[Agrecan and articular cartilage: assessment of glycosyltransferases for the restoration of cartilage matrix in osteoarthritis].

Abstract

Articular cartilage is a connective tissue containing a single type of cells, chondrocytes, which synthesise a dense extracellular matrix, mainly composed of collagens, hyaluronic acid and proteoglycans. These macromolecules play a major role in the resistance and elastic properties of the tissue. They also favour interactions with small active substances, such as growth factors and cytokines. Chondrocytes have a low metabolic capacity in relatively hypoxic conditions and absence of vascular supply. In physiopathological conditions, such as osteoarthritis (OA), progressive and irreversible degradation of matrix components is occurring. With the aim of developing new and efficient therapies against OA, we investigated the molecular mechanisms that initiate the disease, in order to identify key-proteins. These targets should hopefully lead to the design of new drugs able to stop degradation and restore cartilage. One of the earliest molecular events in OA is the degradation of aggrecan, the most abundant proteoglycan. The glycosaminoglycan (GAG) chains, chondroitin-sulfate, attached on the core protein, are subjected to hydrolysis into smaller fragments. We were interested in the glycosyltransferases that catalyse the formation of the polysaccharidic chains, namely those involved in the common tetrasaccharidic protein linkage region, GlcAbeta1,3Galbeta1,3Galbeta 1,4Xyl-O-Serine. The galactose beta1,3-glucuronosyltransférase-I (GlcAT-I) which catalyses the final step of this primer and which is markedly repressed during OA is an attractive target in that respect. Indeed, the human recombinant enzyme was found to play a pivotal role in GAG synthesis. Moreover, overexpression of GlcAT-I in cartilage explants treated with IL1beta was able to fully counteract proteoglycan depletion induced by the cytokine. These results prompted us to investigate the structure, function and regulation of this enzyme. This study provides the basis for several therapy approaches (gene delivery, design of glycomimetics able to initiate GAG synthesis) to promote cartilage repair.