Background 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.
Objectives To investigate the role of IL-1α/β in synovitis and cartilage destruction during experimental collagenase-induced OA (CiOA).
Methods Experimental OA was induced by intra-articular injection of collagenase into WT and IL-1αβ–/– mice. At day 7 and 42 after CiOA induction, total knee joints were stained with haematoxylin/eosin (H&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.
Results 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–/– 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–/– 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–/– 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–/– 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)).
Conclusions 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.
van Lent et al. 2012
Acknowledgement This research was supported by the Dutch Arthritis Association.
Disclosure of Interest None declared