PMID- 33799469
OWN - NLM
STAT- MEDLINE
DCOM- 20210430
LR  - 20210430
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 6
DP  - 2021 Mar 14
TI  - JNK and p38 Inhibitors Prevent Transforming Growth Factor-beta1-Induced 
      Myofibroblast Transdifferentiation in Human Graves' Orbital Fibroblasts.
LID - 10.3390/ijms22062952 [doi]
LID - 2952
AB  - Transforming growth factor-beta1 (TGF-beta1)-induced myofibroblast transdifferentiation 
      from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in 
      Graves' ophthalmopathy (GO). However, the signaling pathways through which TGF-beta1 
      activates Graves' orbital fibroblasts remain unclear. This study investigated the 
      role of the mitogen-activated protein kinase (MAPK) pathway in TGF-beta1-induced 
      myofibroblast transdifferentiation in human Graves' orbital fibroblasts. The MAPK 
      pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal 
      kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. 
      The expression of connective tissue growth factor (CTGF), alpha-smooth muscle actin 
      (alpha-SMA), and fibronectin representing fibrogenesis was estimated. The activities 
      of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases 
      (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. 
      Specific pharmacologic kinase inhibitors were used to confirm the involvement of 
      the MAPK pathway. After treatment with TGF-beta1, the phosphorylation levels of p38 
      and JNK, but not ERK, were increased. CTGF, alpha-SMA, and fibronectin, as well as 
      TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were 
      inhibited. The effects of TGF-beta1 on the expression of these factors were 
      eliminated by p38 and JNK inhibitors. The results suggested that TGF-beta1 could 
      induce myofibroblast transdifferentiation in human Graves' orbital fibroblasts 
      through the p38 and JNK pathways.
FAU - Hou, Tzu-Yu
AU  - Hou TY
AUID- ORCID: 0000-0001-9424-592X
AD  - Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112, 
      Taiwan.
AD  - School of Medicine, National Yang Ming University, Taipei 112, Taiwan.
AD  - School of Medicine, National Yang Ming Chiao Tung University, Hsinchu 30010, 
      Taiwan.
FAU - Wu, Shi-Bei
AU  - Wu SB
AD  - Biomedical Commercialization Center, Taipei Medical University, Taipei 110, 
      Taiwan.
FAU - Kau, Hui-Chuan
AU  - Kau HC
AD  - Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112, 
      Taiwan.
AD  - School of Medicine, National Yang Ming University, Taipei 112, Taiwan.
AD  - School of Medicine, National Yang Ming Chiao Tung University, Hsinchu 30010, 
      Taiwan.
AD  - Department of Ophthalmology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei 
      112, Taiwan.
FAU - Tsai, Chieh-Chih
AU  - Tsai CC
AUID- ORCID: 0000-0002-4411-3387
AD  - Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112, 
      Taiwan.
AD  - School of Medicine, National Yang Ming University, Taipei 112, Taiwan.
AD  - School of Medicine, National Yang Ming Chiao Tung University, Hsinchu 30010, 
      Taiwan.
LA  - eng
GR  - MOST109-2314-B-075-012/Ministry of Science and Technology, Executive Yuan, 
      Taiwan/
GR  - V110-C-008/Taipei Veterans General Hospital, Taiwan/
PT  - Journal Article
DEP - 20210314
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (ACTA2 protein, human)
RN  - 0 (Actins)
RN  - 0 (CCN2 protein, human)
RN  - 0 (Fibronectins)
RN  - 0 (TGFB1 protein, human)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 139568-91-5 (Connective Tissue Growth Factor)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
SB  - IM
MH  - Actins/genetics
MH  - Cell Transdifferentiation/*genetics
MH  - Cells, Cultured
MH  - Connective Tissue Growth Factor/genetics
MH  - Fibroblasts/drug effects/metabolism
MH  - Fibronectins/genetics
MH  - Gene Expression Regulation, Developmental/drug effects
MH  - Humans
MH  - MAP Kinase Kinase 4/*genetics
MH  - Myofibroblasts/drug effects
MH  - Phosphorylation/drug effects
MH  - Transforming Growth Factor beta1/*genetics/pharmacology
MH  - p38 Mitogen-Activated Protein Kinases/*genetics
PMC - PMC7998969
OTO - NOTNLM
OT  - Graves' ophthalmopathy
OT  - Graves' orbital fibroblasts
OT  - c-Jun N-terminal kinase
OT  - mitogen-activated protein kinase
OT  - p38
OT  - transforming growth factor-beta1
COIS- The authors declare no conflict of interest.
EDAT- 2021/04/04 06:00
MHDA- 2021/05/01 06:00
PMCR- 2021/03/14
CRDT- 2021/04/03 01:02
PHST- 2021/02/06 00:00 [received]
PHST- 2021/03/08 00:00 [revised]
PHST- 2021/03/12 00:00 [accepted]
PHST- 2021/04/03 01:02 [entrez]
PHST- 2021/04/04 06:00 [pubmed]
PHST- 2021/05/01 06:00 [medline]
PHST- 2021/03/14 00:00 [pmc-release]
AID - ijms22062952 [pii]
AID - ijms-22-02952 [pii]
AID - 10.3390/ijms22062952 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Mar 14;22(6):2952. doi: 10.3390/ijms22062952.