The elevated expression of IL-38 serves as an anti-inflammatory factor in osteoarthritis and its protective effect in osteoarthritic chondrocytes

The objective of this study is to investigate the role of IL-38 in osteoarthritis (OA). IL-38 levels in serum and synovial fluid (SF) of patients with OA were examined to identify the correlation between IL-38 expression and OA activity and to determine its anti-inflammatory effects in IL-1β-induced chondrocytes. A total of 75 patients with OA who underwent joint replacement surgery and 25 age- and sex-matched healthy volunteers were recruited. The levels of IL-38 in serum and SF are shown to be significant elevated in OA patients compared with that of healthy controls. Serum and SF IL-38 levels of OA patients are positively correlated with Kellgren-Lawrence (K-L) grades 2 to 3, as well as with pro-inflammatory cytokines IL-6, IL-23, and TNF-α, but are negatively correlated with the anti-inflammatory cytokine IL-10 in K-L grades 3 to 4. Furthermore, overexpression of IL-38 in vitro is shown to attenuate the expression of pro-inflammatory cytokines such as COX-2, IL-6, IL-8, IL-36Ra, IL-36α/β/γ, iNOS, and TNF-α, as well as matrix degrading enzymes such as MMP3, MMP13, and ADAMTS5, and apoptosis-related indicators Bax/Bcl-2, cleaved caspase 3/pro-caspase 3, and cleaved caspase 9/pro-caspase 9. IL-38 overexpression also reduces expression of the signaling proteins p-p38, p-p65, p-JNK, and RhoA significantly. Taken together, our results show that expression of IL-38 is increased in OA tissues and OA rat chondrocytes, and is positively correlated with early disease activity. This increased IL-38 expression lead to the inactivation of MAPK, NF-κB, JNK, and RhoA signaling pathways, which might have impletion on OA chondrocytes apoptosis, degradation and inflammatory effect. Thus, IL-38 probably serves as a novel therapeutic target for the treatment of OA.