2). Despite different approaches employed for detection and characterization of synovitis (e.g. imaging or histologic assessment), published studies provide evidence of a correlation between synovial inflammation and symptoms such as pain, in patients with knee OA. Torres L. et al. [107] investigated the relationship between knee pain and specific joint pathology detected by MRI in patients with knee OA. They noted that synovitis or effusion, as well as meniscal tears and bone marrow lesions, were among findings that best correlated with knee pain measured on a visual analog scale (VAS). Others [43] specifically

examined the relationship between pain and synovitis on MRI and noted that changes in pain scores over time varied with changes in synovitis, strengthening the notion of a causal high throughput screening compounds relationship. A similar association between pain and synovitis was reported more recently [4] using contrast enhanced MRI. In that study, higher grades of synovitis conferred a 9-fold greater risk (95% confidence interval 3.2–26.3) of having painful knee OA. Using serum HA as a marker of synovitis, Ishijima et al. [46] also demonstrated a relationship between synovitis and pain. We [87] contributed further evidence of an association between

synovitis (defined histologically) and knee symptoms measured by the Lysholm score (which measures pain, swelling, limp, locking, instability, and functional disability on a single scale) in patients with early knee OA undergoing arthroscopic EPZ5676 mouse meniscectomy. Synovitis has not only been related to knee pain, but also to knee joint function using objective outcome measures of walking and stair-climbing times [100]. One recent study of patients with end-stage knee OA undergoing joint replacement did not support a relationship between synovitis [64] and pain simply measured by a VAS. The reasons for this are unclear, but Fossariinae may be due to differences in patient populations

studied, or differences in symptom assessments. We speculate that at advanced stages of knee OA where denuded bony surfaces are abutting each other, pain and symptoms may have multiple origins related to extensive structural alterations. Despite some disagreement in the literature, the majority of available studies provide compelling evidence that synovial inflammation is a rationale target for therapeutic intervention to control joint symptoms in OA. Future work should help define specific patient populations for whom targeting synovitis may have the greatest benefit. In 2005, Ayral and colleagues published a study demonstrating a relationship between synovitis and progression of cartilage erosion [3]. This was a secondary analysis of 422 patients enrolled in a clinical trial with medial compartment knee OA who had been followed longitudinally for over one-year. Synovitis and cartilage integrity was documented by the visual appearance of the synovial membrane and cartilage surfaces during baseline arthroscopy.