Osteoclastic superoxide production and bone resorption: Stimulation and inhibition by modulators of NADPH oxidase

Abstract

Production of superoxide radicals by osteoclasts is necessary for normal bone degradation. White blood cell superoxide, needed for bacterial killing, is produced by activated NADPH oxidase. Since osteoclasts and white blood cells share a common hematopoietic origin, we initiated experiments to test the hypothesis that superoxide radicals at the osteoclast-bone interface are produced by NADPH oxidase. Diphenyl iodonium (IDP), an inhibitor of NADPH oxidase, blocked superoxide generation and decreased osteoclastic bone resorption in cultures of calvarial explants from normal mice. Interferon (IFN) gamma, a stimulant of NADPH oxidase activity, increased superoxide production and bone resorption in cultures of calvarial explants from osteopetrotic (microphthalmic) mice. IDP blocked the stimulatory effects of IFN in this bone resorption model. These data suggest that osteoclastic superoxide is produced by NADPH oxidase.

Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases

“…Subsequent studies from other groups also found that superoxide production was present within the osteoclast and suggested that it may be derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase localized to the bone-osteoclast interface within the osteoclast ruffled border [14][15][16]. Further evidence for the involvement of NADPH oxidase was found when addition of a specific inhibitor of NADPH oxidase, diphenylene iodonium (DPI), resulted in a reduction in superoxide production and bone resorption [17,18]. Other studies, however, indicated that rather than superoxide, H 2 O 2 was the primary ROS responsible for promoting osteoclast formation and activity [8,[19][20][21].…”

Role of NADPH Oxidase in Formation and Function of Multinucleated Giant Cells

“…The level of Nox2 expressed in murine osteoclasts is almost double of that in phagocytes, suggesting that the NADPH oxidase complex is highly expressed in osteoclasts [72] , which may explain the higher levels of O 2 -ؒ generated by these cells [68,84,85] . O 2 -ؒ has been detected at the ruffled border of osteoclasts, which suggests that ROS are produced at sites of resorption and may participate in matrix degradation.…”

“…Based on their cellular origin, it is not surprising that the various types of multinucleated giant cells have been shown to generate ROS, as ROS production is one of the hallmarks of all professional phagocytes, including neutrophils and monocyte/macrophages [reviewed in 66 ]. Among the multinucleated giant cells known to generate ROS are osteoclasts [67,68] and multinucleated giant cells of noninfectious and infectious granulomas [69][70][71] . Note, however, that multinucleated giant cells generally exhibit an enhanced ROS-generating capacity (20-to 30-fold) compared with unfused macrophages [69] .…”

A pilot study of copper supplementation effects on plasma F2α isoprostanes and urinary collagen crosslinks in young adult women

“…Theoretically, copper should impact bone since the copper enzyme lysyl oxidase crosslinks collagen, which contributes to bone strength [1,11]. Also, Cu-Zn SOD eliminates the oxidant superoxide, which promotes bone breakdown [13].…”