Abstract
Bone is a dynamic tissue constantly adapting to daily mechanical forces. Suppressing the bone’s ability to adapt to increased forces may lead to insufficient strength and ultimately fracture. Non-steroidal anti-inflammatory drugs (NSAIDs) block the bone formation response to a single load. However, the effect of chronic NSAID use on the bone formation response to multiple loads is unknown. Since Cox-2 inhibitors are used for treating chronic pain, it is essential to investigate their effects on bone. NSAIDs inhibit the cyclooxygenase (Cox) enzyme which is the rate limiting step in prostaglandin E2 (PGE2) production and a key step in the bone response to loading. PGE2 activates downstream signaling molecules of the low-density lipoprotein receptor related protein 5 (Lrp5) pathway independent of Lrp5 receptor activation. The Lrp5 pathway is a primary mediator of mechanical loading in bone. To better understand the interaction of the PGE2 and Lrp5 pathways, Lrp5-/- and gain of function mice (HBM) were used to test the effects of chronic Cox-2 inhibition with loading. |The results confirmed that Cox inhibitors block the bone formation response to a single load; however, chronic Cox-2 inhibition did not suppress the bone formation response to multiple loads. Furthermore there was no interaction between Cox-2 inhibition and varying levels of Lrp5 expression. |Cox-2 is the primary isoform in the bone response to a single mechanical load. To investigate the difference in response to a single versus multiple loads, Cox-1 and Cox-2 gene responses were measured. Cox-2 gene expression in osteocytes increased after loading while Cox-1 gene expression did not. However, immunohistochemistry showed cells expressing Cox-1 increased along the periosteal and endocortical surfaces following multiple loads.|In conclusion, Cox inhibition suppressed the bone formation response to a single load but not to multiple loads. Osteocyte Cox-1 gene expression was not upregulated to compensate for Cox-2 inhibition but Cox-1 activation along the periosteal and endocortical surfaces may play a role in the adaptive response to loading. While Cox-2 is important in the initial response to loading, Cox-1 may play a role in bone adaptation to multiple loading sessions.