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High synovial fluid interleukin-6 levels are associated with increased matrix metalloproteinase levels and severe radiographic changes in osteoarthritis patients

      Purpose: Interleukin-6 (IL-6) is a proinflammatory mediator contributing to the pathogenesis of rheumatoid arthritis, but its role in osteoarthritis is not so clear. In the present study, we report the levels of IL-6 in plasma and synovial fluid obtained from 100 OA patients as well as the association of IL-6 with matrix metalloproteinases (MMPs), YKL-40 and radiographic severity of OA.
      Methods: Synovial fluid and blood samples, as well as clinical data, were collected from 100 OA patients [BMI 29.7 (8.3) kg/m2, age 72 (14) years, median (IQR); 62/38 females/males] undergoing knee replacement surgery in Coxa Hospital for Joint Replacement, Tampere, Finland. Preoperative radiographs were evaluated using Ahlbäck classification criteria for knee OA. For primary chondrocyte cultures the OA cartilage was processed and chondrocytes were isolated by enzymatic digestion for 16 h at 37°C in a shaker by using collagenase enzyme blend. Isolated chondrocytes were washed, plated and cultured at 37°C in humidified 5% CO2 atmosphere. IL-6, MMPs and YKL-40 were measured by immunoassays. The results are given as median (IQR). This study was approved by the Ethics Committee of Tampere University Hospital, Finland, and was carried out in accordance with the Declaration of Helsinki.
      Results: Synovial fluid levels of IL-6 [119.8  (193.5) pg/ml] were considerably higher than plasma levels [3.1 (2.7) pg/ml] and there was no correlation between these two, suggesting that IL-6 is produced locally within the joint. Synovial fluid IL-6 correlated with MMP-1 (r=0.446, p<0.001), MMP-3 (r=0.486, p<0.001), and YKL-40 (r=0.353, p=0.013). Further, synovial fluid IL-6 levels were over twice as high in patients with radiologically most advanced OA [Ahlbäck grades 4–5, 234.1 (264.7) pg/ml, n=74] than in patients with less severe disease [Ahlbäck grades 1–3, 94.6 (183.0) pg/ml, n=17; p=0.027]. Primary human OA chondrocytes produced IL-6 and its expression was enhanced by IL-1β. In addition, when primary chondrocytes were exposed to exogenous IL-6, the production of YKL-40 and MMP-3 was enhanced.
      Conclusions: The results show that IL-6 is produced within OA joints, and it is associated with increased levels of MMPs and YKL-40 as well as with the radiographic severity of OA. The findings propose a remarkable role for IL-6 in the pathogenesis of OA and as a target for disease-modifying drugs for the treatment of OA.