Abstract
SummaryA single injection of the cyclooxygenase-2 (COX-2) selective inhibitor NS-398 reduces bone’s osteogenic response to a single period of mechanical loading in female rats, while women taking COX-2 selective inhibitors do not have lower bone mass. We show that daily NS-398 injection does not influence bone gain from repeated loading in female mice.IntroductionProstaglandins are mediators of bone cells’ early response to mechanical stimulation. COX-2 expression is up-regulated by exposure of these cells to mechanical strain or fluid flow, and the osteogenic response to a single loading period is reduced by COX-2 inhibition. This study determined, in female mice in vivo, the effect of longer term COX-2 inhibition on adaptive (re)modelling of cortical and trabecular bone in response to repeated loading.MethodsNineteen-week-old female C57BL/6 mice were injected with vehicle or NS-398 (5 mg/kg/day) 5 days a week for 2 weeks. On three alternate days each week, the right tibiae/fibulae were axially loaded [40 cycles (7 min)/day] three hours after injection. Left limbs acted as internal controls. Changes in three-dimensional bone architecture were analysed by high-resolution micro-computed tomography.ResultsIn control limbs NS-398 was associated with reduced trabecular number but had no influence on cortical bone. In loaded limbs trabecular thickness and cortical periosteally enclosed volume increased. NS-398 showed no effect on this response.ConclusionPharmacological inhibition of COX-2 by NS-398 does not affect trabecular or cortical bone’s response to repeated mechanical loading in female mice and thus would not be expected to impair the functional adaptation of bone to physical activity in women.
Highlights
Mechanical loading is the principal functional determinant of bone mass and architecture [1,2,3], and numerous studies have shown that prostaglandin signalling plays a key role in mechanotransduction, with cyclooxygenase-2 (COX-2) expression being rapidly up-regulated in both osteoblasts and osteocytes following exposure to fluid flow or mechanical strain in vitro [4,5,6]
Blocking prostaglandin production with indomethacin in experimental animals in vivo has repeatedly been shown to impair the osteogenic response to a single period of mechanical loading in cortical and trabecular bone [7,8,9]
Two studies in female rats have shown that a single injection of the COX-2 selective inhibitor NS-398, 3 h prior to a single period of mechanical loading, reduces the osteogenic response in the cortex [9, 10]
Summary
Mechanical loading is the principal functional determinant of bone mass and architecture [1,2,3], and numerous studies have shown that prostaglandin signalling plays a key role in mechanotransduction, with cyclooxygenase-2 (COX-2) expression being rapidly up-regulated in both osteoblasts and osteocytes following exposure to fluid flow or mechanical strain in vitro [4,5,6]. Blocking prostaglandin production with indomethacin in experimental animals in vivo has repeatedly been shown to impair the osteogenic response to a single period of mechanical loading in cortical and trabecular bone [7,8,9]. The osteogenic response to two Osteoporos Int (2013) 24:383–388 episodes of mechanical loading in genetically modified female mice lacking COX-2 was not impaired [11]. This could be due to compensation for the complete absence of COX-2 over the animals’ life time, a response which is less relevant to the clinical situation using COX-2 selective inhibitors if similar compensation occurs over the comparatively shorter term
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