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Proc Natl Acad Sci U S A. 2018 Jan 16;115(3):E428-E437. doi: 10.1073/pnas.1713710115. Epub 2017 Dec 27.

Expression of an active Gαs mutant in skeletal stem cells is sufficient and necessary for fibrous dysplasia initiation and maintenance.

Author information

1
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
2
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
3
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
4
International College of Dentistry, Walailak University, Nakhon Si Thammarat, 80161, Thailand.
5
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
6
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115.
7
Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
8
Section on Skeletal Disorders and Mineral Homeostasis, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892.
9
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093.
10
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093; sgutkind@ucsd.edu.

Abstract

Fibrous dysplasia (FD) is a disease caused by postzygotic activating mutations of GNAS (R201C and R201H) that encode the α-subunit of the Gs stimulatory protein. FD is characterized by the development of areas of abnormal fibroosseous tissue in the bones, resulting in skeletal deformities, fractures, and pain. Despite the well-defined genetic alterations underlying FD, whether GNAS activation is sufficient for FD initiation and the molecular and cellular consequences of GNAS mutations remains largely unresolved, and there are no currently available targeted therapeutic options for FD. Here, we have developed a conditional tetracycline (Tet)-inducible animal model expressing the GαsR201C in the skeletal stem cell (SSC) lineage (Tet-GαsR201C/Prrx1-Cre/LSL-rtTA-IRES-GFP mice), which develops typical FD bone lesions in both embryos and adult mice in less than 2 weeks following doxycycline (Dox) administration. Conditional GαsR201C expression promoted PKA activation and proliferation of SSCs along the osteogenic lineage but halted their differentiation to mature osteoblasts. Rather, as is seen clinically, areas of woven bone admixed with fibrous tissue were formed. GαsR201C caused the concomitant expression of receptor activator of nuclear factor kappa-B ligand (Rankl) that led to marked osteoclastogenesis and bone resorption. GαsR201C expression ablation by Dox withdrawal resulted in FD-like lesion regression, supporting the rationale for Gαs-targeted drugs to attempt FD cure. This model, which develops FD-like lesions that can form rapidly and revert on cessation of mutant Gαs expression, provides an opportunity to identify the molecular mechanism underlying FD initiation and progression and accelerate the development of new treatment options.

KEYWORDS:

GNAS; PKA; fibrous dysplasia; mouse models; skeletal stem cell

PMID:
29282319
PMCID:
PMC5776975
DOI:
10.1073/pnas.1713710115
[Indexed for MEDLINE]
Free PMC Article

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