NADPH oxidase 4 deficiency attenuates experimental osteoarthritis in mice

Article Article scientifique Article NADPH oxidase 4 deficiency attenuates experimental osteoarthritis in mice eng 2023-02-21 author Renaudin Félix 0000-0002-5712-582X Department of Cell Physiology and Metabolism, Université de Genève Faculté de médecine, Geneve, Switzerland.,Department of Orthopaedic Surgery, Geneva University Hospitals, Geneve, Switzerland. 948527 author Oudina Karim-Stephane Department of Cell Physiology and Metabolism, Université de Genève Faculté de médecine, Geneve, Switzerland.,Department of Orthopaedic Surgery, Geneva University Hospitals, Geneve, Switzerland. 859963 author Gerbaix Maude Coline Service of Bone Diseases, Department of Medicine, Geneva University Hospitals, Geneve, Switzerland. 790754 Département de médecine (DEMED) author Subilia Manon Department of Cell Physiology and Metabolism, Université de Genève Faculté de médecine, Geneve, Switzerland.,Department of Orthopaedic Surgery, Geneva University Hospitals, Geneve, Switzerland. 930078 author Paccaud Joris Department of Cell Physiology and Metabolism, Université de Genève Faculté de médecine, Geneve, Switzerland.,Department of Orthopaedic Surgery, Geneva University Hospitals, Geneve, Switzerland. 697370 author Jaquet Vincent Department of Pathology and Immunology, Université de Genève Faculté de médecine, Geneve, Switzerland. 639300 Département de pathologie et immunologie (PATIM) author Krause Karl-Heinz Department of Pathology and Immunology, Université de Genève Faculté de médecine, Geneve, Switzerland. 23022 Département de pathologie et immunologie (PATIM) author Ferrari Serge Livio Service of Bone Diseases, Department of Medicine, Geneva University Hospitals, Geneve, Switzerland. 24314 Département de médecine (DEMED) author Laumonier Thomas 0000-0002-8662-2972 Department of Cell Physiology and Metabolism, Université de Genève Faculté de médecine, Geneve, Switzerland.,Department of Orthopaedic Surgery, Geneva University Hospitals, Geneve, Switzerland. 135589 Département de chirurgie (CHIRU) author Hannouche Didier 0000-0003-2060-2394 Department of Cell Physiology and Metabolism, Université de Genève Faculté de médecine, Geneve, Switzerland Didier.Hannouche@hcuge.ch.,Department of Orthopaedic Surgery, Geneva University Hospitals, Geneve, Switzerland. 842478 Département de chirurgie (CHIRU) e002856 10.1136/rmdopen-2022-002856 36810185 2056-5933 PMC9945017 https://rmdopen.bmj.com/content/9/1/e002856 Objective: Low-grade inflammation plays a pivotal role in osteoarthritis (OA) through exposure to reactive oxygen species (ROS). In chondrocytes, NADPH oxidase 4 (NOX4) is one of the major ROS producers. In this study, we evaluated the role of NOX4 on joint homoeostasis after destabilisation of the medial meniscus (DMM) in mice. Methods: Experimental OA was simulated on cartilage explants using interleukin-1β (IL-1β) and induced by DMM in wild-type (WT) and NOX4 knockout (NOX4-/-) mice. We evaluated NOX4 expression, inflammation, cartilage metabolism and oxidative stress by immunohistochemistry. Bone phenotype was also determined by micro-CT and histomorphometry. Results: Whole body NOX4 deletion attenuated experimental OA in mice, with a significant reduction of the OARSI score at 8 weeks. DMM increased total subchondral bone plate (SB.Th), epiphysial trabecular thicknesses (Tb.Th) and bone volume fraction (BV/TV) in both NOX4-/-and wild-type (WT) mice. Interestingly, DDM decreased total connectivity density (Conn.Dens) and increased medial BV/TV and Tb.Th only in WT mice. Ex vivo, NOX4 deficiency increased aggrecan (AGG) expression and decreased matrix metalloproteinase 13 (MMP13) and collagen type I (COL1) expression. IL-1β increased NOX4 and 8-hydroxy-2'-deoxyguanosine (8-OHdG) expression in WT cartilage explants but not in NOX4-/-. In vivo, absence of NOX4 increased anabolism and decreased catabolism after DMM. Finally, NOX4 deletion decreased synovitis score, 8-OHdG and F4/80 staining following DMM. Conclusion: NOX4 deficiency restores cartilage homoeostasis, inhibits oxidative stress, inflammation and delays OA progression after DMM in mice. These findings suggest that NOX4 represent a potential target to counteract for OA treatment. Cytokines Inflammation Osteoarthritis Animals Mice Disease Models, Animal NADPH Oxidase 4 / deficiency NADPH Oxidase 4 / genetics Osteoarthritis / genetics Reactive Oxygen Species Mice, Knockout Dewey 612 Dewey 616 Dewey 616.07 Dewey 617 57 Département de chirurgie 222 134 Département de physiologie cellulaire et métabolisme 21C 56 Département de médecine 221 137 Département de pathologie et immunologie 21F false 955 Mécanismes physiopathologiques de l'arthrose 960 38 Radicaux libres et cellules souches embryonnaires 60 289 Génétique des ostéoporoses 544 RMD open 9 1 d22449c1-e73b-4f9f-87eb-3539a9a222be Article (Published version) Public Article-scientifique-from-europePmc.pdf 3999725 application/pdf CC BY-NC-4.0 01f441a28ff4c9143e2d5e68a3191f0cff0bfb2c814b37f4b14cb6cec8ae4901 openAccess Faculté de médecine / Section de médecine clinique / Département de chirurgie Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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NADPH oxidase 4 deficiency attenuates experimental osteoarthritis in mice	RMD open			2023	246	131

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