Genetic disorders of osteogenesis provide valuable insight into the regulation of bone formation. Progressive osseous heteroplasia (POH) is a rare and disabling genetic disorder in which the body produces bone in skin, fat and skeletal muscle. Gene mutations in POH patients inactivate one of the two copies of the GNAS gene and alter the fate of cells to cause bone formation in inappropriate locations (heterotopic ossification). GNAS encodes the G(s)alpha protein, which couples signaling via cell surface receptors to intracellular second messengers, however the specific effects of these mutations on bone cell differentiation are unknown. Ectopic bone formation in POH patients often arises within subcutaneous fat, suggesting a close, perhaps reciprocal, relationship between bone and fat cell differentiation. In addition to continuing investigations of GNAS inheritance and expression in POH, a primary goal of this proposal is to examine the effects of heterozygous inactivating GNAS mutations on bone (osteoblast) and fat (adipocyte) cell differentiation. We hypothesize that: (1) Heterozygous inactivating mutation of the GNAS gene alters cellular signaling that directs osteoblast and/or adipocyte differentiation, and (2) The complex phenotypic consequences of inactivating GNAS mutations are influenced by maternal/paternal inheritance of GNAS. The following Specific Aims will be conducted: 1. Investigate the parental origin of the GNAS allele that carries GNAS mutations in POH patients. 2. Examine POH genomic DNA for methylation characteristic of imprinting at the GNAS locus. 3. Examine the differential expression of GNAS mRNAs during osteoblast and adipocyte differentiation. 4. Examine the effects of heterozygous GNAS gene inactivation on osteoblast and adipocyte differentiation. 5. Investigate the effects of an inactive GNAS gene on expression of specific GNAS transcripts during osteoblast and adipocyte differentiation. The overall goal of this project is to characterize the role of the GNAS gene in the regulation of bone cell differentiation. The studies described in this proposal will provide the foundation to examine the specific pathways through which GNAS regulates osteogenesis. These investigations will provide important information for developing diagnostic and treatment strategies for a wide range of disorders of bone such as POH and more common conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046831-06
Application #
7118627
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Mcgowan, Joan A
Project Start
2000-09-01
Project End
2009-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
6
Fiscal Year
2006
Total Cost
$340,506
Indirect Cost
Name
University of Pennsylvania
Department
Orthopedics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Loro, Emanuele; Ramaswamy, Girish; Chandra, Abhishek et al. (2017) IL15RA is required for osteoblast function and bone mineralization. Bone 103:20-30
Ramaswamy, Girish; Kim, Hyunsoo; Zhang, Deyu et al. (2017) Gs? Controls Cortical Bone Quality by Regulating Osteoclast Differentiation via cAMP/PKA and ?-Catenin Pathways. Sci Rep 7:45140
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