IL-15 and IL15RA in Osteoarthritis: Association With Symptoms and Protease Production, but Not Structural Severity.

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 () for an association with OA with radiographic severity and symptoms. Cartilage samples from donors ( = 10) were analyzed for expression of the IL15 receptor α-chain using immunohistochemistry, and for responses to IL-15 using explant cultures. Data from two independent Nottinghamshire-based studies ( = 795 and = 613) were used to test genetic variants in the gene (rs2228059 and rs7097780) for an association with radiographic severity, symptomatic vs. asymptomatic OA and NP. 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 gene are associated with risk of symptomatic vs. asymptomatic OA (rs7097780 OR = 1.48 95% 1.10-1.98 < 0.01) and with the risk of NP post-total joint replacement (rs2228059 OR = 0.76 95% 0.63-0.92 < 0.01) but not with radiographic severity. In two different cohorts of patients, we show an association between genetic variation at the IL15 receptor and pain. Although 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 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.