Background/Purpose: Osteoarthritis (OA) is characterized by severe cartilage destruction, with a putative role for synovial macrophages. Up to 50% of the patients also show low grade joint inflammation reflected by a thickened synovial lining and elevated release of macrophage-derived mediators like interleukin-1 (IL-1) and S100A8/A9. The deteriorating role of S100A8/A9 in OA has been studied extensively, but the contribution of IL-1 to OA pathology is still unclear. IL-1 mediates cartilage destruction by degrading existing proteoglycans through stimulating degradative enzyme production, and by inhibiting new formation of proteoglycans. However, treatment of OA patients with IL-1 inhibitors has so far been disappointing. Here we investigated the role of IL-1α and IL-1βin synovitis and cartilage destruction during collagenase-induced OA (CiOA).

Methods: CiOA was induced by intra-articular injection of collagenase in WT and IL-1αβ^-/-mice. In addition, IL-1 signaling was inhibited in WT mice with CiOA using osmotic pumps containing IL-1RA. Histology of total knee joints was used to assess synovitis and cartilage destruction with a modified Pritzker score. Activity of cartilage-degrading enzymes was determined using antibodies against aggrecan neo-epitopes VDIPEN and NITEGE. Synovial gene expression was analyzed using qRT-PCR. Serum protein levels were measured with Luminex. S100A8/A9 protein levels were determined with a sandwich ELISA.

Results: At early stage (day 7) of CiOA, gene expression of IL-1β within inflamed synovium was significantly elevated when compared to synovium of naïve control knees. In later stages (day 21 and 42), IL-1β expression levels showed a steep decline. This is in contrast to pro-inflammatory mediators like S100A8 and S100A9 which remained elevated on day 21. Remarkably, synovial inflammation on day 7 in IL-1αβ^-/- mice was not different from WT controls (2.9±0.2 vs. 2.7±0.4), suggesting that IL-1 does not aggravate synovitis. Absence of IL-1α and IL-1β had no effect on the synovial gene expression levels of pro-inflammatory factors KC, S100A8 and S100A9. IL-6 mRNA levels, however, were significantly decreased in the synovium of IL-1αβ^-/- mice. The lack of IL-1α and IL-1β also did not affect gene expression of anti-inflammatory cytokines IL-10 and iNOS. Moreover, serum protein levels of KC, IL-6, IL-10 and S100A8/A9 on day 7 of CiOA in IL-1αβ^-/- mice were not different when compared to WT mice. No difference was found in MMP and ADAMTS activity on day 7 between WT and IL-1αβ^-/- mice. In line, cartilage destruction on day 42 was not significantly different between both strains (mean OA score of 59.2±25.4 and 74.8±27.0, respectively), which was supported by our finding that IL-1RA treatment in WT mice with CiOA did not alter joint destruction (mean OA score of 44.7±33.3 in treated mice vs. 56.2±20.5in untreated mice). 

Conclusion: IL-1α and IL-1β are not involved in synovial inflammation and cartilage destruction during collagenase-induced osteoarthritis, implicating that other mediators are responsible for the joint damage.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interleukin-1-is-not-involved-in-synovial-inflammation-and-cartilage-destruction-in-collagenase-induced-osteoarthritis/