title: Osteocyte apoptosis controls activation of intracortical resorption in response to bone fatigue.
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.
authors.affiliation: Department of Biomedical Engineering, The City College of New York, New York, New York 10031, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Cardoso
authors.forename: Brad C
authors.initials: BC
authors.lastname: Herman
authors.forename: Olivier
authors.initials: O
authors.lastname: Verborgt
authors.forename: Damien
authors.initials: D
authors.lastname: Laudier
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Majeska
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Schaffler
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D061945:Caspase Inhibitors; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D010011:Osteocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016474:Weight-Bearing / Q000502:physiology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D011804:Quinolines; C468548:quinoline-val-asp(OMe)-CH2-OPH