Calebin A Downregulates Osteoclastogenesis Through Suppression of RANKL Signalling

Arch Biochem Biophys. 2016 Mar 1;593:80-9. doi: 10.1016/j.abb.2016.02.013. Epub 2016 Feb 11.

Abstract

Osteoporosis is a bone disease that is exacerbated by aging and age-associated chronic diseases such as cancer. Cancer-induced bone loss is usually treated with bisphosphonates or denosumab, an antibody against receptor activator of nuclear factor (NF)-κB ligand (RANKL). Because these drugs are expensive and have numerous side effects and high rates of toxicity, safer, more effective, and more affordable therapies for osteoporosis are still needed. We identified a compound, calebin A (CA), derived from turmeric (Curcuma longa) that affects osteoclastogenesis through modulation of the RANKL signalling pathway. The CA's effect on NF-κB activation was examined by electrophoretic mobility shift assay. Using mouse macrophages in vitro model, we found that CA suppressed RANKL-induced osteoclast differentiation of macrophages into osteoclasts, and downregulate RANKL-induced osteoclastogenesis-related marker gene expression, including NFATc-1, TRAP, CTR, and cathepsin K. CA also suppressed the osteoclastogenesis induced by multiple myeloma and breast cancer cells. This effect of CA was correlated with suppression of the phosphorylation and degradation of inhibitor of κB and, thus, inhibition of NF-κB activation. Furthermore, we found that an NF-κB-specific inhibitory peptide blocked RANKL-induced osteoclastogenesis, demonstrating that the NF-κB signalling pathway is mandatory for RANKL-induced osteoclastogenesis. Our results conclusively indicate that CA downmodulates the osteoclastogenesis induced by RANKL and by tumour cells through suppression of NF-κB pathway.

Keywords: Calebin A; Cancer; NF-κB; Osteoclastogenesis; RANKL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • Cinnamates / pharmacology*
  • Coculture Techniques
  • Curcuma / chemistry*
  • Humans
  • I-kappa B Kinase / metabolism
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Mice
  • Monoterpenes / pharmacology*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Osteoclasts / cytology
  • Osteoclasts / drug effects*
  • Osteoclasts / metabolism
  • Phosphorylation
  • RANK Ligand / antagonists & inhibitors*
  • RANK Ligand / metabolism
  • Signal Transduction

Substances

  • Cinnamates
  • Monoterpenes
  • NF-kappa B
  • RANK Ligand
  • calebin-A
  • Macrophage Colony-Stimulating Factor
  • I-kappa B Kinase