title: From mysteries to medicines: drug development for fibrodysplasia ossificans progressive.
abstract: BACKGROUND
  Fibrodysplasia ossificans progressiva (FOP) is the most disabling disorder of skeletal metamorphosis in humans and leads to the formation of a second skeleton of heterotopic bone. Presently, there is no effective treatment.
  
  
  METHODS
  In this review, the authors discuss heterozygous activating mutations in Activin receptor A, type I/ Activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor that are the genetic cause of FOP and reveal a promising pharmacologic target in the BMP signaling pathway. Despite these germline mutations, episodic disease activation is induced by soft tissue injury and resultant inflammatory triggers that are dependent on responding progenitor cells and a tissue microenvironment that supports heterotopic ossification.
  
  
  CONCLUSIONS
  Here we review opportunities and challenges for the development of effective therapeutics for FOP. There are many potential approaches that may eventually be used to harness FOP. The long-term treatment of FOP is likely to involve not one, but several concomitant approaches that acknowledge molecular mechanisms involved in the induction and progression of the disease.
authors.affiliation: Department of Orthopaedic Surgery, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104 ; Department of Medicine, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104 ; The Center for Research In FOP and Related Disorders; The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Kaplan
authors.affiliation: Department of Orthopaedic Surgery, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104 ; Department of Medicine, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104 ; The Center for Research In FOP and Related Disorders; The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Pignolo
authors.affiliation: Department of Orthopaedic Surgery, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104 ; Department of Genetics, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104 ; The Center for Research In FOP and Related Disorders; The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Shore
keywords: Bone morphogenetic protein receptors; Fibrodysplasia ossificans progressiva; Heterotopic endochondral ossification; Skeletal metamorphosis