ECU CHONDROITIN SULFATE EXERTS BENEFICIAL EFFECTS ON THE MECHANISMS LEADING TO OSTEOARTHRITIS SUBCHONDRAL BONE REMODELING

摘要

Objective: In osteoarthritis (OA), the increased subchondral bone remodelling is associated with the development of cartilage iesions. These changes are related to an altered metabolism of the osteo-blasts. The aim of this study was to determine the effect of chon-droitin sulfate on the expression/production of the major osteoblast factors involved in the remodelling of human OA subchondral g/ ml) on human OAjxbone.Method: The effect of chondroitin sulfate (200 subchondral bone osteoblasts, before and after stimulation with vitamin D3 (1,25 (OH)2D3; 50 nM), was measured on the major phenotypic factors, alkaline phosphatase, and osteocalcm; on the inflammatory mediators, IL-6 and COX-2; and on the bone remodeling factors, RANKL and OPG.Results: Data showed that the level of alkaline phospbatase activity upon stimulation by vitamin-D3 challenge was increased by a 1.6-fold over basal values. Chondroitin sulfate did not affect basal and vitamin D3-induced alkaline phosphatase or osteocalcin release. On themetabolic factors, chondroitin sulfate had no significant effect on IL-6, but significantly inhibited either basal or vitamin D3-stimulated COX-2. In the presence of vitamin D3, chondroitin sulfate upregulated OPG expression and production. On the protein level, chondroitin sulfate significantly increased OPG in both basal conditions and in the presence of vitamin D3. RANKL expression was almost abrogated with chondroitin sulfate under basal conditions. Interestingly, under basal conditions, chondroitin sulfate significantly upregulated the expression ratio of OPG/RANKL. Vitamin D3 decreased this ratio, but chondroitin sulfate in the presence of vitamin D3 reversed this decrease.Conclusions: Our data indicate that chondroitin sulfate does not appear to overly affect cell integrity or osteoblast phenotypic cell markers. However, chondroitin sulfate by increasing the ratio of OPG/RANKL could exert a positive effect on OA subchondral bone structural changes, indicating a potential direct beneficial effect. Indeed, the expression of RANKL is increased in abnormal osteoblasts, thereby weighting the balance of OPG/RANKL toward bone destruction. Consequently, our data are of major significance as it is the ratio OPG/RANKL that dictates the magnitude of osteo-clastogenesis. These findings may help explain the mechanisms by which this drug could exert its effect on the progression of OA structural changes.