A new era for fibrodysplasia ossificans progressiva: a druggable target for the second skeleton.
Fibrodysplasia ossificans progressiva (FOP) is a disabling genetic condition that leads to the formation of a second (heterotopic) skeleton, and is the most catastrophic disorder of heterotopic ossification in humans. Throughout childhood and early adult life, FOP progressively immobilizes all of the joints of the normotopic skeleton, rendering movement impossible. At present, there is no effective prevention or treatment. Recently, a recurrent mutation in the glycine-serine activation domain of the activin receptor IA/activin-like kinase-2, a bone morphogenetic protein type I receptor, was reported in all sporadic and familial cases of classic FOP, making this one of the most highly specific disease-causing mutations in the human genome. The discovery of the FOP gene establishes a critical milestone in understanding FOP, reveals a highly conserved druggable target in the TGF-beta/bone morphogenetic protein signaling pathway and compels therapeutic approaches for the development of small molecule signal transduction inhibitors for activin-like kinase-2. Effective therapies for FOP, and possibly for a vast array of more common conditions of heterotopic ossification, will be based on blocking activin-like kinase-2, a critical node in the BMP signaling pathway.
Kaplan
Frederick S
FS
University of Pennsylvania School of Medicine, Department of Orthopaedic Surgery, Hospital of the University of Pennsylvania, Silverstein Two, 34th & Spruce Street, Philadelphia, PA 19104, USA. frederick.kaplan@uphs.upenn.edu
Glaser
David L
DL
Pignolo
Robert J
RJ
Shore
Eileen M
EM
D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D009154:Mutation; D009221:Myositis Ossificans / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009999:Ossification, Heterotopic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D047428:Protein Kinase Inhibitors; D016212:Transforming Growth Factor beta; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; D052004:Bone Morphogenetic Protein Receptors