Osteoprotegerin Induces Apoptosis of Osteoclasts and Osteoclast Precursor Cells via the Fas/Fas Ligand Pathway

PLoS One. 2015 Nov 16;10(11):e0142519. doi: 10.1371/journal.pone.0142519. eCollection 2015.

Abstract

Osteoprotegerin (OPG) is known to inhibit differentiation and activation of osteoclasts (OCs) by functioning as a decoy receptor blocking interactions between RANK and RANKL. However, the exact role of OPG in the survival/apoptosis of OCs remains unclear. OPG caused increased rates of apoptosis of both OCs and osteoclast precursor cells (OPCs). The expression of Fas and activated caspase-8 was increased by both 20 ng/mL and 40 ng/mL of OPG, but was markedly decreased at 80 ng/mL. Interestingly, we noted that while levels of Fas ligand (FasL) increased with increasing doses of OPG, the soluble form of FasL in the supernatant decreased. The results of a co-immunoprecipitation assay suggested that the decrease of sFasL might be caused by the binding of OPG. This would block the inhibition of the apoptosis of OCs and OPCs. Furthermore, changes in expression levels of Bax/Bcl-2, cleaved-caspase-9, cleaved-caspased-3 and the translocation of cytochrome c, illustrated that OPG induced apoptosis of OCs and OPCs via the classic Fas/FasL apoptosis pathway, and was mediated by mitochondria. Altogether, our results demonstrate that OPG induces OCs and OPCs apoptosis partly by the Fas/FasL signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cells, Cultured
  • Fas Ligand Protein / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Osteoblasts / physiology*
  • Osteoclasts / physiology*
  • Osteoprotegerin / physiology*
  • Signal Transduction
  • Solubility
  • fas Receptor / metabolism

Substances

  • Fas Ligand Protein
  • Fas protein, mouse
  • Osteoprotegerin
  • Tnfrsf11b protein, mouse
  • fas Receptor

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China [grant numbers 31172373, 31372495, 31302154], the Project of Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) and the Graduate Innovation Project of Jiangsu Province (KYZZ_0369).