title: Granting immunity to FOP and catching heterotopic ossification in the Act.
abstract: The progressive transformation of one organ system into another is a fundamental signature of fibrodysplasia ossificans progressiva (FOP), the most catastrophic form of extraskeletal bone formation in humans. In all affected individuals, FOP is caused by heterozygous missense gain-of-function mutations in Activin receptor A type I (ACVR1), a bone morphogenetic protein (BMP) type I receptor. Loss of autoinhibition of the mutant receptor (mACVR1) results in dysregulated BMP pathway signaling, and is necessary for the myriad developmental features of FOP, but does not appear sufficient to induce the episodic flare-ups that lead to disabling post-natal heterotopic endochondral ossification (HEO) and that are a hallmark of the disease. Post-natal FOP flare-ups strongly implicate an underlying immunological trigger involving inflammation and the innate immune system. Recent studies implicate canonical and non-canonical TGFβ/BMP family ligands in the amplification of mACVR1 signaling leading to the formation of FOP lesions and resultant HEO. BMP and Activin ligands that stimulate mACVR1 signaling also have critical regulatory functions in the immune system. Cross-talk between the morphogenetic and immunological pathways that regulate tissue maintenance and wound healing identifies potential robust therapeutic targets for FOP. Here we review current evidence for an immunological trigger for flare-ups and HEO in FOP, propose a working schema for the pathophysiology of observed phenomena, and highlight outstanding questions under investigation.
authors.affiliation: The Department of Orthopaedic Surgery, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA; The Department of Medicine, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA; The Center for Research in FOP & Related Disorders, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: frederick.kaplan@uphs.upenn.edu.
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Kaplan
authors.affiliation: The Department of Orthopaedic Surgery, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA; The Department of Medicine, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA; The Center for Research in FOP & Related Disorders, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: pignolo@mail.med.upenn.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Pignolo
authors.affiliation: The Department of Orthopaedic Surgery, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA; The Department of Genetics, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA; The Center for Research in FOP & Related Disorders, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: shore@mail.med.upenn.edu.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Shore
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics; D028341:Activins / Q000502:physiology; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D020125:Mutation, Missense; D009221:Myositis Ossificans / Q000235:genetics / Q000276:immunology*; D009999:Ossification, Heterotopic / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D019485:Bone Morphogenetic Proteins; C422405:activin A; D028341:Activins; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I
keywords: ACVR1; Activin A; Bone morphogenetic protein (BMP); Bone morphogenetic protein signaling; Fibrodysplasia ossificans progressiva (FOP); Heterotopic ossification; Innate immune system; Toll-like receptor (TLR)