Suppression of prostaglandin synthesis with NS-398 has different effects on endocortical and periosteal bone...

Prostaglandins mediate adaptive bone formation induced by mechanical loading. Inhibition of cyclooxygenase-2 (COX-2) with NS-398 effectively blocks loading-induced osteogenesis on the endocortical bone surface of the tibia. In this study, we compared the effects of selective inhibition of COX-2 with NS-398 on mechanically induced osteogenesis at the endocortical surface (tibia) with that on the periosteal surface (ulna). We further tested the effect of NS-398 administered at different times before (3 hrs or 30 min) or after (30 min) mechanical loading. Mechanical loading induced lamellar bone formation on the endocortical surface of the tibia and the periosteal surface of the ulna. Oral administration of either indomethacin or NS-398 3 hrs before loading significantly decreased loading-induced bone formation rate (BFR) and mineralizing surface (MS/BS), but not mineral apposition rate (MAR), at the endocortical surface of the tibia and the periosteal surface of the ulna. NS-398 reduced loading-induced MS/BS by 96% on the endocortical surface of the tibia, but only by 37% on the periosteal surface of the ulna (significantly different from endocortical, P <0.05). Indomethacin reduced MS/BS and BFR to a lesser extent than NS-398 and did not have different effects on the periosteal and endocortical surfaces. These data suggest that the endocortical bone adaptive response to mechanical loading is more dependent upon COX-2 activity than is the periosteal bone response. Intraperitoneal injection of NS-398 3 hrs before loading suppressed load-induced bone formation rate at the endocortical surface of the tibia significantly more (27%) than when administered 30 min before loading. When NS-398 was given 30 min after loading, bone formation was not significantly suppressed. These data suggest that a primary cellular mechanism of bone formation following brief bouts of mechanical loading involves release of prostaglandins from cells at the time mechanical loading is applied, rather than new prostaglandin synthesis associated with a mechanically induced COX-2 expression.