However, IL-1β is not consistently

elevated in the synovial fluid of OA patients [53] and [92] and the endogenous IL-1 receptor antagonist, which blocks IL-1 activity, is produced by synoviocytes at higher levels in OA than Selleckchem Osimertinib in RA [33]. Attempts to block IL-1 activity therapeutically in patients have been associated with only minimal symptom-reducing efficacy at best [18] and [20]. However, it is possible that IL-1 activity is important in specific clinical settings in OA. Production of active IL-1 requires activation of the NALP3 inflammasome; activation of the inflammasome by uric acid crystals has been implicated in flares of gouty arthritis [69]. Other crystals, including basic calcium phosphate [76] and hydroxyapatite [48] have recently been shown to activate inflammasome-mediated IL-1 production. Both hydroxyapatite and basic calcium phosphate crystal deposition occurs in patients with OA. Therefore, it is possible that IL-1 is important in patients with OA and evidence of crystalline deposition. TNF-α is readily detectable in SF in patients

with OA [92]. Like B-Raf inhibition IL-1, TNF can activate chondrocyte-mediated catabolic protease production [51]. The well-established clinical efficacy of TNF inhibition in the setting of RA, and the availability of blocking agents, led to trials of a TNF-inhibitor in an open-label pilot study to treat pain and inflammation in twelve patients with erosive hand OA [67]. Like the IL-1 trials, this trial did not demonstrate significant efficacy, but improvement in pain and physical function scores was reported for some individuals. It remains to be seen whether different patient subsets will respond to targeted therapies

blocking the actions of TNF. The perivascular inflammatory cell infiltrates observed in the OA synovium are largely composed of lymphocyte populations [7]. Based on this observation, our group investigated the expression and activity of cytokines involved in lymphocyte biology in OA synovium. We focused our efforts on the common-γ chain family of cytokines (including IL-2, IL-15, and IL-21) which are involved in recruitment, survival and activity of lymphocytes [89]. IL-15 was consistently Anacetrapib detectable and elevated in patients with early stage OA, compared with end-stage OA patients undergoing total knee arthroplasty. In rheumatoid synovial fibroblasts, TLR-2 and -4 stimulation were shown to induce IL-15 production in vitro [49]. Both synoviocytes [89] and chondrocytes (Scanzello, unpublished results) from OA patients express the specific IL-15 receptor, suggesting there may be multiple cellular targets of IL-15. Serum IL-15 detected using a proteomic approach was associated with the presence and progression of radiographic OA [62]. Studies by Long et al. showed that IL-7, another common-γ chain cytokine which activates lymphocytes, is produced by chondrocytes [66].