Abstract

Purpose: There is a high risk of developing post-traumatic OA after a joint injury. Around fifty percent of patients with either an anterior cruciate ligament or a meniscus tear show signs of OA after 10 to 20 years post injury. The Interleukin-1 (IL-1) signaling pathway has frequently been proposed as a crucial pathway in cartilage destruction in OA. The targeting of this pathway for general OA has been not successful. We hypothesized that the initial inflammatory response of cartilage and synovial tissue after the trauma during the healing process induces a slow cartilage degrading process, resulting in post-traumatic OA after several years. Therefore, we propose that the inhibition of inflammation using an interleukin-1 receptor antagonist (IL-1RA) may reduce the occurrence of post-traumatic OA. Methods: Explanted murine hip caps were fractured in vitro as a model of cartilage injury. These murine hip caps as well as cartilage from patients who underwent surgery after experiencing a joint trauma were treated either with IL-1RA or PBS control for 72 hours. Changes in gene expression of chondrocyte phenotypic markers (MMP13, aggrecan, collagen 2 and L-1 beta) were analyzed by quantitative RT PCR. Twenty 10 weeks old male wild type mice underwent meniscal/ligamentous injury (MLI) to induce post-traumatic OA. These mice were treated either with three injections of 500ng IL-1RA or PBS as control for 1 week directly after surgery. OA severity was measured using safranin-orange staining and the Chamber’s score after eight weeks post-surgery. Immunohistological stainings for chondrocyte marker genes (MMP13, collagen 2 and aggrecan) of murine and human cartilage samples were performed and quantified using Image J. Results: The 3 injections with 500 ng IL-1RA within one week after induction of OA were sufficient to prevented murine OA-like cartilage changes in the MLI model. As expected, the mice that received MLI surgery displayed an increased OA score compared to sham operated mice (sham: 0.6250 ± 0.1915; PBS: 4.4000 ± 0.4761; p:<0.0001). Treatment with IL-1RA significantly reduced cartilage degradation in comparison to PBS control treated mice (PBS: 4.4000 ± 0.4761; IL-1RA: 3.0000 ± 0.2687; p: 0.0184). IL-1RA treatment reduced significantly the expression of catabolic molecules in explanted and fractured murine hip caps such as IL-1β and MMP13. On the other side, Collagen 2 was significantly upregulated after treatment and the expression of aggrecan was slightly, but not significantly, upregulated. Treatment with IL-1RA almost completely reduced MMP13 upregulation in vivo in the cartilage.Human cartilage was taken from trauma patients where a piece of cartilage was chipped off the articular cartilage due to a traumatic event and could not be repaired during surgery. We analyzed samples from 10 patients (male: 4; female: 6) no more than 7 days post trauma and no signs of histological OA. In line with the murine samples, we found that the expression of IL-1β and MMP13, which have been both associated with cartilage degradation, were significantly decreased by IL-1RA treatment. The expression of the anabolic markers Col2 and aggrecan showed a trend of upregulation, although it did not reach significance. When looking at the protein level using immunofluorescence stained cartilage samples, again MMP13 showed a significant downregulation, while Col2 and aggrecan did not change significantly. Conclusions: As IL-1RA treatment is approved for rheumatoid arthritis and therapeutics like Anakinra are already on the market, a short term therapy for 2-3 month post-trauma could result in a lower post-traumatic OA rate. However, long-term studies are needed to evaluate the effectiveness of IL-1RA treatment after trauma. We could show that IL-1RA has an OA protective effect on human cartilage reinforcing the hypothesis that early short-term treatment with IL-1RA after traumatic injury might be a therapeutic strategy to prevent post-traumatic OA and protect further cartilage degradation.

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