title: O-linked N-acetylglucosamine (O-GlcNAc) protein modification is increased in the cartilage of patients with knee osteoarthritis.
abstract: OBJECTIVE
  There is increasing evidence that the addition of O-linked N-acetylglucosamine (O-GlcNAc) to proteins plays an important role in cell signaling pathways. In chondrocytes, accumulation of O-GlcNAc-modified proteins induces hypertrophic differentiation. Osteoarthritis (OA) is characterized by cartilage degradation, and hypertrophic-like changes in hyaline chondrocytes. However, the mechanisms responsible for these changes have not been described. Our aim was to study whether O-GlcNAcylation and the enzymes responsible for this modification are dysregulated in the cartilage of patients with knee OA and whether interleukin-1 could induce these modifications in cultured human OA chondrocytes (HOC).
  
  
  METHODS
  Human cartilage was obtained from patients with knee OA and from age and sex-matched healthy donors. HOC were cultured and stimulated with the catabolic cytokine IL-1α. Global protein O-GlcNAcylation and the synthesis of the key enzymes responsible for this modification, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), were assessed by western blot.
  
  
  RESULTS
  OA was associated with a 4-fold increase in the global O-GlcNAcylation in the cartilage. OA cartilage showed a re-distribution of the OGT and OGA isoforms, with a net increase in the presence of both enzymes, in comparison to healthy cartilage. In HOC, IL-1α stimulation rapidly increased O-GlcNAcylation and OGT and OGA synthesis.
  
  
  CONCLUSIONS
  Our results indicate that a proinflammatory milieu could favor the accumulation of O-GlcNAcylated proteins in OA cartilage, together with the dysregulation of the enzymes responsible for this modification. The increase in O-GlcNAcylation could be responsible, at least partially, for the re-expression of hypertrophic differentiation markers that have been observed in OA.
authors: Bone and Joint Research Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain.
authors: L
authors: L
authors: Tardio
authors: Bone and Joint Research Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain.
authors: J
authors: J
authors: Andrés-Bergós
authors: Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: N E
authors: NE
authors: Zachara
authors: Bone and Joint Research Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain.
authors: A
authors: A
authors: Larrañaga-Vera
authors: Donation Unit, Transplant Services Foundation, Hospital Clinic, Barcelona, Spain.
authors: C
authors: C
authors: Rodriguez-Villar
authors: Bone and Joint Research Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain.
authors: G
authors: G
authors: Herrero-Beaumont
authors: Bone and Joint Research Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain. Electronic address: rlargo@fjd.es.
authors: R
authors: R
authors: Largo
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000215:Acylation; D000328:Adult; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D017351:N-Acetylglucosaminyltransferases / Q000096:biosynthesis; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000473:pathology; D046188:Protein Modification, Translational / Q000187:drug effects / Q000502:physiology*; D001619:beta-N-Acetylhexosaminidases / Q000096:biosynthesis
chemical_list: D018836:Inflammation Mediators; D007375:Interleukin-1; D007527:Isoenzymes; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine
keywords: Cartilage; Chondrocytes; Glycosylation; Hypertrophic differentiation; O-GlcNAcylation