期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 3, 页码 E428-E437出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1713710115
关键词
GNAS; skeletal stem cell; fibrous dysplasia; mouse models; PKA
资金
- 111 Project from the Ministry of Education of China [B14038]
- National Natural Science Foundation of China [81520108009, 81621062, 81722014, 81671024, 81371171, 81571009]
- University of Pennsylvania Orphan Disease Center
- Fibrous Dysplasia Foundation
- University of California, San Diego (UCSD) Department of Pharmacology and Moores Cancer Center
- Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health
- UCSD Graduate Training Program in Cellular and Molecular Pharmacology through National Institute of General Medical Sciences Institutional Training Grant [T32 GM007752]
- NATIONAL CANCER INSTITUTE [ZIABC011763] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH [ZIADE000649, R01DE025866] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007752] Funding Source: NIH RePORTER
Fibrous dysplasia (FD) is a disease caused by postzygotic activating mutations of GNAS (R201C and R201H) that encode the alpha-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 G alpha(R201C)(s) in the skeletal stem cell (SSC) lineage (Tet-G alpha(R201C)(s)/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 G alpha(R201C)(s) 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. G alpha(R201C)(s) caused the concomitant expression of receptor activator of nuclear factor kappa-B ligand (Rankl) that led to marked osteoclastogenesis and bone resorption. G alpha(R201C)(s) expression ablation by Dox withdrawal resulted in FD-like lesion regression, supporting the rationale for G alpha(s)-targeted drugs to attempt FD cure. This model, which develops FD-like lesions that can form rapidly and revert on cessation of mutant G alpha(s) expression, provides an opportunity to identify the molecular mechanism underlying FD initiation and progression and accelerate the development of new treatment options.
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