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‐1β, 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‐β1 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, N., Barre, L., Magdalou, J., Mainard, D., Netter, P., Fournel‐Gigleux, S., Ouzzine, M. Modulation of xylosyltransferase I expression provides a mechanism regulating glycosaminoglycan chain synthesis during cartilage destruction and repair. FASEB J. 23, 813–822 (2009)

[1]  Kenneth D Brandt,et al.  Etiopathogenesis of osteoarthritis. , 2008, Rheumatic diseases clinics of North America.

[2]  R. Körfer,et al.  Transforming Growth Factor β1-regulated Xylosyltransferase I Activity in Human Cardiac Fibroblasts and Its Impact for Myocardial Remodeling* , 2007, Journal of Biological Chemistry.

[3]  C. Little,et al.  Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair. , 2007, The Journal of clinical investigation.

[4]  P. D. Kraan,et al.  TGF-β and osteoarthritis , 2007 .

[5]  J. Saklatvala.  Inflammatory signaling in cartilage: MAPK and NF-kappaB pathways in chondrocytes and the use of inhibitors for research into pathogenesis and therapy of osteoarthritis. , 2007, Current drug targets.

[6]  W. B. van den Berg,et al.  Cytokine targeting in osteoarthritis. , 2007, Current drug targets.

[7]  P. Roughley,et al.  The structure and function of cartilage proteoglycans. , 2006, European cells & materials.

[8]  J. Magdalou,et al.  Evidence of calcium‐dependent pathway in the regulation of human β1,3‐glucuronosyltransferase‐1 (GlcAT‐I) gene expression: a key enzyme in proteoglycan synthesis , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  L. Joosten,et al.  Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1. , 2005, The American journal of pathology.

[10]  C. Chu,et al.  p38 MAPK and COX2 inhibition modulate human chondrocyte response to TGF‐β , 2005, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[11]  J. Magdalou,et al.  Stimulation of proteoglycan synthesis by glucuronosyltransferase-I gene delivery: A strategy to promote cartilage repair , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[12]  C. Dinarello.  Therapeutic strategies to reduce IL-1 activity in treating local and systemic inflammation. , 2004, Current opinion in pharmacology.

[13]  J. O'dell,et al.  Therapeutic strategies for rheumatoid arthritis. , 2004, The New England journal of medicine.

[14]  W. Hozack,et al.  Transforming Growth Factor-β-mediated Chondrogenesis of Human Mesenchymal Progenitor Cells Involves N-cadherin and Mitogen-activated Protein Kinase and Wnt Signaling Cross-talk* , 2003, Journal of Biological Chemistry.

[15]  J. Pelletier,et al.  Metalloproteases and inhibitors in arthritic diseases. , 2001, Best practice & research. Clinical rheumatology.

[16]  M. D. de Caestecker,et al.  Transcriptional Cross-talk between Smad, ERK1/2, and p38 Mitogen-activated Protein Kinase Pathways Regulates Transforming Growth Factor-β-induced Aggrecan Gene Expression in Chondrogenic ATDC5 Cells* , 2001, The Journal of Biological Chemistry.

[17]  J. Magdalou,et al.  Interleukin-1beta down-regulates the expression of glucuronosyltransferase I, a key enzyme priming glycosaminoglycan biosynthesis: influence of glucosamine on interleukin-1beta-mediated effects in rat chondrocytes. , 2001, Arthritis and rheumatism.

[18]  H. Kitagawa,et al.  Recent advances in the study of the biosynthesis and functions of sulfated glycosaminoglycans. , 2000, Current opinion in structural biology.

[19]  S. Selleck,et al.  sqv-3, -7, and -8, a set of genes affecting morphogenesis in Caenorhabditis elegans, encode enzymes required for glycosaminoglycan biosynthesis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[20]  R. Midura,et al.  Adaptation of FACE methodology for microanalysis of total hyaluronan and chondroitin sulfate composition from cartilage. , 2000, Glycobiology.

[21]  J. V. van Meurs,et al.  Adenoviral vector-mediated overexpression of IL-4 in the knee joint of mice with collagen-induced arthritis prevents cartilage destruction. , 1999, Journal of immunology.

[22]  H. Horvitz,et al.  Three proteins involved in Caenorhabditis elegans vulval invagination are similar to components of a glycosylation pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[23]  W. B. van den Berg,et al.  Early elevation of transforming growth factor-beta, decorin, and biglycan mRNA levels during cartilage matrix restoration after mild proteoglycan depletion. , 1997, The Journal of rheumatology.

[24]  S. Yoshino,et al.  Antigen-induced arthritis in rats is suppressed by the inducing antigen administered orally before, but not after immunization. , 1995, Cellular immunology.

[25]  P. Roughley,et al.  Large and small proteoglycans of osteoarthritic and rheumatoid articular cartilage. , 1995, Arthritis and rheumatism.

[26]  I. Otterness,et al.  Protection against cartilage proteoglycan synthesis inhibition by antiinterleukin 1 antibodies in experimental arthritis. , 1992, The Journal of rheumatology.

[27]  Roland W. Moskowitz,et al.  Osteoarthritis: Diagnosis and Medical/Surgical Management , 1992 .

[28]  S. Krane,et al.  Interleukin 1 suppresses expression of cartilage-specific types II and IX collagens and increases types I and III collagens in human chondrocytes. , 1988, The Journal of clinical investigation.

[29]  H. Muir,et al.  In vivo and in vitro stimulation of chondrocyte biosynthetic activity in early experimental osteoarthritis. , 1984, Arthritis and rheumatism.

[30]  C. Leveille,et al.  Proteoglycan structure and metabolism in normal and osteoarthritic cartilage of guinea pigs. , 1981, Arthritis and rheumatism.

[31]  T. Oegema,et al.  Metabolic activity of articular cartilage in osteoarthritis. An in vitro study. , 1979, The Journal of bone and joint surgery. American volume.

[32]  H. Mankin,et al.  The glycosaminoglycans of normal and arthritic cartilage. , 1971, The Journal of clinical investigation.

[33]  Kenneth D Brandt,et al.  Etiopathogenesis of osteoarthritis. , 2009, The Medical clinics of North America.

[34]  M. Feldmann,et al.  The role of TNF alpha and IL-1 in rheumatoid arthritis. , 2001, Current directions in autoimmunity.

[35]  C. Cobra,et al.  [Etiology and pathogenesis of rheumatoid arthritis. I. ]. , 1956, Revista brasileira de medicina.