Inhibition of osteocyte apoptosis prevents the increase in osteocytic receptor activator of nuclear factor κB ligand (RANKL) but does not stop bone resorption or the loss of bone induced by unloading

J Biol Chem. 2015 Jul 31;290(31):18934-42. doi: 10.1074/jbc.M115.642090. Epub 2015 Jun 17.


Apoptosis of osteocytes and osteoblasts precedes bone resorption and bone loss with reduced mechanical stimulation, and receptor activator of NF-κB ligand (RANKL) expression is increased with unloading in mice. Because osteocytes are major RANKL producers, we hypothesized that apoptotic osteocytes signal to neighboring osteocytes to increase RANKL expression, which, in turn, increases osteoclastogenesis and bone resorption. The traditional bisphosphonate (BP) alendronate (Aln) or IG9402, a BP analog that does not inhibit resorption, prevented the increase in osteocyte apoptosis and osteocytic RANKL expression. The BPs also inhibited osteoblast apoptosis but did not prevent the increase in osteoblastic RANKL. Unloaded mice exhibited high serum levels of the bone resorption marker C-telopeptide fragments of type I collagen (CTX), elevated osteoclastogenesis, and increased osteoclasts in bone. Aln, but not IG9402, prevented all of these effects. In addition, Aln prevented the reduction in spinal and femoral bone mineral density, spinal bone volume/tissue volume, trabecular thickness, mechanical strength, and material strength induced by unloading. Although IG9402 did not prevent the loss of bone mass, it partially prevented the loss of strength, suggesting a contribution of osteocyte viability to strength independent of bone mass. These results demonstrate that osteocyte apoptosis leads to increased osteocytic RANKL. However, blockade of these events is not sufficient to restrain osteoclast formation, inhibit resorption, or stop bone loss induced by skeletal unloading.

Keywords: RANKL; apoptosis; bone; immobilization; osteoblast; osteoclast; osteocyte; resorption.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alendronate / pharmacology
  • Animals
  • Apoptosis / drug effects*
  • Bone Density Conservation Agents / pharmacology
  • Bone Resorption / metabolism*
  • Cells, Cultured
  • Collagen Type I / pharmacology*
  • Female
  • Hindlimb Suspension
  • Mice, Inbred C57BL
  • Osteocytes / drug effects
  • Osteocytes / physiology*
  • Peptides / pharmacology*
  • RANK Ligand / metabolism*


  • Bone Density Conservation Agents
  • Collagen Type I
  • Peptides
  • RANK Ligand
  • Tnfsf11 protein, mouse
  • collagen type I trimeric cross-linked peptide
  • Alendronate