title: Regulation of xylosyltransferase I gene expression by interleukin 1β in human primary chondrocyte cells: mechanism and impact on proteoglycan synthesis.
abstract: Xylosyltransferase I (XT-I) is an essential enzyme of proteoglycan (PG) biosynthesis pathway catalyzing the initial and rate-limiting step in glycosaminoglycan chain assembly. It plays a critical role in the regulation of PG synthesis in cartilage; however, little is known about underlying mechanism. Here, we provide evidence that, in human primary chondrocytes, IL-1β regulates XT-I gene expression into an early phase of induction and a late phase of down-regulation. Based on promoter deletions, the region up to -850 bp was defined as a major element of XT-I gene displaying both constitutive and IL-1β-regulated promoter activity. Point mutation and signaling analyses revealed that IL-1β-induced promoter activity is achieved through AP-1 response elements and mediated by SAP/JNK and p38 signaling pathways. Transactivation and chromatin immunoprecipitation assays indicated that AP-1 is a potent transactivator of XT-I promoter and that IL-1β-induced activity is mediated through increased recruitment of AP-1 to the promoter. Finally, we show that Sp3 is a repressor of XT-I promoter and bring evidence that the repressive effect of IL-1β during the late phase is mediated through Sp3 recruitment to the promoter. This suggests that modulation of Sp3 in cartilage could prevent IL-1β inhibition of PG synthesis and limit tissue degradation.
authors.affiliation: UMR 7561 CNRS, Faculty of Medicine, University of Lorraine, 54505 Vandœuvre-lès-Nancy, France.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Khair
authors.forename: Mustapha
authors.initials: M
authors.lastname: Bourhim
authors.forename: Lydia
authors.initials: L
authors.lastname: Barré
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.forename: Patrick
authors.initials: P
authors.lastname: Netter
authors.forename: Jacques
authors.initials: J
authors.lastname: Magdalou
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fournel-Gigleux
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ouzzine
mesh_terms: D000368:Aged; D001483:Base Sequence; D001665:Binding Sites; D002356:Cartilage / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010430:Pentosyltransferases / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011509:Proteoglycans / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D051705:Sp3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000097608:UDP Xylose-Protein Xylosyltransferase
chemical_list: D053583:Interleukin-1beta; D048670:MAP Kinase Kinase 4; D010430:Pentosyltransferases; D011509:Proteoglycans; D051705:Sp3 Transcription Factor; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases; D000097608:UDP Xylose-Protein Xylosyltransferase; C497121:SP3 protein, human