Osteoarthritis (OA) is a leading cause of disability in adults, is characterized by chronic progressive cartilage damage. Current treatment, particularly for early stages of disease, is limited and does not prevent progressive joint damage. Furthermore, factors related to joint dysfunction are poorly understood. Low-grade inflammation of the 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 presenting for meniscal arthroscopy due to degenerative meniscal tears. 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 genetic loss of CCR7 will prevent synovial inflammation and diminish cartilage damage in OA, as well as OA-related joint dysfunction. We will use the well-characterized murine destabilization of the medial meniscus (DMM) model. Mice deficient in CCR7 expression (CCR7 -/-) will be compared to C57BL/6 wild-type controls. Cartilage and bone changes will be measured by histopathology and micro-CT while synovitis will be measured by flow cytometric analysis of enzymatically released cells from microdissected tissues. These outcomes will be measured at 2, 4, 8, and 16 weeks post-DMM surgery, and compared to sham-operated and age-matched unoperated controls. In a third set of experiments, we will measure locomotion and normal activity (climbing, distance traveled, speed of locomotion) longitudinally every 4 weeks up to 16 weeks post- DMM and sham surgery, comparing CCR7-/- and C57BL/6 age-matched mice. Results of this study will support subsequent proposals to understand specific mechanisms by which CCR7 impacts OA, and test pharmacologic CCR7 blockade intra-articularly.
This work will benefit both Veterans and civilians who have osteoarthritis, by leading to the development of novel treatments that reduce arthritis joint damage and related disability. To date, there is no treatment that addresses both of these important problems. The number of patients in the US estimated to have symptomatic osteoarthritis approaches 27 million. Incidence rate is 26% higher than the general population in active duty service members 20-24 years old, and >100% higher for those >40 years old. This project will identify inflammatory mechanisms important in driving joint damage and joint dysfunction in a model of osteoarthritis. Methods to block the inflammatory pathway studied are already available, increasing the chances that our results will lead to usable treatments in the near future.
|Sambamurthy, Nisha; Nguyen, Vu; Smalley, Ryan et al. (2018) Chemokine receptor-7 (CCR7) deficiency leads to delayed development of joint damage and functional deficits in a murine model of osteoarthritis. J Orthop Res 36:864-875|
|Scanzello, Carla R (2017) Role of low-grade inflammation in osteoarthritis. Curr Opin Rheumatol 29:79-85|
|Scanzello, Carla R (2017) Chemokines and inflammation in osteoarthritis: Insights from patients and animal models. J Orthop Res 35:735-739|