Fas/CD95 is associated with glucocorticoid-induced osteocyte apoptosis

G. Kogianni, V. Mann, F. Ebetino, M. Nuttall, P. Nijweide, H. Simpson, B. Noble

Research output: Contribution to journalArticlepeer-review

Abstract

Prolonged use of glucocorticoids is associated with decreased bone formation, increased resorption and osteonecrosis, through direct and indirect effects on the activity and viability of bone effector cells, osteoblasts and osteoclasts, and osteocytes. This study has investigated molecular pathways implicated in Dexamethasone-induced apoptosis of osteocytes, using a cell line and primary chicken cells. MLO-Y4 osteocytes were pre-treated with several bisphosphonates representing a range of anti-resorptive activities and conformation/structure relationships, and were subsequently challenged with Dexamethasone. Apoptotic cells were detected at various times after treatment using morphological and biochemical criteria. Dex was shown to induce apoptosis associated with the Fas/CD95 death receptor and in a caspase 8 dependent manner. The apoptotic response was inhibited by all variants of the BP molecules, including those with reduced anti-resorptive activity, indicating that Dex-induced apoptosis is independent of anti-osteoclastic activity. Dex-induced apoptosis was associated with a transient increase in phosphorylated ERK 1/2 and was blocked by the ERK inhibitor UO126. In addition, both UO126 and BPs decreased localization of Fas to the cell membrane. ERK activation by PMA did not induce death or Fas upregulation, suggesting that Fas may be important for the induction of apoptosis and the existence of an additional factor activated by Dex which enables the cooperation between the Dex-activated ERK and Fas pathways, during apoptosis of osteocytes. Furthermore, upregulation of death and Fas was not accompanied by upregulation of FasL, pointing to the possible existence of FasL-independent Fas-associated death in these cells.

Original languageEnglish
Pages (from-to)2879-2895
Number of pages17
JournalLife Sciences
Volume75
Issue number24
DOIs
Publication statusPublished - 29 Oct 2004

Keywords

  • Apoptosis
  • Bisphosphonates
  • Dexamethasone
  • ERK
  • Fas
  • Osteocyte

Fingerprint

Dive into the research topics of 'Fas/CD95 is associated with glucocorticoid-induced osteocyte apoptosis'. Together they form a unique fingerprint.

Cite this