The lonely death: chondrocyte apoptosis in TNF-induced arthritis

Autoimmunity. 2007 Jun;40(4):333-6. doi: 10.1080/08916930701356721.


Inflammatory joint disease typically provokes progressive cartilage damage. The proliferative synovial inflammatory tissue directly invades the cartilage and induces the expression and activation of degrading enzymes such as matrix metalloproteases (MMPs) and aggrecanases. However, also chondrocyte apoptosis has been observed in cartilage samples of inflamed joints. It remains unclear whether this is a secondary phenomenon due to cartilage damage or a primary event initiated by the synovial inflammation. To determine the presence or absence of chondrocyte death in experimental arthritis, we longitudinally assessed proteoglycan depletion and chondrocyte apoptosis in paw sections from human tumor necrosis factor transgenic (hTNFtg) mice and wild-type littermates. Whereas, wild-type mice showed no signs of cartilage damage, hTNFtg mice exhibited progressive proteoglycan loss starting at clinical onset of arthritis. However, we already found the first apoptotic chondrocytes well before cartilage matrix breakdown occurred indicating that chondrocyte death can be induced before matrix resorption. Chondrocyte death could constantly be observed until late stages of arthritis causing a continuous increase in the number of empty cartilage lacunae. As apoptotic cells in cartilage cannot be cleared by phagocytes due to their spatial isolation in the avascular lacunae of cartilage, having no contact to professional or amateur phagocytes. The dying cells are compelled to undergo a "lonely death" inevitable ending up in secondary necrosis giving rise to perpetuation of a pro-inflammatory cascade. These data indicate that chondrocyte death may play a primary role in inflammatory arthritis fueling cartilage inflammation and damage due to secondary necrosis.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology*
  • Arthritis / genetics
  • Arthritis / immunology*
  • Arthritis / pathology
  • Cartilage / immunology*
  • Cartilage / pathology
  • Chondrocytes / immunology*
  • Chondrocytes / pathology
  • Extracellular Matrix / immunology
  • Extracellular Matrix / pathology
  • Humans
  • Matrix Metalloproteinases / immunology
  • Mice
  • Mice, Transgenic
  • Necrosis / immunology
  • Necrosis / pathology
  • Phagocytes / immunology
  • Phagocytes / pathology
  • Proteoglycans / immunology
  • Synovial Membrane / immunology*
  • Synovial Membrane / pathology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology*


  • Proteoglycans
  • Tumor Necrosis Factor-alpha
  • Matrix Metalloproteinases