NADPH oxidase 4 limits bone mass by promoting osteoclastogenesis

Abstract

ROS are implicated in bone diseases. NADPH oxidase 4 (NOX4), a constitutively active enzymatic source of ROS, may contribute to the development of such disorders. Therefore, we studied the role of NOX4 in bone homeostasis. Nox4(-/-) mice displayed higher bone density and reduced numbers and markers of osteoclasts. Ex vivo, differentiation of monocytes into osteoclasts with RANKL and M-CSF induced Nox4 expression. Loss of NOX4 activity attenuated osteoclastogenesis, which was accompanied by impaired activation of RANKL-induced NFATc1 and c-JUN. In an in vivo model of murine ovariectomy–induced osteoporosis, pharmacological inhibition or acute genetic knockdown of Nox4 mitigated loss of trabecular bone. Human bone obtained from patients with increased osteoclast activity exhibited increased NOX4 expression. Moreover, a SNP of NOX4 was associated with elevated circulating markers of bone turnover and reduced bone density in women. Thus, NOX4 is involved in bone loss and represents a potential therapeutic target for the treatment of osteoporosis.

p47 -Nox2-dependent ROS Signaling Inhibits Early Bone Development in Mice but Protects against Skeletal Aging

“…4). Although there are disagreements from a recent study using global Nox4 knock-out animal (30), cell type-specific conditional knock-out animal models may be used to untangle this possibility. However, in the current study, we used an ex vivo cell culture model and determined that knocking down Nox4 in cells from p47 phoxϪ/Ϫ mice blocked temporal osteoblastic cell differentiation signaling.…”

Nox/Duox Family of NADPH Oxidases: Lessons from Knockout Mouse Models

“…Nox4 knockout animals have higher bone density, a phenotype that is likely caused by impaired formation and activation of osteoclasts [49]. In a murine model of postmenopausal osteoporosis, pharmacological or genetic inhibition of Nox4 reduced the loss of trabecular bone [49].…”

NADPH oxidase 4 represents a potential target for the treatment of osteoporosis

“…Recently, Goettsch et al 4 identified nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) as a potential target for the treatment of osteoporosis. The nicotinamide adenine dinucleotide phosphate oxidases represent a family of enzymes that solely produce reactive oxygen species (ROS).…”

“…Goettsch et al 4 identified NOX4 as the relevant enzymatic source of ROS during bone metabolism and analyzed the mechanisms of osteoclastogenesis induced by ROS.…”