Acute Changes in NADPH Oxidase 4 in Early Post‐Traumatic Osteoarthritis

Abstract

Knee injuries cause structural damage and acute inflammation that initiates the development of post‐traumatic osteoarthritis (PTOA). NADPH oxidase 4 (Nox4), a member of a family of enzymes that generates reactive oxygen species (ROS), plays a pivotal role in normal development of the musculoskeletal system, but may increase ROS production to harmful levels after joint injury. The role of ROS in both normal joint homeostasis and injury is poorly understood, but inhibition of excessive ROS production by Nox4 after joint injury could be protective to the joint, decreasing oxidative stress, and initiation of PTOA. Knee injuries were simulated using inflammatory cytokines in cultured primary human chondrocytes and a non‐invasive mouse model of PTOA in C57BL/6N and Nox4 knockout mice. There is an acute decrease in Nox4 activity within 24 h after injury in both systems, followed by a subsequent sustained low‐level increase, a novel finding not seen in any other system. Inhibition of Nox4 activity by GKT137831 was protective against early structural changes after non‐invasive knee injury in a mouse model. Nox4 knockout mice had significant differences in structural and mechanical properties of bone, providing further evidence for the role of Nox4 in development of joint tissues and biochemical response after joint injury. Nox4 plays a significant role in the acute phase after joint injury, and targeted inhibition of inflammation caused by Nox4 may be protective against early joint changes in the pathogenesis of PTOA. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2429–2436, 2019

The evaluation of oxidative stress in osteoarthritis

“…There is a study that investigated the clinical utility of selective iNOS inhibitors as disease-modifying OA drugs, as they have been shown to reduce joint inflammation and erosion in animal models of OA. The same study demonstrated that nNOS is more frequently expressed by normal chondrocytes, while iNOS prevails in OA chondrocytes [49].…”

NADPH oxidases in bone and cartilage homeostasis and disease: A promising therapeutic target

“…99 In a mouse model of post-traumatic osteoarthritis induced by ACL-rupture, Nox4 activity was acutely decreased within 24 hours of injury, and this was followed by a subsequent increase of Nox4 activity. 75 Inhibition of Nox4 using GKT137831 was protective against early structural changes in the mouse knee joints, suggesting a possible role for Nox4 in the pathogenesis of post-traumatic osteoarthritis. 75…”

“…75 Inhibition of Nox4 using GKT137831 was protective against early structural changes in the mouse knee joints, suggesting a possible role for Nox4 in the pathogenesis of post-traumatic osteoarthritis. 75…”

Identification of the Resveratrol Potential Targets in the Treatment of Osteoarthritis

“…NOX4 constitutively produces hydrogen peroxide (H 2 O 2 ) [45] and participates in the development and homeostasis of tissues that make up normal joints [46]. NOX4 plays a signi cant role in the acute phase after joint injury, and targeted inhibition of in ammation caused by NOX4 may help prevent early joint changes in the pathogenesis of post-traumatic osteoarthritis [47]. However, the role of NOX4 in the OA progress and resveratrol treatment remains blank.…”