Effect of 12 months treatment with chondroitin sulfate on cartilage volume in knee osteoarthritis patients: a randomized, double-blind, placebo-controlled pilot study using MRI.

This pilot study aimed to evaluate the correlation between clinical symptoms and cartilage volume through MRI in patients with knee osteoarthritis after 48 weeks of treatment with Structum®. Multicenter, double-blind, placebo-controlled, parallel-group study. Symptomatic knee osteoarthritis patients aged 50-75 years received either Structum® (500 mg twice daily; N = 22) or placebo (N = 21) during 48 weeks. Inclusion criteria were global pain in the target knee ≥30 mm (VAS 0-100) and radiological Kellgren-Lawrence grade 2 or 3. Clinical assessments included Lequesne index and VAS for pain on motion, at baseline, 24 and 48 weeks, and MRI at baseline and at 24 and 48 weeks. Global and compartments cartilage volume, joint cartilage abnormalities, meniscal lesions, ligaments abnormalities, synovitis, synovial effusion, osteophytes, subchondral cysts, popliteal cysts and subchondral oedema were quantified. The quantitative and qualitative reproducibility of MRI was tested by the Spearman correlation coefficient and kappa coefficients, respectively. Treatments were compared by an analysis of covariance with baseline value as covariate. Groups were comparable at baseline for demographics, disease characteristics, and cartilage volumes. A significant inter-readers correlation was seen for the assessment of cartilage volumes, number of cysts, and osteophytes (correlation coefficients from 0.951 to 0.980 within investigator and from 0.714 to 0.957). After 48 weeks, symptoms improved in both groups. The total cartilage volume increased in the Structum® group (+180 mm(3) + SD) which opposed to a loss in the placebo (-46 mm(3) + SD; NS). No statistically significant differences between groups were observed for the other MRI parameters. No correlations were evidenced between key MRI parameters changes and symptoms. The difference in the evolution of cartilage volume between the two groups could reflect a structure modifying effect of Structum®. This pilot study confirms the usefulness of quantitative and qualitative MRI as a sensitive tool to assess a structure modifying drugs in knee osteoarthritis.

A potential role of chondroitin sulfate on bone in osteoarthritis: inhibition of prostaglandin E2 and matrix metalloproteinases synthesis in interleukin-1ß-stimulated osteoblasts.

OBJECTIVES: To determine the effect of chondroitin sulfate (CS) on inflammatory mediators and proteolytic enzymes induced by interleukin-1ß (IL-1ß) and related to cartilage catabolism in murine osteoblasts. DESIGN: Osteoblasts were obtained by enzymatic digestion of calvaria from Swiss mice and cultured for 3 weeks as a primary culture. Cells were then stimulated with IL-1ß (1 or 10 ng/ml). CS-treated osteoblasts were incubated with 100 µg/ml of CS during the last week of culture w/o IL-1ß for the last 24 h. Expressions of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), 15-PG dehydrogenase (15-PGDH), matrix metalloproteinases-3 and -13 (MMP-3 and -13), osteoprotegerin (OPG) and receptor activator of nuclear factor-kappa B ligand (RANKL) were determined by real-time polymerase chain reaction (PCR). PGE2, MMP-3 and MMP-13 release were assessed in the medium by enzyme-linked immunosorbent assay or western-blotting. RESULTS: IL-1ß increased COX-2, mPGES-1, MMP-3, MMP-13, RANKL expressions, decreased 15-PGDH expression, and increased PGE2, MMP-3 and MMP-13 release. Interestingly, 7 days of CS treatment significantly counteracted IL-1ß-induced expression of COX-2 (-62%, P<0.001), mPGES-1 (-63%, P<0.001), MMP-3 (-39%, P=0.08), MMP-13 (-60%, P<0.001) and RANKL (-84%, P<0.001). Accordingly, IL-1ß-induced PGE2, MMP-3 and MMP-13 releases were inhibited by 86% (P<0.001), 58%(P<0.001) and 38% (P<0.01) respectively. CONCLUSIONS: In conclusion, our data demonstrate that, in an inflammatory context, CS inhibits the production of PGE2 and MMPs. Since CS has previously been shown to counteract the production of these mediators in chondrocytes, we speculate that the beneficial effect of CS in Osteoarthritis (OA) could not only be due to its action on cartilage but also on subchondral bone.

Chondroitin sulfate modulation of matrix and inflammatory gene expression in IL-1beta-stimulated chondrocytes--study in hypoxic alginate bead cultures.

OBJECTIVE: To determine the effect of avian chondroitin sulfate (CS) on interleukin-1beta (IL-1beta)-induced expression of genes related to catabolic, anabolic and inflammatory aspects in chondrocytes cultured in hypoxic alginate beads. DESIGN: Articular chondrocytes from bovine metacarpal joint were isolated and cultured in alginate beads, using low oxygen atmosphere (5% O2). After 1-week exposure to CS (1, 10 and 100microg/ml), they were treated by recIL-1beta (10ng/ml) for 24 or 48h, in the presence of CS. RNA was extracted and used to determine, by quantitative reverse transcription-polymerase chain reaction, the steady-state levels of mRNAs encoding several genes related to anabolic, catabolic and inflammatory aspects. Glycosaminoglycan (GAG) synthesis was also assayed by 35S-sulfate incorporation. RESULTS: CS decreased IL-1beta-induced expression of matrix metalloproteases-1, -3 and -13 and aggrecanases-1 and -2. It slightly enhanced the aggrecan core protein mRNA and the GAG synthesis. Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA levels were found to be reduced by CS treatment. However, no CS-induced decrease of NO was observed in IL-1beta-treated chondrocytes, whereas prostaglandin E2 production was diminished in correlation with the COX-2 mRNA amounts. Furthermore, CS was capable of counteracting IL-1beta-depressed expression of transforming growth factor-beta (TGF-beta) receptors. CONCLUSIONS: CS can repress expression of genes encoding proteolytic enzymes involved in cartilage degradation. It also inhibits IL-1beta-induced expression of the pro-inflammatory genes iNOS and COX-2 and restores TGF-beta receptors I and II (TGF-betaRI and RII) mRNA levels. These data suggest that CS may exert both chondroprotective and anti-inflammatory limited effects on articular cartilage that could have long-term beneficial action on the osteoarthritic process.