Heterotopic ossification (HO), the formation of ectopic endochondral bone in skeletal muscle and soft tissues, is a significant cause of morbidity from joint immobility and pain. The precise mechanisms responsible for HO remain incompletely understood; however, the association with genetic gain-of- function syndromes affecting receptors and ligands of the bone morphogenetic protein (BMP) and activin signaling pathways has generated important insights and translatable strategies. We have previously identified activin A as the dominant ligand responsible for the congenital HO syndrome fibrodysplasia ossificans progressiva (FOP), being transduced via mutant ACVR1 encoding ALK2. In subsequent work using a ligand trap, we and collaborators found that ligands of the BMP type I receptor ALK3 account for a major portion of non-genetic forms of HO, frequently complicating joint replacement surgeries, burn injuries, blast trauma, or inflammatory arthropathies. In the parent grant for this supplement we describe several pharmacologic and genetic strategies for narrowing the identify of ligands and receptors responsible for non-genetic forms of HO, using genetically modified human derived tissue cultures and genetically modified mouse reagents and tissues. Here we propose to generate a panel of novel reagents that can selectively target signaling via specific type I and type II receptors in this pathway in non-transfected or non-engineered tissues, and thus permit complementary studies in unmodified human and rodent tissues without artifacts due to genetic modification or off-target effects confounding interpretation. Moreover, these antibody-based reagents would have pharmacokinetics suitable for in vivo validation studies and could be rapidly translated into therapies for tissue regeneration or orthopedic applications. Importantly. these studies will provide a robust set of tools that can be used to further elucidate the molecular blueprint for development, wound healing, as well as HO involving skeletal muscle and tendon niches, and create a broad platform for scientific discovery and translational work in musculoskeletal disease.
The bone morphogenetic protein (BMP) and transforming growth factor b (TGFb) are potent regulators of normal bone development as well as inappropriate (heterotopic) bone formation. The naturally occurring ligands of this pathway are promiscuous in their binding with multiple receptors, and have poor pharmacokinetics, limiting their utility as probes of function or as potential drug molecules. This proposal develops novel reagents that can initiate or modulate signaling of BMP and TGFb with high specificity and potency, and may thus be able to target intended tissues with greater selectivity, and with the potential for rapid translation as therapeutic molecules.
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