Saurolactam inhibits osteoclast differentiation and stimulates apoptosis of mature osteoclasts

J Cell Physiol. 2009 Dec;221(3):618-28. doi: 10.1002/jcp.21892.


The receptor activator of nuclear factor-kappaB ligand (RANKL) plays a critical role in the differentiation and bone resorptive activity of osteoclasts. Recently, the development of anti-resorptive agents from natural substances has become a subject of interest. Therefore, we evaluated the effects of 222 natural compounds on the RANKL-induced tartrate-resistance acid phosphatase (TRAP; a marker for osteoclast differentiation) activity and multinucleated osteoclast formation in RAW264.7 murine macrophage cells. We found that saurolactam was one of the compounds inhibiting the RANKL-induced osteoclastogenesis; it significantly inhibited the RANKL-induced TRAP activity and formation of multinucleated osteoclasts without any cytotoxicity. Interestingly, saurolactam prevented RANKL-induced activation of MAP kinases and NF-kappaB, and mRNA expression of osteoclast-related genes and transcription factors (c-Fos, Fra-2, and NFATc1). We also observed the inhibitory effect of saurolactam on the differentiation of mouse bone marrow-derived macrophages into osteoclasts. Furthermore, saurolactam inhibited the bone resorptive activity of mature osteoclasts with the induction of apoptotic signaling cascade and the inhibition of survival signaling pathways such as c-Src/PI3K/Akt, Ras/ERK, and JNK/c-Jun. In conclusion, although further studies are needed to determine the precise mechanism and biological efficacy of saurolactam in osteoclast-mediated bone disorders, our results demonstrate that saurolactam potentially inhibits osteoclast differentiation by preventing the activation of MAP kinases and transcription factors that consequently affect the regulation of genes required for osteoclastogenesis, and the bone resorptive activity of mature osteoclasts by inhibiting osteoclast survival-related signaling pathways and triggering the apoptotic signaling cascade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Phosphatase / genetics
  • Acid Phosphatase / metabolism
  • Alkaloids / pharmacology*
  • Animals
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism
  • Bone Resorption / pathology
  • Bone Resorption / prevention & control
  • Caspase 3 / metabolism
  • Cell Differentiation / drug effects*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cytochromes c / metabolism
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Lactams / pharmacology*
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinases / metabolism
  • NFATC Transcription Factors / genetics
  • Osteoclasts / cytology*
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • Phosphorylation / drug effects
  • RANK Ligand / pharmacology
  • Receptor Activator of Nuclear Factor-kappa B / genetics
  • Saururaceae / chemistry
  • Tartrate-Resistant Acid Phosphatase
  • Transcription Factor AP-1 / genetics
  • Transcription Factor RelA / metabolism


  • Alkaloids
  • Apoptosis Regulatory Proteins
  • Isoenzymes
  • Lactams
  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Rela protein, mouse
  • Tnfsf11 protein, mouse
  • Transcription Factor AP-1
  • Transcription Factor RelA
  • Macrophage Colony-Stimulating Factor
  • Cytochromes c
  • Mitogen-Activated Protein Kinases
  • Acid Phosphatase
  • Acp5 protein, mouse
  • Tartrate-Resistant Acid Phosphatase
  • Casp3 protein, mouse
  • Caspase 3