Immune cells and cytokines mediating fibrodysplasia ossificans progressiva



 DESCRIPTION (provided by applicant): Fibrodysplasia ossificans progressiva (FOP) is am untreatable rare congenital disease that results heterotopic ossification (HO) in skeletal muscle leading to immobilization, extreme pain, and eventual death. FOP patients carry an activating single point mutation in one copy of the Acvr1 gene that encodes the bone morphogenetic protein (BMP) Type I receptor, Alk2. Despite widespread expression of mutant Alk2 in numerous tissues the formation of HO lesions is not continuous. Rather, HO appears in distinct sporadic "flares" associated with systemic infections or muscle contusions. Hence, clinicians and researchers have long suspected that HO flares are initiated by inflammation and/or immune cells. Using mouse models of FOP, this laboratory and others have shown that increasing inflammation enhances HO, while high-dose glucocorticoids suppress HO. Unfortunately, glucocorticoids are not clinically effective and little is known about the mechanisms by which inflammation or the immune system trigger HO. TNFa is the most highly expressed cytokine at sites of inflammation, while macrophages are the most abundant immune cells in sites of skeletal muscle damage. Interestingly, both TNFa and macrophages have been shown to enhance endochondral bone formation in certain settings, suggesting possible roles in FOP. This proposal will address the overall hypothesis that macrophages and endogenous expression of TNFa are critical mediators of heterotopic ossification in FOP. Aim 1 will determine the role of endogenous TNFa and Aim 2 will determine the role of macrophages in the initiation and development of HO in a mouse model of FOP. The results of these studies hold to potential to identify new targets that could lead to treatments to prevent or reduce HO in this deadly disease.