PMID- 31075239
OWN - NLM
STAT- MEDLINE
DCOM- 20200113
LR  - 20200113
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Linking)
VI  - 856
DP  - 2019 Aug 5
TI  - Activation of G-protein-coupled bile acid receptor Gpbar1 (TGR5) inhibits 
      degradation of type II collagen and aggrecan in human chondrocytes.
PG  - 172387
LID - S0014-2999(19)30320-6 [pii]
LID - 10.1016/j.ejphar.2019.05.016 [doi]
AB  - Abnormal loss of components of the extracellular matrix (ECM) including type II 
      collagen and aggrecan caused by proinflammatory cytokines such as tumor necrosis 
      factor-alpha (TNF-alpha) is an important pathophysiological characteristic of 
      osteoarthritis (OA). G-protein-coupled bile acid receptor, Gpbar1 (TGR5), is an 
      important member of the bile acid receptor subclass of G Protein-Coupled 
      Receptors (GPCRs). Little information regarding the effects of TGR5 in the 
      pathological development of OA has been reported before. In the current study, we 
      showed that TGR5 is expressed in human primary chondrocytes and human 
      chondrosarcoma SW1353 cells. Interestingly, expression of TGR5 was reduced in 
      response to TNF-alpha treatment in SW1353 cells. Our results indicate that activation 
      of TGR5 using its specific agonist INT-777 reduced TNF-alpha-induced degradation of 
      the articular ECM, including type II collagen and aggrecan, by inhibiting 
      expression of matrix metalloproteinase-3 (MMP-3), MMP-13, a disintegrin and 
      metalloproteinase with thrombospondin motifs- 4 (ADAMTS-4) and ADAMTS-5. We also 
      found that INT-777 treatment inhibited phosphorylation of p38 and activation of 
      the IkappaB kinase/inhibitory kappaBalpha/nuclear factor- kappaB (IKK/IkappaBalpha/NF-kappaB) signaling 
      pathway. Notably, knockdown of TGR5 abolished the protective effects of INT-777 
      against ECM degradation, suggesting the involvement of TGR5. Our findings 
      implicate that TGR5 might be considered as a potential therapeutic target for the 
      treatment of OA.
CI  - Copyright (c) 2019 Elsevier B.V. All rights reserved.
FAU - Zhuo, Wenkun
AU  - Zhuo W
AD  - Department of Orthopedics and Traumatology, Jinan Military General Hospital, 
      Jinan, 250031, Shandong, China.
FAU - Li, Bingsheng
AU  - Li B
AD  - Department of Orthopedics and Traumatology, Jinan Military General Hospital, 
      Jinan, 250031, Shandong, China.
FAU - Zhang, Dawei
AU  - Zhang D
AD  - Department of Orthopedics and Traumatology, Jinan Military General Hospital, 
      Jinan, 250031, Shandong, China. Electronic address: zdwasy6161@163.com.
LA  - eng
PT  - Journal Article
DEP - 20190507
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Aggrecans)
RN  - 0 (Collagen Type II)
RN  - 0 (GPBAR1 protein, human)
RN  - 0 (Receptors, G-Protein-Coupled)
SB  - IM
MH  - Aggrecans/*metabolism
MH  - Chondrocytes/cytology/*metabolism
MH  - Collagen Type II/*metabolism
MH  - Extracellular Matrix/metabolism
MH  - Humans
MH  - *Proteolysis
MH  - Receptors, G-Protein-Coupled/*metabolism
OTO - NOTNLM
OT  - Chondrocytes
OT  - Extracellular matrix (ECM)
OT  - Osteoarthritis (OA)
OT  - TGR5
OT  - TNF-alpha
EDAT- 2019/05/11 06:00
MHDA- 2020/01/14 06:00
CRDT- 2019/05/11 06:00
PHST- 2019/01/30 00:00 [received]
PHST- 2019/04/24 00:00 [revised]
PHST- 2019/05/06 00:00 [accepted]
PHST- 2019/05/11 06:00 [pubmed]
PHST- 2020/01/14 06:00 [medline]
PHST- 2019/05/11 06:00 [entrez]
AID - S0014-2999(19)30320-6 [pii]
AID - 10.1016/j.ejphar.2019.05.016 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2019 Aug 5;856:172387. doi: 10.1016/j.ejphar.2019.05.016. Epub 
      2019 May 7.