Osteocyte Apoptosis Controls Activation of Intracortical Resorption in Response to Bone Fatigue

Luis Cardoso, Brad C. Herman, Olivier Verborgt, Damien Laudier, Robert J. Majeska, Mitchell B. Schaffler

Research output: Contribution to journalArticlepeer-review

269 Scopus citations

Abstract

Osteocyte apoptosis is spatially and temporally linked to bone fatigue-induced microdamage and to subsequent intracortical remodeling. Specifically, osteocytes surrounding fatigue microcracks in bone undergo apoptosis, and those regions containing apoptotic osteocytes co-localize exactly with areas subsequently resorbed by osteoclasts. Here we tested the hypothesis that osteocyte apoptosis is a key controlling step in the activation and/or targeting of osteoclastic resorption after bone fatigue. We carried out in vivo fatigue loading of ulna from 4-to 5-mo-old Sprague-Dawley rats treated with an apoptosis inhibitor (the pan-caspase inhibitor Q-VD-OPh) or with vehicle. Intracortical bone remodeling and osteocyte apoptosis were quantitatively assessed by standard histomorphometric techniques on day 14 after fatigue. Continuous exposure to Q-VD-OPh completely blocked both fatigue-induced apoptosis and the activation of osteoclastic resorption, whereas short-term caspase inhibition during only the first 2 days after fatigue resulted in >50% reductions in both osteocyte apoptosis and bone resorption. These results (1) show that osteocyte apoptosis is necessary to initiate intracortical bone remodeling in response to fatigue microdamage, (2) indicate a possible dose-response relationship between the two processes, and (3) suggest that early apoptotic events after fatigue-induced microdamage may play a substantial role in determining the subsequent course of tissue remodeling.

Original languageEnglish
Pages (from-to)597-605
Number of pages9
JournalJournal of Bone and Mineral Research
Volume24
Issue number4
DOIs
StatePublished - Apr 2009

Keywords

  • Apoptosis
  • Bone
  • Bone resorption
  • Caspase inhibitor
  • In vivo fatigue
  • Osteocytes

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