First Place—Resident Basic Science Award 1999: Effects of Leukotriene and Cyclo-Oxygenase Inhibition on Adaptive Bone Remodeling in the Middle Ear

Abstract

Abnormal bone remodeling is associated with important otolaryngologic diseases. In such diseases, the mechanisms of osteoclastic control underlie the pathologic processes. It is known that strain applied to auditory bullae induces bone resorption—an effect mediated by prostaglandins and blocked by cyclo-oxygenase inhibitors. It is also known that cyclo-oxygenase inhibition shunts arachidonic acid into alternate metabolic pathways, mainly the lipoxygenase pathway with leukotriene production. The role of these metabolites in adaptive bone remodeling is unknown. Using the gerbilline bulla as a model, we infused BW755c (dual lipoxygenase/cyclo-oxygenase inhibitor) and L-663,536 (5-lipoxygenase inhibitor) into animals undergoing middle ear pressurization. After 7 days, the bulla bones were harvested, and osteoclasts were quantified histomorphometrically. The results showed that neither treatment altered pressure-induced resorption. However, BW755c significantly increased resorption in unpressurized bone when compared with control values. Because BW775c blocks both lipoxygenase and cyclo-oxygenase pathways, the results suggest an alternate pathway in middle ear bone resorption. Otosclerosis, cholesteatoma, Paget's disease of bone, osteogenesis imperfecta, and chronic otitis media are important otologic diseases with pathologies linked to inappropriate bone remodeling. 1 In these diseases, the mechanisms of osteoclastic recruitment and activation must underlie the bone resorption associated with each condition. Numerous effectors have been implicated as modulating the local recruitment and activation of osteoclasts. One group of effectors, the metabolites of arachidonic acid (AA), has been shown to exert significant effects on osteoclastic bone resorption both in vivo and in vitro. 2