Autophagy Is a Protective Mechanism in Normal Cartilage, and Its Aging-Related Loss Is Linked With Cell Death and Osteoarthritis

Arthritis Rheum. 2010 Mar;62(3):791-801. doi: 10.1002/art.27305.

Abstract

Objective: Autophagy is a process for turnover of intracellular organelles and molecules that protects cells during stress responses. We undertook this study to evaluate the potential roles of Unc-51-like kinase 1 (ULK1), an inducer of autophagy, Beclin1, a regulator of autophagy, and microtubule-associated protein 1 light chain 3 (LC3), which executes autophagy, in the development of osteoarthritis (OA) and in cartilage cell death.

Methods: Expression of ULK1, Beclin1, and LC3 was analyzed in normal and OA human articular cartilage and in knee joints of mice with aging-related and surgically induced OA, using immunohistochemistry and Western blotting. Poly(ADP-ribose) polymerase (PARP) p85 expression was used to determine the correlation between cell death and autophagy.

Results: ULK1, Beclin1, and LC3 were constitutively expressed in normal human articular cartilage. ULK1, Beclin1, and LC3 protein expression was reduced in OA chondrocytes and cartilage, but these 3 proteins were strongly expressed in the OA cell clusters. In mouse knee joints, loss of glycosaminoglycans (GAGs) was observed at ages 9 months and 12 months and in the surgical OA model, 8 weeks after knee destabilization. Expression of ULK1, Beclin1, and LC3 decreased together with GAG loss, while PARP p85 expression was increased.

Conclusion: Autophagy may be a protective or homeostatic mechanism in normal cartilage. In contrast, human OA and aging-related and surgically induced OA in mice are associated with a reduction and loss of ULK1, Beclin1, and LC3 expression and a related increase in apoptosis. These results suggest that compromised autophagy represents a novel mechanism in the development of OA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aging / physiology*
  • Animals
  • Apoptosis Regulatory Proteins / analysis
  • Apoptosis Regulatory Proteins / physiology*
  • Autophagy / drug effects
  • Autophagy / physiology*
  • Autophagy-Related Protein-1 Homolog
  • Beclin-1
  • Blotting, Western
  • Cartilage, Articular / physiology*
  • Cell Death / physiology*
  • Chondrocytes / physiology
  • Humans
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / analysis
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Membrane Proteins / analysis
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / analysis
  • Microtubule-Associated Proteins / physiology*
  • Osteoarthritis / physiopathology*
  • Protein-Serine-Threonine Kinases / analysis
  • Protein-Serine-Threonine Kinases / physiology*
  • Young Adult

Substances

  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • Becn1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • light chain 3, human
  • Autophagy-Related Protein-1 Homolog
  • Protein-Serine-Threonine Kinases
  • ULK1 protein, human