Nox2 Deficiency Reduces Cartilage Damage and Ectopic Bone Formation in an Experimental Model for Osteoarthritis

Peter M Van Der Kraan,Yvonne Van Gemert,Thomas Vogl,Arjen B Blom,Fons A J Van De Loo,Birgitte Walgreen,Martijn H J Van Den Bosch,Nik N L Kruisbergen,Johannes Roth,Peter L E M Van Lent,Annet W Slöetjes,Irene Di Ceglie,Monique M A Helsen,Marije I Koenders

doi:10.3390/antiox10111660

Abstract

Osteoarthritis (OA) is a destructive disease of the joint with age and obesity being its most important risk factors. Around 50% of OA patients suffer from inflammation of the synovial joint capsule, which is characterized by increased abundance and activation of synovial macrophages that produce reactive oxygen species (ROS) via NADPH-oxidase 2 (NOX2). Both ROS and high blood levels of low-density lipoprotein (LDL) are implicated in OA pathophysiology, which may interact to form oxidized LDL (oxLDL) and thereby promote disease. Therefore, targeting NOX2 could be a viable treatment strategy for OA. Collagenase-induced OA (CiOA) was used to compare pathology between wild-type (WT) and Nox2 knockout (Nox2−/−) C57Bl/6 mice. Mice were either fed a standard diet or Western diet (WD) to study a possible interaction between NOX2-derived ROS and LDL. Synovial inflammation, cartilage damage and ectopic bone size were assessed on histology. Extracellular ROS production by macrophages was measured in vitro using the Amplex Red assay. Nox2−/− macrophages produced basal levels of ROS but were unable to increase ROS production in response to the alarmin S100A8 or the phorbol ester PMA. Interestingly, Nox2 deficiency reduced cartilage damage, synovial lining thickness and ectopic bone size, whereas these disease parameters were not affected by WD-feeding. These results suggest that NOX2-derived ROS are involved in CiOA development.

Highlights

Osteoarthritis (OA) is a debilitating joint disease characterized by degradation of articular cartilage, formation of ectopic bone, and inflammation of the synovial membrane, which is the tissue that lines the joint cavity
Macrophage Marker CD68 and Oxidation Marker 4HNE Are Present in the Lining of Human OA Synovium, and CD163 Positively Correlates with nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase 2 (NOX2)
Since macrophages are strongly involved in OA pathology, NOX2-mediated reactive oxygen species (ROS) production in the synovium might be a disease-promoting process in a subtype of OA characterized by synovial inflammation

Summary

Introduction

Osteoarthritis (OA) is a debilitating joint disease characterized by degradation of articular cartilage, formation of ectopic bone, and inflammation of the synovial membrane, which is the tissue that lines the joint cavity. The most important risk factors for OA include age, obesity, and previous joint injury. OA accounts for 2,4% percent of years lived with disability, while the global prevalence of knee and hip OA is approaching 5%, and without effective intervention will keep increasing as a result of an aging and advancingly obese population [1]. The classical view of OA as a mechanical ‘wear-and-tear’ process of the cartilage has changed in the last two decades towards a more complex disease of the whole joint. Many researchers consider that chronic low-grade inflammation of the synovium comediates and accelerates OA development by causing an imbalance in both catabolic and Antioxidants 2021, 10, 1660.

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