Post-traumatic osteoarthritis (PTOA) is characterized by progressive articular cartilage erosion initiated by a variety of joint injuries ranging in severity from non-contact anterior cruciate ligament tears (ACLT) to intra-articular fracture (IAF). Even in the case of IAF, the immediate damage to cartilage and chondrocytes typically amounts to only a few percent of the joint surface. Yet, such localized lesions can expand over time;a phenomenon associated with release of mediators from injured cartilage. However, cartilage erosion also occurs away from originally damaged cartilage, indicating that catabolic factors carried in synovial fluid initiate degeneration in undamaged cartilage. Thus, an intervention centered on preventing trauma-induced inflammation holds great potential for reducing trauma-induced cartilage loss. Mechanical injuries to articular cartilage cause the death of chondrocytes and matrix degeneration in injury sites and, over time, in adjacent cartilage. Matrix fragments and cell debris signaling tissue damage (known collectively as "alarmins") induce catabolic responses via innate immune receptors expressed by chondrocytes synoviocytes, and other cells in the joint. In addition to their tissue-level effects, alarmins exert organ-level effects by recruiting monocytes and neutrophils to damaged tissues. This implies that abatement of alarmin signaling will prevent not just local catabolic effects in cartilage, but also the development of destructive whole-joint inflammation. For these reasons targeting alarmins is a promising strategy for cartilage preservation in injured joints. Support for this comes from trauma models, which show that blocking chondrocyte death by any of several means appears to slow or block cartilage loss, and from studies describing the anti-inflammatory and tissue-sparing effects of innate immune-suppressive drugs in numerous other organ systems. Based on these precedents we propose to investigate the potential of cell death inhibitors and innate immune/alarmin-targeted therapies to prevent progressive cartilage loss in mice with intra-articular fractures. In the first aim, transgenic mice with single gene knockouts affecting alarmin or cytokine signaling will be studied. In the second aim, upstream and downstream inhibitors will be used to simultaneously block multiple pathways. A gene therapy strategy for long-term suppression of alarmin or cytokine production will be tested in Aim 3. In the last aim, human reference data will be obtained by measuring alarmin and cytokine levels in patients with intra-articular fractures or anterior cruciate ligament tears.
This research is designed to generate new, critically needed treatments to suppress the development of post-traumatic osteoarthritis in a wide variety of joint injuries. The early intervention strategy targeting the initial molecular cross talk between injured tissues and inflammatory immune cells is intended to prevent, rather than merely ameliorate the actions of mediators that cause progressive cartilage loss.
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