Many Veterans and civilians sustain traumatic joint injuries, which frequently lead to poor rehabilitation outcomes, joint dysfunction, and development of osteoarthritis (OA) in the injured joint. Existing treatments for joint injury and OA only alleviate symptoms, and are ineffective in promoting healing or preventing OA. Increasing evidence implicates ?low-grade? inflammation following joint injury in poor rehabilitation outcomes, and in the eventual development of post-traumatic OA. A better understanding of the underlying inflammatory mechanisms and identification of pharmacologic agents that target the dysregulated pathways could transform the care and rehabilitation for military personnel, Veterans, and civilians with traumatic joint injuries. Our preliminary studies suggest a critical role for mast cells in mediating inflammatory responses following joint injury and in promoting the development of post-traumatic OA. In this proposal, we aim to elucidate the roles of mast cells in poor rehabilitation outcomes following joint injury and in the development of post-traumatic OA. Mast cells are detected in OA synovium as well as in post-trauma non-OA joints, and are capable of producing pro-inflammatory and degradative mediators. We found overexpression of mast cell mediators, including mast cell-specific tryptases, in synovial membranes and fluids from individuals with joint injury or OA. Data from two mouse models indicated that lack of mast cells attenuated OA-related pathologies, whereas engraftment of mast cells restored this phenotype. Pharmacologic inhibition of mast cell activation confirmed these results. Our in vitro studies showed that tryptase induces several processes integral to OA pathogenesis: degeneration of human cartilage, apoptosis of articular chondrocytes, and pro-inflammatory responses and proliferation of synovial fibroblasts. Further, we found that IgE signaling mediated by Fc?RI, Syk, and histamine-releasing factor (HRF) is involved in the pathogenesis of post-traumatic OA. Nevertheless, important questions remain about the upstream mechanisms underlying mast cell activation following joint trauma and in OA, the role of IgE, and whether targeting mast cell pathways or products might improve rehabilitation and prevent OA. We hypothesize that following joint injury, IgE-mediated activation of mast cells involving Fc?RI, Syk, and HRF promotes inflammation, which impairs rehabilitation and accelerates the development of OA. Further, we hypothesize that injury-induced joint and cartilage breakdown products lead to an IgE response and/or production of HRF that activates mast cells, and that biomarkers can be identified to guide pharmacologic targeting of mast cells to promote successful rehabilitation and prevent the development of post-traumatic OA. To test these hypotheses, in Aim 1, we propose to characterize mast cell activation, degranulation, and biomarkers in human joints post-injury, in rehabilitation, and in OA.
In Aim 2, we will characterize the IgE response in joint injury, rehabilitation, and OA.
In Aim 3, we will identify strategies that pharmacologically target mast cell pathways to improve rehabilitation outcomes and to prevent secondary OA following joint injury in the destabilization of the medial meniscus (DMM) mouse model. Importantly, Aim 3 will focus on FDA-approved drugs that target mast cells, thereby providing a path for rapid translation and evaluation of promising candidates for efficacy in promoting successful rehabilitation outcomes and preventing development of secondary OA following joint injury in humans. If successful, the proposal will elucidate the roles of mast cells and IgE in rehabilitation outcomes and development of OA following joint injury (Aims 1 and 2), establish biomarkers to identify individuals who are likely to suffer from mast-cell-mediated poor rehabilitation outcomes and post-traumatic OA (Aims 1 and 2), and identify candidate pharmacologic interventions that target mast cells to promote successful rehabilitation and optimal functional outcomes (Aim 3).
of the proposed research to Veterans' health issues: Many military personnel and Veterans incur traumatic joint injuries that result in joint dysfunction, poor rehabilitation outcomes, and eventually lead to development of post-traumatic osteoarthritis (OA). This proposal will investigate the role of mast cells and related pathways in poor rehabilitation outcomes following joint injury and in the development of post-traumatic OA. The success of the proposed studies could lead to novel biomarkers to identify individuals likely to experience mast-cell-mediated poor rehabilitation outcomes and/or development of post-traumatic OA, as well as identify FDA-approved pharmacologic agents targeting mast cells that could be rapidly translated into therapeutics to improve rehabilitation outcomes and prevent the development of post-traumatic OA in humans.
