Cytokine-mediated bone resorption is cytochrome P-450 dependent

Localized bone loss leads to much of the morbidity of chronic otitis media. Although the cellular events of bone remodeling have been well established , their regulation remains poorly understood. Various cytokines, including tumor necrosis factor-alpha, interleukin-1 beta, and interferon-gamma, used alone and in combination, are powerful inducers of bone resorption. One of the modulators of cytokine-induced bone resorption is nitric oxide (NO), a product of the action of NO synthase (NOS) on L-arginine to form NO. Cytoc hrome P-450, an enzyme that is similar to NOS both structurally and functio nally, may also have a role In NO production in various cellular systems. T he goal of this study was to elucidate a possible role of cytochrome P-450 in bone. In this study cytokine-induced bone resorption was blocked with ci metidine and clotrimazole, which are selective inhibitors of the cytochrome P-450 IIIA family and 7-ethoxyresorufin, a nonspecific cytochrome P-450 in hibitor. A concomitant reduction of NO was also observed. This effect may b e explained by cytochrome P-450 being a preferred alternative pathway or pr oviding an essential cofactor to NOS in bone.