O-linked N-acetylglucosamine (O-GlcNAc) protein modification is increased in the cartilage of patients with knee osteoarthritis

Osteoarthritis Cartilage. 2014 Feb;22(2):259-63. doi: 10.1016/j.joca.2013.12.001. Epub 2013 Dec 12.

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).

Design: 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.

Keywords: Cartilage; Chondrocytes; Glycosylation; Hypertrophic differentiation; O-GlcNAcylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / metabolism*
  • Acylation
  • Adult
  • Cartilage, Articular / metabolism*
  • Cartilage, Articular / pathology
  • Case-Control Studies
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Chondrocytes / drug effects
  • Chondrocytes / metabolism
  • Female
  • Humans
  • Inflammation Mediators / pharmacology
  • Interleukin-1 / pharmacology
  • Isoenzymes / biosynthesis
  • Male
  • Middle Aged
  • N-Acetylglucosaminyltransferases / biosynthesis
  • Osteoarthritis, Knee / metabolism*
  • Osteoarthritis, Knee / pathology
  • Protein Modification, Translational / drug effects
  • Protein Modification, Translational / physiology*
  • beta-N-Acetylhexosaminidases / biosynthesis

Substances

  • Inflammation Mediators
  • Interleukin-1
  • Isoenzymes
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase
  • hexosaminidase C
  • beta-N-Acetylhexosaminidases
  • Acetylglucosamine