PMID- 35910349
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220802
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 13
DP  - 2022
TI  - An Inducible Nitric Oxide Synthase Dimerization Inhibitor Prevents the 
      Progression of Osteoarthritis.
PG  - 861183
LID - 10.3389/fphar.2022.861183 [doi]
LID - 861183
AB  - 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 muM) 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-1beta-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-1beta-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.
CI  - Copyright (c) 2022 Xian Bo, Yan Jie, De Chao, Sai, Zhe, Ya Kun, Hui Hui, Chen, 
      Xiao, Zhong Yao, Hao Ran, Ji Sen and Wen Dan.
FAU - Xian Bo, Shang
AU  - Xian Bo S
AD  - Department of Orthopedic, The Second Affiliated Hospital of Anhui Medical 
      University, Hefei, China.
FAU - Yan Jie, Wang
AU  - Yan Jie W
AD  - Department of Orthopedic, Third Affiliated Hospital of Anhui Medical University, 
      Hefei, China.
FAU - De Chao, Cai
AU  - De Chao C
AD  - Department of Orthopedic, The Second Affiliated Hospital of Anhui Medical 
      University, Hefei, China.
FAU - Sai, Ma
AU  - Sai M
AD  - Department of Orthopedic, The Second Affiliated Hospital of Anhui Medical 
      University, Hefei, China.
FAU - Zhe, Wang
AU  - Zhe W
AD  - Department of Orthopedic, The Second Affiliated Hospital of Anhui Medical 
      University, Hefei, China.
FAU - Ya Kun, Zhu
AU  - Ya Kun Z
AD  - Fuyang Hospital of Anhui Medical University, Anhui, China.
FAU - Hui Hui, Guo
AU  - Hui Hui G
AD  - Department of Orthopedic, The Second Affiliated Hospital of Anhui Medical 
      University, Hefei, China.
FAU - Chen, Wang
AU  - Chen W
AD  - Department of Orthopedic, The Second Affiliated Hospital of Anhui Medical 
      University, Hefei, China.
FAU - Xiao, Ma
AU  - Xiao M
AD  - Department of Orthopedic, The Second Affiliated Hospital of Anhui Medical 
      University, Hefei, China.
FAU - Zhong Yao, Hu
AU  - Zhong Yao H
AD  - Department of Orthopedic, The Second Affiliated Hospital of Anhui Medical 
      University, Hefei, China.
FAU - Hao Ran, Yu
AU  - Hao Ran Y
AD  - Department of Orthopedic, The Second Affiliated Hospital of Anhui Medical 
      University, Hefei, China.
FAU - Ji Sen, Zhang
AU  - Ji Sen Z
AD  - Department of Orthopedic, The Second Affiliated Hospital of Anhui Medical 
      University, Hefei, China.
FAU - Wen Dan, Cheng
AU  - Wen Dan C
AD  - Department of Orthopedic, The Second Affiliated Hospital of Anhui Medical 
      University, Hefei, China.
LA  - eng
PT  - Journal Article
DEP - 20220715
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC9334866
OTO - NOTNLM
OT  - extracellular matrix
OT  - inducible nitric oxide synthase
OT  - inhibitor
OT  - nitric oxide
OT  - osteoarthritis
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/08/02 06:00
MHDA- 2022/08/02 06:01
PMCR- 2022/07/15
CRDT- 2022/08/01 03:29
PHST- 2022/01/24 00:00 [received]
PHST- 2022/06/17 00:00 [accepted]
PHST- 2022/08/01 03:29 [entrez]
PHST- 2022/08/02 06:00 [pubmed]
PHST- 2022/08/02 06:01 [medline]
PHST- 2022/07/15 00:00 [pmc-release]
AID - 861183 [pii]
AID - 10.3389/fphar.2022.861183 [doi]
PST - epublish
SO  - Front Pharmacol. 2022 Jul 15;13:861183. doi: 10.3389/fphar.2022.861183. 
      eCollection 2022.