To improve our understanding of the fine-scale processes that control bone deposition, Yingzi Yang at the Harvard School of Dental Medicine and co-workers investigated how bone formation occurs in progressive osseous heteroplasia (POH) and fibrous dysplasia (FD), which cause excessive and insufficient bone formation, respectively, during skull development. Using POH and FD model mice, they identified a single molecule underlying both diseases. Pinpointing this molecule allowed the researchers to identify drugs, previously developed for other diseases, that could help treat POH and FD; initial tests showed improved bone formation in both POH and FD model mice.

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Funding

U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR)(R01DE025866)

U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)(R01AR070877)

111 project, MOE(B14038), China