Docosahexaenoic acid is more potent inhibitor of osteoclast differentiation in RAW 264.7 cells than eicosapentaenoic acid

J Cell Physiol. 2008 Jan;214(1):201-9. doi: 10.1002/jcp.21188.


Fish oil rich in n-3 polyunsaturated fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) protects inflammation induced bone loss in chronic inflammatory diseases like rheumatoid arthritis, periodontitis, and osteoporosis. EPA and DHA differentially regulate functional parameters and gene expression in different cell types. One of the risk factors for bone loss in inflammatory bone diseases is the elevation of bone-resorbing osteoclasts and a very few studies so far have indicated that attenuation of osteoclastogenesis might be one of the mechanisms by which n-3 PUFA exert its effect on bone loss protection. However, the precise mechanism underlying this process remains unclear. Receptor activator of NF-kappaB ligand (RANKL) is known to be the most critical mediator of osteoclastogenesis. Therefore, in this study, we examined the differential effect of EPA and DHA on RANKL-stimulated osteoclastogenesis and RANKL signaling using a murine monocytic cell line RAW 264.7. DHA was found to inhibit osteoclast differentiation, activation and function more potently than EPA. The differential potential also closely correlated with the inhibition of osteoclast-specific genes like tartrate resistant acid phosphatase, cathepsin K, calcitonin receptor, matrix metalloproteinase-9 expression and osteoclast-specific transcription factor, c-Fos, as well as osteotropic proinflammatory cytokine, TNF-alpha to a greater extent with DHA than EPA. Further, pretreatment of RAW 264.7 cells with DHA also showed significantly reduced activation of NF-kappaB and p38MAPK than EPA. Our findings suggest that DHA may be much more effective than EPA in alleviating RANKL induced proinflammatory cytokine production, intracellular signaling activation, thereby decreasing osteoclast activation and bone resorption.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acid Phosphatase / metabolism
  • Animals
  • Apoptosis / drug effects
  • Cell Differentiation / drug effects*
  • Cell Line
  • Cell Proliferation / drug effects
  • Docosahexaenoic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Eicosapentaenoic Acid / pharmacology*
  • Fatty Acids / metabolism
  • Isoenzymes / metabolism
  • Linoleic Acid / pharmacology
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism
  • Osteoclasts / cytology
  • Osteoclasts / drug effects*
  • Osteoclasts / metabolism
  • Proto-Oncogene Proteins c-fos / metabolism
  • RANK Ligand / pharmacology
  • Tartrate-Resistant Acid Phosphatase
  • Time Factors
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Fatty Acids
  • Isoenzymes
  • NF-kappa B
  • Proto-Oncogene Proteins c-fos
  • RANK Ligand
  • Tnfsf11 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Docosahexaenoic Acids
  • Linoleic Acid
  • Eicosapentaenoic Acid
  • Mitogen-Activated Protein Kinases
  • Acid Phosphatase
  • Tartrate-Resistant Acid Phosphatase