The BMP4 signaling pathway is dysregulated in the cells of patients who have fibrodysplasia ossificans progressiva (FOP), a disabling autosomal dominant disorder of progressive heterotopic ossification and congenital limb malformations. Our previous studies suggest that FOP cells fail to properly regulate ambient concentrations of BMP4 and fail to appropriately regulate the transcription of BMP pathway target genes, including those for the BMP4 antagonists. Recent preliminary data indicate that the BMP type IA receptor (BMPRIA) is present and active at high levels on the surface of FOP cells, while the BMP type IB receptor (BMPRIB) is present at low levels. These data for FOP cells are consistent with developmental studies, which show that postnatal over-expression of BMPRIA can cause heterotopic ossification and that embryonic underexpression of BMPRIB can lead to digital malformations that closely mimic those seen in patients who have FOP. There are no mutations in the genes encoding BMP4, multiple BMP4 antagonists, pathway-specific or inhibitory Smads, or the BMP receptors in FOP patients. Taken together, these data suggest that a primary defect may exist in the BMP4 signaling pathway in FOP ceils and that BMPRIA may be constitutively active and/or unresponsive to normal signaling in FOP cells. We hypothesize that promiscuous BMP signaling in FOP cells (a) results from increased amounts of BMPRIA on the cell surface, and (b) mediates the pathophysiology of FOP. This research proposal will focus on investigations of cellular signaling events that are associated with the high steady-state levels of BMPRIA protein on the surface of FOP cells. We intend to: (1) characterize the signal transduction pathways that are activated by overabundant BMPRIA in FOP cells; (2) determine the mechanism leading to BMPRIA overabundance on the surface of FOP cells; (3) establish whether BMPRIA signaling in FOP cells is ligand-mediated or ligand independent; and (4) investigate whether over-abundance of BMPRIA on the cell surface is sufficient to mediate an """"""""FOP phenotype"""""""". Analysis of the molecular pathology of the human BMP4 pathway in FOP will foster the long-term goal of elucidating basic mechanisms of normal and disordered bone induction in this disabling human disease. This strategy will also lead to a more rational therapeutic approach to a wide variety of disorders involving the induction of osteogenesis in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR041916-11
Application #
7278679
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Wang, Fei
Project Start
1994-06-01
Project End
2009-08-31
Budget Start
2007-09-01
Budget End
2009-08-31
Support Year
11
Fiscal Year
2007
Total Cost
$330,631
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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Amalfitano, Matthew; Fyfe, Billie; Thomas, Sumi V et al. (2018) A case report of mesenteric heterotopic ossification: Histopathologic and genetic findings. Bone 109:56-60
Al Mukaddam, Mona; Rajapakse, Chamith S; Pignolo, Robert J et al. (2018) Imaging assessment of fibrodysplasia ossificans progressiva: Qualitative, quantitative and questionable. Bone 109:147-152
Brennan, Tracy A; Lindborg, Carter M; Bergbauer, Christian R et al. (2018) Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP). Bone 109:259-266
Haupt, Julia; Xu, Meiqi; Shore, Eileen M (2018) Variable signaling activity by FOP ACVR1 mutations. Bone 109:232-240
Rajapakse, Chamith S; Lindborg, Carter; Wang, Haitao et al. (2017) Analog Method for Radiographic Assessment of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva. Acad Radiol 24:321-327
Kaplan, Frederick S; Pignolo, Robert J; Al Mukaddam, Mona M et al. (2017) Hard targets for a second skeleton: therapeutic horizons for fibrodysplasia ossificans progressiva (FOP). Expert Opin Orphan Drugs 5:291-294
Pacifici, Maurizio; Shore, Eileen M (2016) Common mutations in ALK2/ACVR1, a multi-faceted receptor, have roles in distinct pediatric musculoskeletal and neural orphan disorders. Cytokine Growth Factor Rev 27:93-104
Wang, Haitao; Lindborg, Carter; Lounev, Vitali et al. (2016) Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling. J Bone Miner Res 31:1652-65
Chakkalakal, Salin A; Uchibe, Kenta; Convente, Michael R et al. (2016) Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1(R206H) Fibrodysplasia Ossificans Progressiva (FOP) Mutation. J Bone Miner Res 31:1666-75

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