3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exert favorable effects on lipoprotein metabolism, but may also possess anti-inflammatory properties. Therefore, we explored the activities of simvastatin, a lipophilic statin, in a Th1-driven model of murine inflammatory arthritis. We report in this study that simvastatin markedly inhibited not only developing but also clinically evident collagen-induced arthritis in doses that were unable to significantly alter cholesterol concentrations in vivo. Ex vivo analysis demonstrated significant suppression of collagen-specific Th1 humoral and cellular immune responses. Moreover, simvastatin reduced anti-CD3/anti-CD28 proliferation and IFN-γ release from mononuclear cells derived from peripheral blood and synovial fluid. Proinflammatory cytokine production in vitro by T cell contact-activated macrophages was suppressed by simvastatin, suggesting that such observations have direct clinical relevance. These data clearly illustrate the therapeutic potential of statin-sensitive pathways in inflammatory arthritis.

In rheumatoid synovium interleukin 6 (IL-6) is the most abundantly expressed cytokine. Increased serum levels have been previously reported in patients with rheumatoid arthritis (RA). In this study serum IL-6 levels were measured in a weli defined cohort using a bioassay (B9 celis) and levels were correlated with conventional clinical and laboratory indices of disease activity.Levels were significantly higher in serum from patients with RA (median 55 IU/ml; interquartile range 28-139) compared with serum from disease (median 7 IU/ml; 1-23) and normal controls (median 10 IU/ml; 7-12). No difference was observed between men and women. Levels did not correlate with disease duration. Significant associations were observed between IL-6 and C reactive protein and between the Ritchie articular index and duration of morning stiffness. No other correlations were observed. The value of these findings in the monitoring ofRA and as an indicator of response to second line treatment needs to be established.

SmaryMarkers of the inflammatory response, interleukin 6, C-reactive protein, albumin and full blood count, were measured in non-small-cell lung cancer (NSCLC) patients (n=21) with and without weight loss (>5%). There were significant increases in circulating C-reactive protein (P<0.001), interleukin 6 (P<0.01) and platelets (P<0.01) in the weight-losing group. Moreover, there was a statistically significnt correlation (r=0.785, P<0.001) between interleukin 6 and C-reactive protein concentrations. These results are consistent with interleukin 6 and the acute phase response promoting weight loss in NSCLC.

ObjectiveProteinase-activated receptor 2 (PAR2) deficiency protects against cartilage degradation in experimental osteoarthritis (OA). The wider impact of this pathway upon OA-associated pathologies such as osteophyte formation and pain is unknown. Herein, we investigated early temporal bone and cartilage changes in experimental OA in order to further elucidate the role of PAR2 in OA pathogenesis.MethodsOA was induced in wild-type (WT) and PAR2-deficient (PAR2−/−) mice by destabilisation of the medial meniscus (DMM). Inflammation, cartilage degradation and bone changes were monitored using histology and microCT. In gene rescue experiments, PAR2−/− mice were intra-articularly injected with human PAR2 (hPAR2)-expressing adenovirus. Dynamic weight bearing was used as a surrogate of OA-related pain.ResultsOsteophytes formed within 7 days post-DMM in WT mice but osteosclerosis was only evident from 14 days post induction. Importantly, PAR2 was expressed in the proliferative/hypertrophic chondrocytes present within osteophytes. In PAR2−/− mice, osteophytes developed significantly less frequently but, when present, were smaller and of greater density; no osteosclerosis was observed in these mice up to day 28. The pattern of weight bearing was altered in PAR2−/− mice, suggesting reduced pain perception. The expression of hPAR2 in PAR2−/− mice recapitulated osteophyte formation and cartilage damage similar to that observed in WT mice. However, osteosclerosis was absent, consistent with lack of hPAR2 expression in subchondral bone.ConclusionsThis study clearly demonstrates PAR2 plays a critical role, via chondrocytes, in osteophyte development and subchondral bone changes, which occur prior to PAR2-mediated cartilage damage. The latter likely occurs independently of OA-related bone changes.