SMALL MOLECULE THERAPY IN THE PREVENTION OF HETEROTOPIC OSSIFICATION

Traumatically injured muscle exhibits high susceptibility to heterotopic ossification and likely involves failure in endogenous attenuation of signaling by osteogenesis-inducing factors, i.e., bone morphogenetic proteins (BMPs). Dorsomorphin was recently identified as a small molecule BMP inhibitor that specifically inhibits the kinase domain of BMP type 1 receptors that are upstream of osteogenic differentiation gene targets and are the cellular targets of BMP-4. This novel small molecule BMP inhibitor has low cytotoxicity and presents advantages over native BMP antagonists due to its specificity and because its activity is unlikely to be altered by the biochemical environment of a traumatic wound. We will test the hypothesis that treatment with Dorsomorphin will modulate the heterotopic ossification activity of traumatized muscle by making up for failures in endogenous BMP signaling attenuation mechanisms that result from trauma. We will answer three questions that must be addressed to further develop our hypothesis: (1) To what extent is BMP-4 released from interstitial reservoirs in the muscle following traumatic injury? (2) How does BMP-1 interfere with the attenuation of BMP-4 signaling in the traumatized muscle tissue? (3) Does Dorsomorphin restore the attenuation of BMP-4 signaling in the muscle tissue? We have developed an ex vivo assay using muscle explants, and we will use this model system to evaluate the mechanisms regulating the interactions between BMP-1, BMP-4, and Dorsomorphin.