PMID- 33778274
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210330
IS  - 2470-1343 (Electronic)
IS  - 2470-1343 (Linking)
VI  - 6
IP  - 11
DP  - 2021 Mar 23
TI  - Feprazone Ameliorates TNF-alpha-Induced Loss of Aggrecan via Inhibition of the 
      SOX-4/ADAMTS-5 Signaling Pathway.
PG  - 7638-7645
LID - 10.1021/acsomega.0c06212 [doi]
AB  - Background: Arthritis is a cartilage degenerative disease that is mainly induced 
      by the degradation of the cartilage extracellular matrix (ECM), which is found to 
      be regulated by the expression level of a disintegrin and metalloproteinase with 
      thrombospondin motifs 5 (ADAMT-5), an enzyme degrading Aggrecans in the ECM. 
      Feprazone is a classic nonsteroidal anti-inflammatory drug with promising 
      efficacy in arthritis. The present study aims to investigate the protective 
      effect of Feprazone on the degraded Aggrecan in the human chondrocytes induced 
      with tumor necrosis factor-alpha (TNF-alpha) and to clarify the underlying mechanism. 
      Methods: To investigate the effect of Feprazone, the CHON-001 chondrocytes were 
      stimulated with TNF-alpha (10 ng/mL) in the presence or absence of Feprazone (3, 6 
      muM) for 24 h. Mitochondrial membrane potential was evaluated using the Rhodamine 
      123 assay. The gene expressions of interleukin-1beta (IL-1beta), interleukin-8 (IL-8), 
      monocyte chemotactic protein 1 (MCP-1), and ADAMTS-5 in the treated chondrocytes 
      were detected using real-time quantitative polymerase chain reaction (qRT-PCR), 
      and the protein levels of these targets were determined using enzyme-linked 
      immunosorbent assay (ELISA). SOX-4 was knocked down by transfecting the siRNA 
      into the chondrocytes. Western blot analysis was utilized to evaluate the 
      expression levels of SOX-4, Aggrecan, and protein kinase C (PKCalpha). Results: 
      First, the reduced mitochondrial membrane potential (DeltaPsi(m)) and secretion of 
      proinflammatory factors (IL-1beta, IL-8, and MCP-1) induced by TNF-alpha were 
      significantly reversed by treatment with Feprazone. Second, the expression of 
      Aggrecan was significantly decreased by stimulation with TNF-alpha via upregulation 
      of ADAMTS-5 but was dramatically reversed by the introduction of Feprazone. 
      Third, we found that TNF-alpha elevated the expression of ADAMTS-5 by upregulating 
      SOX-4, which was observed to be related to the activation of PKCalpha. Lastly, the 
      elevated expression of SOX-4 induced by TNF-alpha was significantly reversed by 
      Feprazone. Conclusions: Feprazone might ameliorate TNF-alpha-induced loss of Aggrecan 
      via the inhibition of the SOX-4/ADAMTS-5 signaling pathway.
CI  - (c) 2021 The Authors. Published by American Chemical Society.
FAU - Xiong, Xiaoyang
AU  - Xiong X
AD  - Department of Joint and orthopedics, Traditional Chinese Medicine Hospital of 
      Kunshan, Suzhou, Jiangsu 215300, China.
FAU - Liu, Liang
AU  - Liu L
AD  - Department of Joint and orthopedics, Traditional Chinese Medicine Hospital of 
      Kunshan, Suzhou, Jiangsu 215300, China.
FAU - Xu, Feng
AU  - Xu F
AD  - Department of Joint and orthopedics, Traditional Chinese Medicine Hospital of 
      Kunshan, Suzhou, Jiangsu 215300, China.
FAU - Wu, Xiaofeng
AU  - Wu X
AD  - Department of Joint and orthopedics, Traditional Chinese Medicine Hospital of 
      Kunshan, Suzhou, Jiangsu 215300, China.
FAU - Yin, Zifei
AU  - Yin Z
AD  - Department of Joint and orthopedics, Traditional Chinese Medicine Hospital of 
      Kunshan, Suzhou, Jiangsu 215300, China.
FAU - Dong, Yi
AU  - Dong Y
AD  - Department of Joint and orthopedics, Traditional Chinese Medicine Hospital of 
      Kunshan, Suzhou, Jiangsu 215300, China.
FAU - Qian, Pingkang
AU  - Qian P
AD  - Department of Joint and orthopedics, Traditional Chinese Medicine Hospital of 
      Kunshan, Suzhou, Jiangsu 215300, China.
LA  - eng
PT  - Journal Article
DEP - 20210312
PL  - United States
TA  - ACS Omega
JT  - ACS omega
JID - 101691658
PMC - PMC7992146
COIS- The authors declare no competing financial interest.
EDAT- 2021/03/30 06:00
MHDA- 2021/03/30 06:01
PMCR- 2021/03/12
CRDT- 2021/03/29 06:40
PHST- 2020/12/21 00:00 [received]
PHST- 2021/02/16 00:00 [accepted]
PHST- 2021/03/29 06:40 [entrez]
PHST- 2021/03/30 06:00 [pubmed]
PHST- 2021/03/30 06:01 [medline]
PHST- 2021/03/12 00:00 [pmc-release]
AID - 10.1021/acsomega.0c06212 [doi]
PST - epublish
SO  - ACS Omega. 2021 Mar 12;6(11):7638-7645. doi: 10.1021/acsomega.0c06212. 
      eCollection 2021 Mar 23.