Mast cell involvement in fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a catastrophic genetic disor der of progressive heterotopic ossification associated with dysregulated pr oduction of bone morphogenetic protein 4 (BMP4), a potent osteogenic morpho gen. Postnatal heterotopic ossification in FOP is often heralded by hectic episodes of severe posttraumatic connective tissue swelling and intramuscul ar edema, followed by an intense and highly angiogenic fibroproliferative m ass. The abrupt appearance, intense size, and rapid intrafascial spread of the edematous preosseous fibroproliferative lesions implicate a dysregulate d wound response mechanism and suggest that cells and mediators involved in inflammation and tissue repair may be conscripted in the growth and progre ssion of FOP lesions. The central and coordinate role of inflammatory mast cells and their mediators in tissue edema, wound repair, fibrogenesis, angi ogenesis, and tumor invasion prompted us to investigate the potential invol vement of mast cells in the pathology of FOP lesions. We show that inflamma tory mast cells are present at every stage of the development of FOP lesion s and are most pronounced at the highly vascular fibroproliferative stage. Mast cell density at the periphery of FOP lesional tissue is 40- to 150-fol d greater than in normal control skeletal muscle or in uninvolved skeletal muscle from FOP patients and 10- to 40-fold greater than in any other infla mmatory myopathy examined. These findings document mobilization and activat ion of inflammatory mast cells in the pathology of FOP lesions and provide a novel and previously unrecognized target for pharmacologic intervention i n this extremely disabling disease. Hurt PATHOL 32;842-848. Thus is a US go vernment work. There are no restrictions on its use.