Fibrodysplasia ossificans progressiva (FOP) is a severely disabling human disorder of episodic and extensive heterotopic (extraskeletal) bone formation. This ectopic endochondral ossification forms qualitatively normal bone;the aberration resides within the cellular signals that regulate commitment to the bone formation pathway. We recently discovered that FOP is caused by a recurrent activating mutation in Activin A receptor, type I/Activin-like kinase2 (ACVR1/ALK2), a type I bone morphogenetic protein (BMP) receptor, in all patients with a classic clinical presentation of FOP. Our data support that this mutation (ACVR1 c.617G>A;R206H) is an activating mutation that signals in part through a BMP-independent mechanism. While the discovery of this genetic mutation is rapidly leading to an understanding of the genetic and molecular cause of FOP, little is known about the cellular origins of FOP lesions or the tissue microenvironment that supports episodic lesion formation. Clinical observations in our FOP patients and preliminary data in our FOP animal models suggest a disease model in which an inflammatory microenvironment caused by soft tissue injury mobilizes resident Tie2+ connective tissue progenitor cells of vascular origin. Further, our preliminary in vitro studies and protein homology modeling predict that the mutant ACVR1/ALK2 receptor up-regulates BMP signaling through a hypoxia-regulated pH-sensitive switch in the mutant receptor. Our central hypothesis is that an activated immune system interacts with the soft connective tissue microenvironment and resident chondro/osseous progenitor cells, in association with the highly specific FOP ACVR1 gene mutation, to induce heterotopic ossification in FOP. We propose to investigate the cellular and microenvironmental conditions that induce the formation of FOP lesions through three specific aims.
Aim 1 : Identify the inflammatory cells (and associated factors) that activate heterotopic ossification in a background of enhanced BMP signaling.
Aim 2 : Determine if cells expressing both Tie2 and mature endothelial markers differentiate to cartilage and bone during heterotopic ossification.
Aim 3 : Determine whether a) hypoxia increases BMP signaling by the mutant ACVR1/ALK2 receptor in FOP cells, and b) whether this effect is due, in part, to an acidic intracellular microenvironment that activates the mutant ACVR1/ALK2 receptor. These investigations will provide critical information for understanding the process of heterotopic bone formation, a serious clinical complication that is relevant not only to FOP but also to patients with more common forms of heterotopic ossification that form after head injuries, motor vehicle accidents, hip replacements, multiple trauma, and war wounds. This knowledge will contribute to our long-term goal of developing more effective treatments for FOP and other disorders of heterotopic ossification.

Public Health Relevance

We propose to investigate the inflammatory cells, connective tissue progenitor cells, and microenvironmental changes that interact with the mutant gene to cause disabling extraskeletal bone formation in fibrodysplasia ossificans progressiva (FOP). Such knowledge will stimulate development of more effective therapies for FOP and for common disorders of extraskeletal bone formation, such as those caused by motor vehicle accidents, injuries to the head and spinal cord, and war wounds - disorders that plague both the civilian and military population of our nation.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Special Emphasis Panel (ZRG1-MOSS-C (03))
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Sharrock, William J
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University of Pennsylvania
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Culbert, Andria L; Chakkalakal, Salin A; Theosmy, Edwin G et al. (2014) Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification. Stem Cells 32:1289-300
Haupt, Julia; Deichsel, Alexandra; Stange, Katja et al. (2014) ACVR1 p.Q207E causes classic fibrodysplasia ossificans progressiva and is functionally distinct from the engineered constitutively active ACVR1 p.Q207D variant. Hum Mol Genet 23:5364-77
Pignolo, Robert J; Shore, Eileen M; Kaplan, Frederick S (2013) Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. Pediatr Endocrinol Rev 10 Suppl 2:437-48
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Kaplan, Frederick S; Lounev, Vitali Y; Wang, Haitao et al. (2011) Fibrodysplasia ossificans progressiva: a blueprint for metamorphosis. Ann N Y Acad Sci 1237:5-10

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