Epigallocatechin-3-gallate inhibits lysophosphatidic acid-stimulated connective tissue growth factor via JNK and Smad3 suppression in human gingival fibroblasts.
OBJECTIVE
Connective tissue growth factor (CTGF/CCN2) is involved in the development and progression of fibrotic diseases, including gingival overgrowth (GO). Recent studies indicate that lysophosphatidic acid (LPA) is also significantly involved in wound healing and the development of fibrosis. This study investigated whether epigallocatechin-3-gallate (EGCG) can inhibit LPA-induced CCN2 expression in human gingival fibroblast (GF) and its mechanism.


METHODS
Western blot analyses were used to study the signaling pathways of LPA-induced CCN2 expression in human GFs and the effects of EGCG on this pathway.


RESULTS
LPA stimulated CCN2 synthesis in human GFs. This effect can be significantly inhibited bytransforming growth factor-β type I receptor/ALK5, Smad3, and JNK inhibitors but not ERK, P38, and MAPK inhibitors. EGCG completely inhibited LPA-induced CCN2 expression through attenuating the LPA-induced JNK and Smad3 phosphorylation in human GFs.


CONCLUSIONS
LPA produced at the surgical wound may contribute to the recurrence of GO by upregulating CCN2 expression in human GFs. This effect was mediated by Smad3 and JNK activation and ALK5 transactivation. EGCG could be a useful agent for reducing the recurrence of GO after surgery through suppression of JNK and Smad3 activations.
School of Dentistry and Department of Dentistry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chen-Ying
CY
Wang
School of Dentistry and Department of Dentistry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
Yi-Ting
YT
Deng
School of Dentistry and Department of Dentistry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
Shih-Yung
SY
Huang
School of Dentistry and Department of Dentistry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
Cheing-Meei
CM
Liu
School of Dentistry and Department of Dentistry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
Hao-Hueng
HH
Chang
School of Dentistry and Department of Dentistry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: veronica@ntuh.gov.tw.
Man-Ying
MY
Wong
D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000032:analysis / Q000502:physiology*; D003474:Curcumin / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism*; D005881:Gingiva / Q000166:cytology*; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D051900:Smad3 Protein / Q000037:antagonists & inhibitors*; D014945:Wound Healing / Q000187:drug effects
D008246:Lysophospholipids; D051900:Smad3 Protein; D055513:Connective Tissue Growth Factor; D002392:Catechin; C045651:epigallocatechin gallate; D048670:MAP Kinase Kinase 4; D003474:Curcumin; C032881:lysophosphatidic acid
CTGF/CCN2; EGCG; JNK; LPA; Smad3; gingival overgrowth