Modulation of xylosyltransferase I expression provides a mechanism regulating glycosaminoglycan chain synthesis during cartilage destruction and repair

Abstract

Osteoarthritis and rheumatoid arthritis are characterized by loss of proteoglycans (PGs) and their glycosaminoglycan (GAG) chains that are essential for cartilage function. Here, we investigated the role of glycosyltransferases (GTs) responsible for PG-GAG chain assembly during joint cartilage destruction and repair processes. At various times after antigen-induced arthritis (AIA) and papain-induced cartilage repair in rats, PG synthesis and deposition, expression of GTs, and GAG chain composition were analyzed. Our data showed that expression of the GT xylosyltransferase I (XT-I) gene initiating PG-GAG chain synthesis was significantly reduced in AIA rat cartilage and was associated with a decrease in PG synthesis. Interestingly, interleukin-1beta, the main proinflammatory cytokine incriminated in joint diseases, down-regulated the XT-I gene expression with a concomitant decrease in PG synthesis in rat cartilage explants ex vivo. However, cartilage from papain-injected rat knees showed up-regulation of XT-I gene expression and increased PG synthesis at early stages of cartilage repair, a process associated with up-regulation of TGF-beta1 gene expression and mediated by p38 mitogen-activated protein kinase activation. Consistently, silencing of XT-I expression by intraarticular injection of XT-I shRNA in rat knees prevented cartilage repair by decreasing PG synthesis and content. These findings show that GTs play a key role in the loss of PG-GAGs in joint diseases and identify novel targets for stimulating cartilage repair.

Identification and Characterization of the Human Xylosyltransferase I Gene Promoter Region

“…The enzyme can be used as a diagnostic marker for systemic sclerosis (11,12), participates in bone development (13), and was recently proven to exhibit a key role in cartilage repair (14). Additionally, Hurtado et al (15) demonstrated that a knockdown of XT-I significantly improves axon growth through scar tissue in the adult rat spinal chord.…”

Regulation of Xylosyltransferase I Gene Expression by Interleukin 1β in Human Primary Chondrocyte Cells

“…Indeed, this enzyme catalyzes the first and rate-limiting step in the biosynthesis pathway (16,17) and is therefore considered as a regulatory factor of GAG biosynthesis process. Accordingly, it has been shown that loss of XT-I expression was associated with strong decrease in GAG synthesis during arthritis development in rats, whereas high expression of XT-I was associated with high rate of GAG synthesis during cartilage repair in a rat model of cartilage regen-eration, suggesting that XT-I regulates GAG synthesis during cartilage destruction and repair (18).…”

“…Primary Chondrocyte Cells-Accumulating evidence indicates that XT-I catalyzes a rate-limiting step in PG synthesis pathway and plays a central role in the regulation of the PG synthesis process both in physiological and physiopathological conditions (18,21,26,27). To understand the mechanism of IL-1␤-mediated alteration of PG synthesis in OA disease and particularly the role of XT-I in this process, we investigated the effect of the cytokine on the expression of XT-I gene in human primary chondrocytes.…”

Incomplete Elongation of the Chondroitin Sulfate Linkage Region on Aggrecan and Response to Interleukin-1β

“…IL-1β is a proinflammatory cytokine that is associated with catabolism in articular cartilage and is known to diminish the production of aggrecan while increasing the expression of ECM-targeted proteinases, including matrix metalloproteinases À3, À9, and À13 and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) À1, À4, and À5 [56]. Interestingly, IL-1β leads to both a dramatic decrease in aggrecan core protein as well as production of the key enzymes involved in CS initiation [28,29]. With this, we propose that CS addition to the aggrecan core protein may become deregulated during chronic inflammation contributing to the progression of OA, thereby promoting diminished cartilage structural integrity and viscoelastic properties.…”

“…On decorin, the xylose-2-phosphate has been shown to be a transient modification that may help provide a high degree of substrate specificity for the GlcAT I, which appears to engage the nascent trisaccharide linkage region and not the final sugar moiety (e.g., galactose 2) alone [26]. Purportedly, these sulfations and phosphorylations affect the catalytic efficiency of the GlcAT I, providing a mechanism to regulate chain elongation beyond expression of the glycosyl transferase enzymes or aggrecan core protein [27,28]. Further, the GlcAT I has also been described being interleukin-1 (IL-1) dependent [29].…”