TY - JOUR
T1 - A new era for fibrodysplasia ossificans progressiva
T2 - A druggable target for the second skeleton
AU - Kaplan, Frederick S.
AU - Glaser, David L.
AU - Pignolo, Robert J.
AU - Shore, Eileen M.
N1 - Funding Information:
This work was supported in part by The International FOP Association, The Center for Research in FOP & Related Disorders, The Ian Cali FOP Endowment, the Weldon Family FOP Endowment, The OREF Clinician-Scientist Award, The Isaac & Rose Nassau Professorship of Orthopaedic Molecular Medicine and The National Institutes of Health (NIH RO1-AR41916)
PY - 2007/5
Y1 - 2007/5
N2 - 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 1A/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-β/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.
AB - 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 1A/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-β/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.
KW - Activin receptor IA
KW - Activin-like kinase-2
KW - Activin-like kinases
KW - Bone morphogenetic protein
KW - Bone morphogenetic protein receptors
KW - Fibrodysplasia ossificans progressiva
KW - Heterotopic ossification
KW - Metamorphosis
KW - Small molecule signal transduction inhibitor
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U2 - 10.1517/14712598.7.5.705
DO - 10.1517/14712598.7.5.705
M3 - Review article
C2 - 17477807
AN - SCOPUS:34248223174
SN - 1471-2598
VL - 7
SP - 705
EP - 712
JO - Expert Opinion on Biological Therapy
JF - Expert Opinion on Biological Therapy
IS - 5
ER -