A new era for fibrodysplasia ossificans progressiva: a druggable target for the second skeleton

Abstract

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-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.

Keywords::

• activin-like kinases
• activin-like kinase-2
• activin receptor IA
• bone morphogenetic protein
• bone morphogenetic protein receptors
• fibrodysplasia ossificans progressiva
• heterotopic ossification
• metamorphosis
• small molecule signal transduction inhibitor

Acknowledgements

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)

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