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Gα(s) signaling controls intramembranous ossification during cranial bone development by regulating both Hedgehog and Wnt/β-catenin signaling

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 skel...

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Autores principales: Xu, Ruoshi, Khan, Sanjoy Kumar, Zhou, Taifeng, Gao, Bo, Zhou, Yaxing, Zhou, Xuedong, Yang, Yingzi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242855/
https://www.ncbi.nlm.nih.gov/pubmed/30479847
http://dx.doi.org/10.1038/s41413-018-0034-7
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author Xu, Ruoshi
Khan, Sanjoy Kumar
Zhou, Taifeng
Gao, Bo
Zhou, Yaxing
Zhou, Xuedong
Yang, Yingzi
author_facet Xu, Ruoshi
Khan, Sanjoy Kumar
Zhou, Taifeng
Gao, Bo
Zhou, Yaxing
Zhou, Xuedong
Yang, Yingzi
author_sort Xu, Ruoshi
collection PubMed
description 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.
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spelling pubmed-62428552018-11-26 Gα(s) signaling controls intramembranous ossification during cranial bone development by regulating both Hedgehog and Wnt/β-catenin signaling Xu, Ruoshi Khan, Sanjoy Kumar Zhou, Taifeng Gao, Bo Zhou, Yaxing Zhou, Xuedong Yang, Yingzi Bone Res Article 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. Nature Publishing Group UK 2018-11-20 /pmc/articles/PMC6242855/ /pubmed/30479847 http://dx.doi.org/10.1038/s41413-018-0034-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Xu, Ruoshi
Khan, Sanjoy Kumar
Zhou, Taifeng
Gao, Bo
Zhou, Yaxing
Zhou, Xuedong
Yang, Yingzi
Gα(s) signaling controls intramembranous ossification during cranial bone development by regulating both Hedgehog and Wnt/β-catenin signaling
title Gα(s) signaling controls intramembranous ossification during cranial bone development by regulating both Hedgehog and Wnt/β-catenin signaling
title_full Gα(s) signaling controls intramembranous ossification during cranial bone development by regulating both Hedgehog and Wnt/β-catenin signaling
title_fullStr Gα(s) signaling controls intramembranous ossification during cranial bone development by regulating both Hedgehog and Wnt/β-catenin signaling
title_full_unstemmed Gα(s) signaling controls intramembranous ossification during cranial bone development by regulating both Hedgehog and Wnt/β-catenin signaling
title_short Gα(s) signaling controls intramembranous ossification during cranial bone development by regulating both Hedgehog and Wnt/β-catenin signaling
title_sort gα(s) signaling controls intramembranous ossification during cranial bone development by regulating both hedgehog and wnt/β-catenin signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242855/
https://www.ncbi.nlm.nih.gov/pubmed/30479847
http://dx.doi.org/10.1038/s41413-018-0034-7
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