An Inducible Nitric Oxide Synthase Dimerization Inhibitor Prevents the Progression of Osteoarthritis

Shang Xian Bo; Wang Yan Jie; Cai De Chao; Ma Sai; Wang Zhe; Zhu Ya Kun; Guo Hui Hui; Wang Chen; Ma Xiao; Hu Zhong Yao; Yu Hao Ran; Zhang Ji Sen; Cheng Wen Dan

doi:10.3389/fphar.2022.861183

An Inducible Nitric Oxide Synthase Dimerization Inhibitor Prevents the Progression of Osteoarthritis

Front Pharmacol. 2022 Jul 15:13:861183. doi: 10.3389/fphar.2022.861183. eCollection 2022.

Authors

Shang Xian Bo¹, Wang Yan Jie², Cai De Chao¹, Ma Sai¹, Wang Zhe¹, Zhu Ya Kun³, Guo Hui Hui¹, Wang Chen¹, Ma Xiao¹, Hu Zhong Yao¹, Yu Hao Ran¹, Zhang Ji Sen¹, Cheng Wen Dan¹

Affiliations

¹ Department of Orthopedic, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
² Department of Orthopedic, Third Affiliated Hospital of Anhui Medical University, Hefei, China.
³ Fuyang Hospital of Anhui Medical University, Anhui, China.

Abstract

Objective: Osteoarthritis (OA) is a degenerative joint disease. Excessive nitric oxide (NO) mediates the chondrocyte inflammatory response, apoptosis, and extracellular matrix (ECM) degradation during the occurrence and development of OA. NO in chondrocytes is mainly produced by inducible nitric oxide synthase (iNOS). The aim of this study was to design and synthesize an iNOS dimerization inhibitor and evaluate its effects on chondrocyte inflammation and articular cartilage injury in OA via in vitro and in vivo experiments. Design: The title compound 22o was designed, synthesized, and screened based on a previous study. The effects of different concentrations (5, 10, and 20 μM) of compound 22o on chondrocyte inflammatory response and ECM anabolism or catabolism were evaluated by Western blot and real-time quantitative reverse transcription-polymerase chain reaction using the rat chondrocyte model of IL-1β-induced OA. Furthermore, different doses (40 and 80 mg/kg) of compound 22o were administered by gavage to a rat OA model induced by anterior cruciate ligament transection (ACLT), and their protective effects on the articular cartilage were evaluated by histopathology and immunohistochemistry. Results: Compound 22o showed effective iNOS inhibitory activity by inhibiting the dimerization of iNOS. It inhibited the IL-1β-induced expression of cyclooxygenase-2 (COX-2) and matrix metalloproteinase 3 (MMP3) in the chondrocytes, decreased NO production, and significantly increased the expression levels of the ECM anabolic markers, aggrecan (ACAN), and collagen type II (COL2A1). Gavage with compound 22o was found to be effective in the rat OA model induced by ACLT, wherein it regulated the anabolism and catabolism and exerted a protective effect on the articular cartilage. Conclusions: Compound 22o inhibited the inflammatory response and catabolism of the chondrocytes and reduced articular cartilage injury in the rat OA model, indicating its potential as a disease-modifying OA drug.

Keywords: extracellular matrix; inducible nitric oxide synthase; inhibitor; nitric oxide; osteoarthritis.