Wednesday, May 15, 2024
5/15/2024
DESCRIPTION (provided by applicant): Heterotopic ossification (HO) is a pathologic process which results in mineralization, and potential ossification, of soft tissue structures. HO contributes to numerous disease processes, most notably post traumatic myositis ossificans, heart valve calcification and atherosclerosis. Aberrant tissue mineralization imposes significant morbidity and mortality as it prevents the essential native motion causing tissue dysfunction and ultimately, failure. The pathophysiologic process leading to HO is not completely understood. However, recent evidence suggests that HO pathogenesis may be divided into two distinct phases; initiation and maturation. Importantly, in myositis ossificans, mature HO imposes a devastating, and to date untreatable, clinical impact on patients. Notably, myositis ossificans can be detected during initiation. However, current surgical and pharmacological approaches of preventing HO maturation are ineffective. Thus, there is a considerable need for novel therapies designed to prevent the maturation of HO. Aims: In this proposal, we will test the hypothesis that maturation of HO can be prevented by: 1) Digesting immature HO with a protease capable of degrading the coagulation matrix protein fibrin and 2) Inhibition of mesenchymal cell transformation into osteoblasts residing in immature HO by targeting the bone morphogenic protein (BMP) type I receptor. The rationale for this hypothesis is rooted recent findings regarding the etiology of myositis ossificans involving fibrin, a critical coagulation matrix proten, and aberrant BMP type I receptor signaling. Methods: Using our established traumatic myositis ossificans model in mice unable to remove fibrin, we will monitor HO maturation using previously employed techniques with and without the administration of 1) plasminogen (the precursor protein for the main fibrinolytic protease, plasmin) or 2) an inhibitor of the BMP type I receptor (ALK2/3). We anticipate that digesting immature HO with plasmin will result in inhibition of HO maturation and resolution of immature fibrin whereas inhibition of the BMP type I receptor will prevent maturation, but not resolution of, immature HO. Impact: The findings generated in this study should provide proof-of-principal evidence for two novel, molecular-distinct methods of pharmaceutically preventing HO maturation. If found true, we would subsequently pursue studies in combination therapies with the goal of finding the ideal combination of 1) digesting immature HO and 2) preventing mesenchymal cell transformation or differentiation into osteoblasts. In addition, as soft tissue calcification plays a significant role in multiple other diseases, these findings have the potential to reveal novel means of preventing and treating other pathologic processes such as atherosclerosis and valvular calcification.
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