FRI0035 Joint Inflammation and Cartilage Destruction in Experimental Osteoarthritis Is Not Mediated by Interleukin-1
Authors: S. Van Dalen, A. Blom, L. Joosten, A. Sloetjes, M. Helsen, W. van den Berg, P. van Lent
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Osteoarthritis (OA) is a degenerative disease of the joint 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 (1), 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. <h3>Objectives</h3> To investigate the role of IL-1α/β in synovitis and cartilage destruction during experimental collagenase-induced OA (CiOA). <h3>Methods</h3> Experimental OA was induced by intra-articular injection of collagenase into WT and IL-1αβ<sup>–/–</sup> mice. At day 7 and 42 after CiOA induction, total knee joints were stained with haematoxylin/eosin (H&amp;E) to score synovial activation (arbitrary score from 0–3). Cartilage destruction was determined in knee sections stained with safranin O/fast green using a modified Pritzker score. Gene expression in inflamed synovium was analyzed using qPCR with primers for several cytokines. Serum protein levels of inflammatory mediators were measured with Luminex. <h3>Results</h3> At early stage (day 7) of CiOA, gene expression of IL-1 within inflamed synovium of knee joints was elevated 65 times compared to synovium of naïve control knees. However in later stages (day 21 and 42), IL-1 expression levels were reduced to basal levels. This is in contrast to pro-inflammatory mediators like S100A8 and S100A9 which remained elevated at day 21 and 42 (30–35-fold and 66–69-fold, respectively). Histological examination of knee joints showed a moderate synovitis at day 7 which waned thereafter but was still significant at day 21 and 42. Remarkably, synovial inflammation at day 7 in IL-1αβ<sup>–/–</sup> mice was not different from WT controls (2.89±0.15 vs. 2.71±0.44), suggesting that IL-1 does not aggravate synovitis. Absence of IL-1α/β 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<sup>–/–</sup> mice (3-fold reduction). The lack of IL-1α/β also did not affect gene expression of anti-inflammatory cytokines IL-10, TGFβ and iNOS. Moreover, serum protein levels of KC, IL-6, MCP-1, IL-10 and S100A8/A9 at day 7 of CiOA in IL-1αβ<sup>–/–</sup> mice were not different compared to WT mice. Cartilage destruction in CiOA clearly aggravated over time, but we found no significant differences between IL-1αβ<sup>–/–</sup> mice and WT controls. No difference in cartilage damage was measured at day 42 of CiOA when compared to WT (medial femur (95.3±42.0 vs. 65.5±54.5), medial tibia (84.5±36.6 vs. 55.1±38.9), lateral femur (69.6±43.9 vs. 60.8±35.8), and lateral tibia (49.8±26.3 vs. 55.4±17.1)). <h3>Conclusions</h3> IL-1 does not affect synovial inflammation and cartilage destruction during collagenase-induced osteoarthritis, implicating that other macrophage-derived mediators such as S100A8/A9 are responsible for the joint damage. <h3>References</h3> van Lent et al. 2012 <h3>Acknowledgement</h3> This research was supported by the Dutch Arthritis Association. <h3>Disclosure of Interest</h3> None declared