title: Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss.
abstract: Mechanical stimulation of cultured osteocytic cells attenuates their apoptosis. We report here that, conversely, reduced mechanical forces in the murine model of unloading by tail suspension increases the prevalence of osteocyte apoptosis, followed by bone resorption and loss of mineral and strength.
  
  
  BACKGROUND
  Mechanical loading is critical for the maintenance of bone mass; weightlessness, as with reduced physical activity in old age, bed rest, or space flight, invariably leads to bone loss. However, the cellular and molecular mechanisms responsible for these phenomena are poorly understood. Based on our earlier findings that physiologic levels of mechanical strain prevent apoptosis of osteocytic cells in vitro, we examined here whether, conversely, reduced mechanical forces increase the prevalence of osteocyte apoptosis in vivo and whether this event is linked to bone loss.
  
  
  METHODS
  Swiss Webster mice or OG2-11beta-hydroxysteroid dehydrogenase type 2 (OG2-11beta-HSD2) transgenic mice and wildtype littermates were tail-suspended or kept under ambulatory conditions. Static and dynamic histomorphometry and osteocyte and osteoblast apoptosis by in situ end-labeling (ISEL) were assessed in lumbar vertebra; spinal BMD was measured by DXA; and bone strength was measured by vertebral compression.
  
  
  RESULTS
  We show that within 3 days of tail suspension, mice exhibited an increased incidence of osteocyte apoptosis in both trabecular and cortical bone. This change was followed 2 weeks later by increased osteoclast number and cortical porosity, reduced trabecular and cortical width, and decreased spinal BMD and vertebral strength. Importantly, whereas in ambulatory animals, apoptotic osteocytes were randomly distributed, in unloaded mice, apoptotic osteocytes were preferentially sequestered in endosteal cortical bone--the site that was subsequently resorbed. The effect of unloading on osteocyte apoptosis and bone resorption was reproduced in transgenic mice in which osteocytes are refractory to glucocorticoid action, indicating that stress-induced hypercortisolemia cannot account for these effects.
  
  
  CONCLUSIONS
  We conclude that diminished mechanical forces eliminate signals that maintain osteocyte viability, thereby leading to apoptosis. Dying osteocytes in turn become the beacons for osteoclast recruitment to the vicinity and the resulting increase in bone resorption and bone loss.
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: J Ignacio
authors.initials: JI
authors.lastname: Aguirre
authors.forename: Lilian I
authors.initials: LI
authors.lastname: Plotkin
authors.forename: Scott A
authors.initials: SA
authors.lastname: Stewart
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weinstein
authors.forename: A Michael
authors.initials: AM
authors.lastname: Parfitt
authors.forename: Stavros C
authors.initials: SC
authors.lastname: Manolagas
authors.forename: Teresita
authors.initials: T
authors.lastname: Bellido
mesh_terms: D000818:Animals; D017209:Apoptosis; D015519:Bone Density; D001862:Bone Resorption / Q000473:pathology*; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000166:cytology* / Q000473:pathology; D010011:Osteocytes / Q000473:pathology*; D014893:Weightlessness / Q000009:adverse effects*