NOVEL THERAPEUTIC STRATEGY TARGETING BONE MORPHOGENETIC PROTEIN RECEPTOR 1 SIGNALING TO PREVENT TRAUMA-INDUCED HETEROTOPIC OSSIFICATION

Background: Over 60% of major burns, 65% of combat injuries, and 50% of joint surgeries will cause heterotopic ossification (HO), the deposition of bone in soft tissues such as muscle, tendon, or fascia. Current treatments require surgical extirpation of HO; however, even after a technically successful operation, >75% of patients have restricted range of motion and pain. Barriers to improved outcomes in HO patients include delayed diagnosis and a lack of treatments that target the key ectopic bone formation pathway, specifically the bone morphogenetic protein (BMP) pathway. Through this proposal, we plan to improve early diagnosis with Raman spectroscopy and HO prevention strategies by targeting the BMP pathway with a panel of potent inhibitors. We aim to change the current paradigm of HO management from one of delayed diagnosis and excision to one of early detection and prevention. Specifically, we will use non-invasive Raman spectroscopy to identify early indicators of HO formation. Once at-risk patients are identified, we will deploy BMP inhibitors LDN-193189, LDN-212854, and ALK3-Fc to prevent HO. This proposal addresses the need outlined in the Clinical and Rehabilitative Medicine Research Program Announcement for optimizing treatment strategies and sequence of progression throughout the rehabilitation process following severe extremity trauma.Objective/Hypothesis: We hypothesize that early HO detection with Raman spectroscopy and early treatment with potent BMP signaling inhibitors (LDN-193189, LDN-212854, and ALK3-Fc) can mitigate MSC osteogenic differentiation and prevent HO formation. We plan to leverage the repository of Warfighter tissue at the Naval Medical Research Center (NMRC), the civilian tissue at the University of Michigan (UM), and the pharmacokinetics program at Brigham and Women's Hospital (BWH). Preliminary data from UM and BWH demonstrate that MSCs from burn patients have sevenfold higher BMP signaling via BMP receptor I than age-matched controls. Clinical data from NMRC demonstrate that BMP2 expression in tissue biopsies from wounded Warfighters who developed HO was elevated 4-8 times compared to biopsies from wounded Warfighters who did not develop HO. Additionally, the NMRC and UM have validated two animal models that verify the central role of BMP signaling in HO formation. Our results support a link between blast and burn injury and enhanced BMP signaling in MSCs and HO. This result provides direct evidence for a causal role of BMP signaling in HO and the therapeutic potential of this approach.Specific Aims: (1) To test the impact of BMP-targeted therapies in two authentic models of blast and burn trauma-induced HO, by non-invasive Raman spectroscopic, functional, radiographic, and histologic approaches. (2) Evaluate the impact of BMP-targeted therapies on recruitment and differentiation of chondrogenic and osteogenic progenitors in blast and burn trauma-induced HO models, and in mesenchymal stem cells derived from patients with blast and burn-induced injuries.Study Design: In Aim 1, we will test the ability of our panel of BMP inhibitors to attenuate HO in vivo using two validated rodent models. Additionally, we will test the ability of Raman spectroscopy to detect early HO in these trauma/burn animal models. In Aim 2, we will analyze BMP signaling and the impact of systemic administration of BMP inhibitors ALK3-Fc, LDN-193189, and LDN-212854 on the chondrogenic and osteogenic differentiation of MSCs harvested from our rodent models and the in vitro efficacy of these inhibitors on MSC isolated from military and civilian HO patients.Military Benefit: An increasing number of injured Soldiers are sustaining extremity blast and burn injuries of which over 60% will develop HO. Furthermore, as Veterans age, an increasing number of patients are having joint arthroplasties, which also have a high HO risk. Current treatment strategies involve surgical extirpation of the heterotopic bone; however, even after a technically successful operation, three out of four patients have difficulty maintaining their range of motion and 35% of patients have residual bone requiring multiple operations further increasing the risk of recurrence. We plan to improve prevention strategies for both acute military and civilian injuries with a high HO risk by (1) the use of Raman spectroscopy to identify which patients are at the highest risk of developing HO and (2) targeting the BMP pathway. We aim to change the current paradigm of HO management, using non-invasive Raman spectroscopy to identify early indicators of risk, monitor effects of intervention, and permit early deployment of a potent intervention to circumvent osteogenic recruitment before the formation of HO.