Endogenous cannabinoid anandamide impairs cell growth and induces apoptosis in chondrocytes

J Orthop Res. 2014 Sep;32(9):1137-46. doi: 10.1002/jor.22660. Epub 2014 Jun 6.


Endocannabinoids has been described to be involved in articular degenerative disease by modulating nociception and immune system. However, the role of the endocannabinoid anandamide on chondrocyte cell viability is still unclear. Therefore, we decided to study anandamide's effects on chondrocytes viability and to evaluate its interactions with the catabolic factor TNF (tumor necrosis factor). Chondrocyte vitality was evaluated by MTT assay. We investigated LDH release, chromatin condensation, cleavage of focal adhesion kinase (FAK), and caspases-3, 8, and 9 activation. c-MYC mRNA levels were determined by RT-PCR. We studied by Western blot the activation patterns of AKT, AMPK, ERK, p38, and JNK kinases. Finally, we evaluate the effect of anandamide in TNF-induced caspase-3 cleavage. Anandamide decreased chondrocyte vitality independently of its receptors. It induced AMPK activation without LDH release. Anandamide induced chromatin condensation, activation of caspase-3, 8, and 9, and FAK cleavage. Surprisingly, despite anandamide inhibited cell proliferation, it increased c-MYC expression. Moreover anandamide inhibited AKT activation, whilst it induced a sustained activation of ERK, JNK, and p38. Finally, anandamide synergized with TNF-α in the cleavage of caspase-3. In conclusion, our findings suggest that anandamide, alone or in combination with TNF-α, may be a potential destructive agent in cartilage.

Keywords: TNF; apoptosis; cannabinoids; chondrocyte physiology; signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / drug effects
  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Apoptosis / drug effects*
  • Arachidonic Acids / pharmacology*
  • Cannabinoids / pharmacology*
  • Caspases / drug effects
  • Caspases / metabolism
  • Cell Line
  • Cell Proliferation / drug effects*
  • Chondrocytes / drug effects
  • Chondrocytes / pathology*
  • Chromatin / drug effects
  • Endocannabinoids / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Mice
  • Models, Animal
  • Polyunsaturated Alkamides / pharmacology*
  • Proto-Oncogene Proteins c-akt / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology


  • Arachidonic Acids
  • Cannabinoids
  • Chromatin
  • Endocannabinoids
  • Polyunsaturated Alkamides
  • Tumor Necrosis Factor-alpha
  • Proto-Oncogene Proteins c-akt
  • AMP-Activated Protein Kinases
  • Caspases
  • anandamide