Abstract
Objective: Interleukin-15 (IL-15) is a pro-inflammatory cytokine that is increased in joint fluids of early-stage osteoarthritis (OA) patients, and has been associated with expression of proteases that can damage cartilage, and the development of neuropathic pain-like symptoms (NP) after nerve injury. The objective of this study was to further explore the role of IL-15 in the pathogenesis of OA cartilage degeneration and test genetic variation in the IL-15 receptor α gene (IL15RA) for an association with OA with radiographic severity and symptoms.Methods: Cartilage samples from donors (n = 10) were analyzed for expression of the IL15 receptor α-chain using immunohistochemistry, and for responses to IL-15 in vitro using explant cultures. Data from two independent Nottinghamshire-based studies (n = 795 and n = 613) were used to test genetic variants in the IL15RA gene (rs2228059 and rs7097780) for an association with radiographic severity, symptomatic vs. asymptomatic OA and NP.Results: IL-15Rα was expressed in chondrocytes from cartilage obtained from normal and degenerative knees. IL-15 significantly increased the release of matrix metalloproteinase-1 and -3 (MMP-1 and -3), but did not affect loss of proteoglycan from the articular matrix. Genetic variants in the IL15RA gene are associated with risk of symptomatic vs. asymptomatic OA (rs7097780 OR = 1.48 95% 1.10–1.98 p < 0.01) and with the risk of NP post-total joint replacement (rs2228059 OR = 0.76 95% 0.63–0.92 p < 0.01) but not with radiographic severity.Conclusions: In two different cohorts of patients, we show an association between genetic variation at the IL15 receptor and pain. Although ex vivo cartilage explants could respond to IL-15 with increased protease production, we found no effect of IL-15 on cartilage matrix loss and no association between IL15RA variants and radiographic severity. Together, these results suggest that IL-15 signaling may be a target for pain, but may not impact structural progression, in OA.
Highlights
The inflammatory response has been shown to play an important role in osteoarthritis (OA) [1], both in symptomatic and structural manifestations, but the relative importance of specific inflammatory mediators in OA joints is yet to be fully elucidated
Cellular responses to IL-15 are mediated by binding to the IL-15 receptor which is composed of three subunits: the interleukin-15 receptor α (IL-15Rα) chain which confers binding specificity for IL-15, and a common β and γ chain shared by the IL-2 receptor [17]
We found no significant differences in the TNF + OSM response when comparing donors that responded to IL-15 vs. non-responders (Supplemental Figures 1C,D, Mann-Whitney P > 0.05), and no statistically significant correlation between the responses to IL-15 and TNF + OSM, for either MMP-1 (Spearman r = 0.54, P = 0.11) or MMP-3 (r = 0.05, p = 0.89) (Supplemental Figures 1E,F)
Summary
The inflammatory response has been shown to play an important role in osteoarthritis (OA) [1], both in symptomatic and structural manifestations, but the relative importance of specific inflammatory mediators in OA joints is yet to be fully elucidated. We previously found IL-15 levels in the SF to be elevated in early-stage disease compared with advanced disease and correlated with SF matrix metalloproteinases-1 and -3 (MMP-1 and MMP-3) levels [2]. Serum IL-15 was associated with radiographic OA changes in the knee and hands, and was elevated in individuals up to 10 years prior to observation of radiographic changes. Taken together, these studies suggest that IL-15 might play a role in early initiation events leading to joint degeneration in OA
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