Potential role of hyaluronic acid on bone in osteoarthritis: matrix metalloproteinases, aggrecanases, and RANKL expression are partially prevented by hyaluronic acid in interleukin 1-stimulated osteoblasts.

OBJECTIVE: To determine the effect of hyaluronic acid (HA) on proteolytic enzymes and bone remodeling mediators induced by interleukin 1ß (IL-1ß) and related to cartilage catabolism in murine osteoblasts. METHODS: Osteoblasts were obtained from Swiss mice and cultured for 3 weeks. HA-treated osteoblasts were incubated with 100 µg/ml HA during the last week of culture, then stimulated with IL-1ß (10 ng/ml) for 24 h. The expression of matrix metalloproteinases 3 and 13 (MMP-3 and MMP-13), ADAMTS-4 and ADAMTS-5, tissue inhibitor of metalloproteinases (TIMP), osteoprotegerin, and receptor activator of nuclear factor-κB ligand (RANKL) was determined by real-time polymerase chain reaction. MMP-3 and MMP-13 release was assessed by Western blot analysis. RESULTS: IL-1ß increased the mRNA levels of MMP-3 and MMP-13 and ADAMTS-4 and ADAMTS-5 and release of MMP-3 and MMP-13. Seven days of HA treatment significantly prevented the IL-1ß-increased mRNA levels of MMP-3 (-61%, p < 0.01), MMP-13 (-56%, p < 0.01), ADAMTS-4 (-58%, p < 0.05), ADAMTS-5 (-52%, p < 0.01), and RANKL (-49%, p < 0.05), but not TIMP. As well, IL-1ß-induced production of MMP-3 and MMP-13 was inhibited, by 27% (p < 0.01) and 40% (p < 0.01), respectively. CONCLUSION: In an inflammatory context in murine osteoblasts, HA can inhibit the expression of MMP and ADAMTS. Because HA can counteract the production of these mediators in chondrocytes, its beneficial effect in osteoarthritis may be due to its action on cartilage and subchondral bone.

Comparative efficacy and safety study of two chondroitin sulfate preparations from different origin (avian and bovine) in symptomatic osteoarthritis of the knee.

INTRODUCTION: Some argued that clinical efficacy of Chondroitin Sulfate (CS) could vary upon the product origin. The objective of this trial is to compare the effect of 2 CS medicinal products from different origin: Structum(®) (avian, 1000mg/day) and Chondrosulf(®) (bovine, 1200mg/day). METHODS: This was a randomized, double-blind, double placebo, active-controlled, parallel-group study using a non-inferiority design. Symptomatic osteoarthritis of the knee patients, according to American College of Rheumatology criteria, aged 50-80 years received either Structum(®) (500mg BID) or Chondrosulf(®) (400mg TID) during 24 weeks. Inclusion criteria were: global pain in the target knee ≥ 40mm on a Visual Analog Scale (VAS 0-100), a Lequesne's Algofunctional Index (LFI) score ≥ 7 (range: 0-24) and a radiological Kellgren-Lawrence grade 2 or 3. Primary outcome was the mean change over 24 weeks of pain VAS and LFI score. Secondary outcomes were patient's and physician's global assessments, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International responders rate, analgesics intake and Medical Outcomes Survey Short-Form 12 (SF-12). Safety was assessed by recording adverse events. A non-inferiority test was performed on the Structum(®)-Chondrosulf(®) difference for VAS and LFI score changes. Predefined non inferiority limit was settled as the lower limit of the 95% CI above -5mm and -1pt for pain VAS and LFI score respectively. RESULTS: 837 patients were randomized: 817 available for the full analysis dataset (FAS), 692 for the per protocol (PP) analysis. No statistical and clinical differences were observed for demographics and disease characteristics between the 2 groups. PP analysis showed no difference between groups on mean variations of pain VAS or LFI scores over 24 weeks. Mean Pain VAS decreased by 23.9mm (17.5) in Structum(®) group and 23.8mm (17.2) in Chondrosulf(®) group (difference: 0.012 [CI95%: -2.6 ; 2.6]). Mean LFI score decreased by 3.2 (2.4) and 3.1 (2.4) respectively (difference: 0.139 [CI95%: -0.2 ; 0.5]). The lower limits of the 2 CI were above predefined non inferiority margin, which demonstrated the non inferiority of Structum(®) in comparison with Chondrosulf(®). FAS analysis gave similar results. Secondary efficacy outcomes analysis showed the same trends. Responders rate were 76.3% and 73.8% respectively (PP, W24). Treatments were well tolerated: 2.4% in Structum(®) group and 4.5% in Chondrosulf(®) group withdrew from the study for safety reasons. CONCLUSION: Structum(®) and Chondrosulf(®) were equally effective in reducing functional impairment and relieving pain over 6 months in knee osteoarthritis patients, without any safety concerns. TRIAL REGISTRATION: http://www.controlled-trials.com Number: ISRCTN04305346.