CCR7 and its ligands in Osteoarthritis

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 DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a leading cause of disability in adults, and is characterized by chronic progressive cartilage damage and bony remodeling. Current treatment options are limited, do not prevent progressive joint damage, and factors related to joint dysfunction are poorly understood. Low-grade inflammation of the joint lining tissue (synovial membrane) is common in OA, and has been associated with severity of knee joint dysfunction, pain, and progression of cartilage loss. This suggests that synovial inflammation could be targeted to reduce both symptoms and progression of OA. We have recently identified expression of the chemokine receptor CCR7 and its two ligands (CCL19 and CCL21) in the synovial membrane of knee OA patients, including patients with early-stage OA knee OA. CCR7 is involved in the recruitment of multiple leukocyte populations suggesting it may promote development and perpetuation of synovial inflammation. In this proposal, we will test the hypothesis that CCR7 promotes synovial inflammation, cartilage damage and bone remodeling in OA, and impacts development of OA related disability, using the well-established murine destabilization of the medial meniscus (DMM) model. In the first aim, OA development will be monitored in mice deficient in CCR7 expression (CCR7 -/-) compared to C57BL/6 wild-type controls. Wild-type mice will also be treated with a fusion protein which counteracts the activity of CCL19. Cartilage and bone changes will be measured by histopathology and micro-CT, while synovial inflammation will be measured by gene expression and flow cytometry. These outcomes will be measured at 2, 4, 8, and 16 weeks post-DMM surgery, and compared to sham-operated and unoperated controls. Locomotion and normal activity (climbing, distance traveled, speed of locomotion) will be measured longitudinally every 4 weeks up to 16 weeks post- DMM and sham surgery, as a reflection of OA-related disability. In the second aim, expression levels and cellular distribution of CCR7 and its ligands will be evaluated in joint tissues from mice subjected to DMM or sham surgery, and in humans with and without OA. Results of this study will support subsequent proposals to understand specific mechanisms by which CCR7 impacts OA, and test pharmacologic CCR7 blockade intra-articularly.