Modulation of xylosyltransferase I expression provides a mechanism regulating glycosaminoglycan chain synthesis during cartilage destruction and repair.
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.
Venkatesan
Narayanan
N
UMR 7561 CNRS-Université Henri Poincaré Nancy 1, Faculté de Médecine, BP 184, 54505 Vandoeuvre-lès-Nancy, France.
Barré
Lydia
L
Magdalou
Jacques
J
Mainard
Didier
D
Netter
Patrick
P
Fournel-Gigleux
Sylvie
S
Ouzzine
Mohamed
M
D053674:Aggrecans / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D020868:Gene Silencing; D006025:Glycosaminoglycans / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008297:Male; D010206:Papain; D010430:Pentosyltransferases / Q000235:genetics / Q000378:metabolism*; D011509:Proteoglycans / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097608:UDP Xylose-Protein Xylosyltransferase
D053674:Aggrecans; D006025:Glycosaminoglycans; D053583:Interleukin-1beta; D010206:Papain; D010430:Pentosyltransferases; D011509:Proteoglycans; D048051:p38 Mitogen-Activated Protein Kinases; D000097608:UDP Xylose-Protein Xylosyltransferase