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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR041916-14
Application #
8241612
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (03))
Program Officer
Sharrock, William J
Project Start
1994-06-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
14
Fiscal Year
2012
Total Cost
$373,264
Indirect Cost
$139,974
Name
University of Pennsylvania
Department
Orthopedics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Pignolo, Robert J; Bedford-Gay, Christopher; Liljesthröm, Moira et al. (2016) The Natural History of Flare-Ups in Fibrodysplasia Ossificans Progressiva (FOP): A Comprehensive Global Assessment. J Bone Miner Res 31:650-6
Rajapakse, Chamith S; Lindborg, Carter; Wang, Haitao et al. (2016) Analog Method for Radiographic Assessment of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva. Acad Radiol :
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
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
Kaplan, Frederick S; Pignolo, Robert J; Shore, Eileen M (2016) Granting immunity to FOP and catching heterotopic ossification in the Act. Semin Cell Dev Biol 49:30-6
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
Kaplan, Frederick S; Kobori, Joyce A; Orellana, Carmen et al. (2015) Multi-system involvement in a severe variant of fibrodysplasia ossificans progressiva (ACVR1 c.772G>A; R258G): A report of two patients. Am J Med Genet A 167A:2265-71
Convente, Michael R; Wang, Haitao; Pignolo, Robert J et al. (2015) The immunological contribution to heterotopic ossification disorders. Curr Osteoporos Rep 13:116-24
Bravenboer, Nathalie; Micha, Dimitra; Triffit, James T et al. (2015) Clinical Utility Gene Card for: Fibrodysplasia ossificans progressiva. Eur J Hum Genet 23:
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

Showing the most recent 10 out of 83 publications