Osteoarthritis (OA) is associated with cartilage destruction, subchondral bone remodeling and inflammation of the synovial membrane, although the etiology and pathogenesis underlying this debilitating disease are poorly understood. Secreted inflammatory molecules, such as proinflammatory cytokines, are among the critical mediators of the disturbed processes implicated in OA pathophysiology. Interleukin (IL)-1β and tumor necrosis factor (TNF), in particular, control the degeneration of articular cartilage matrix, which makes them prime targets for therapeutic strategies. Animal studies provide support for this approach, although only a few clinical studies have investigated the efficacy of blocking these proinflammatory cytokines in the treatment of OA. Apart from IL-1β and TNF, several other cytokines including IL-6, IL-15, IL-17, IL-18, IL-21, leukemia inhibitory factor and IL-8 (a chemokine) have also been shown to be implicated in OA and could possibly be targeted therapeutically. This Review discusses the current knowledge regarding the role of proinflammatory cytokines in the pathophysiology of OA and addresses the potential of anticytokine therapy in the treatment of this disease.

Background: It remains unclear whether an increased risk of type 2 diabetes (T2D) affects the risk of osteoarthritis (OA). Methods: Here, we used two-sample Mendelian randomization (MR) to obtain non-confounded estimates of the effect of T2D and glycemic traits on hip and knee OA. We identi ed single nucleotide polymorphisms (SNPs) strongly associated with T2D, fasting glucose (FG) and 2-hour postprandial glucose (2hGlu) from genome-wide association studies (GWAS). We used MR inverse variance weighted (IVW), the MR-Egger method, the weighted median (WM) and Robust Adjusted Pro le Score (MR.RAPS) to reveal the associations of T2D, FG and 2hGlu with hip and knee OA risk. Sensitivity analyses were also conducted to verify whether heterogeneity and pleiotropy can bias the MR results. Results: We did not nd statistically signi cant causal effects of genetically increased T2D risk, FG and 2hGlu on hip and knee OA (e.g., T2D and hip OA, MR-Egger OR=0.9536, 95% CI 0.5585 to 1.6283, p=0.8629). It was con rmed that horizontal pleiotropy was unlikely to bias the causality (e.g., T2D and hip OA, MR-Egger, intercept=-0.0032, p=0.8518). No evidence of heterogeneity was found between the genetic variants (e.g., T2D and hip OA, MR-Egger Q=40.5481, I 2 =0.1368, p=0.2389). Conclusions: Our MR study did not support causal effects of a genetically increased T2D risk, FG and 2hGlu on hip and knee OA risk.

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Background:The relation between knee meniscal structural damage and cartilage degradation is plausible but not yet clearly proven. Objectives: To quantitate the cartilage volume changes in knee osteoarthritis using magnetic resonance imaging (MRI), and determine whether meniscal alteration predicts cartilage volume loss over time. Methods: 32 patients meeting ACR criteria for symptomatic knee osteoarthritis were studied. MRI knee acquisitions were done every six months for two years. The cartilage volumes of different knee regions were measured. Three indices of structural change in the medial and lateral menisci were evaluateddegeneration, tear, and extrusion-using a semiquantitative scale. Results: 24 patients (75%) had mild to moderate or severe meniscal damage (tear or extrusion) at baseline. A highly significant difference in global cartilage volume loss was observed between severe medial meniscal tear and absence of tear (mean (SD), 210.1 (2.1)% v 25.1 (2.4)%, p = 0.002). An even greater difference was found between the medial meniscal changes and medial compartment cartilage volume loss (214.3 (3.0)% in the presence of severe tear v 26.3 (2.7)% in the absence of tear; p,0.0001). Similarly, a major difference was found between the presence of a medial meniscal extrusion and loss of medial compartment cartilage volume (215.4 (4.1)% in the presence of extrusion v 24.5 (1.7)% with no extrusion; p,0.001). Conclusions: Meniscal tear and extrusion appear to be associated with progression of symptomatic knee osteoarthritis.

The proposed treatment algorithm may represent a new framework for the development of future guidelines for the management of OA, more easily accessible to physicians.

Recently, a new human collagenase, collagenase-3 has been identified. Since collagen changes are of particular importance in cartilage degeneration, we investigated if collagenase-3 plays a role in osteoarthritis (OA).Reverse transcriptase-PCR analysis revealed that in articular tissues collagenase-3 was expressed by the chondrocytes but not by the synoviocytes. Northern blot analysis of the chondrocyte mRNA revealed the presence of two major gene transcripts of 3.0 and 2.5 kb, and a third one of 2.2 kb was occasionally present. Compared to normal, OA showed a significantly higher (3.0 kb, P Յ 0.05; 2.5 kb, P Յ 0.03) level of collagenase-3 mRNA expression. Collagenase-3 had a higher catalytic velocity rate (about fivefold) than collagenase-1 on type II collagen. With the use of two specific antibodies, we showed that human chondrocytes had the ability to produce collagenase-3 as a proenzyme and as a glycosylated doublet. The chondrocyte collagenase-3 protein is produced in a significantly higher ( P Յ 0.04) level in OA ( ‫ف‬ 9.5-fold) than in normal. The synthesis and expression of this new collagenase could also be modulated by two proinflammatory cytokines, IL-1 ␤ and TNF-␣ , in a time-and dosedependent manner.This study provides novel and interesting data on collagenase-3 expression and synthesis in human cartilage cells and suggest its involvement in human OA cartilage pathophysiology. (