J Clin Invest. 2013 Nov;123(11):4731-8. doi: 10.1172/JCI67603.
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.
活性氧簇（ROS）与骨疾病有关。烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶 4（NOX4）作为 ROS 的一种组成型活性酶源，可能有助于这些疾病的发展。因此，我们研究了 NOX4 在骨稳态中的作用。Nox4(-/-) 小鼠表现出更高的骨密度和更少的破骨细胞数量和标志物。体外，用 RANKL 和 M-CSF 将单核细胞分化为破骨细胞诱导了 Nox4 的表达。NOX4 活性丧失减弱了破骨细胞的形成，这伴随着 RANKL 诱导的 NFATc1 和 c-JUN 激活受损。在小鼠卵巢切除诱导骨质疏松症的体内模型中，NOX4 的药理学抑制或急性基因敲低减轻了小梁骨的丢失。从破骨细胞活性增加的患者获得的人骨表现出增加的 NOX4 表达。此外，NOX4 的 SNP 与女性循环骨转换标志物升高和骨密度降低有关。因此，NOX4 参与骨丢失，是治疗骨质疏松症的潜在治疗靶点。
