Adiponectin Is Involved in Connective Tissue Growth Factor-Induced Proliferation,
Migration and Overproduction of the Extracellular Matrix in Keloid Fibroblasts
#MMPMID28498357
Luo L
; Li J
; Liu H
; Jian X
; Zou Q
; Zhao Q
; Le Q
; Chen H
; Gao X
; He C
Int J Mol Sci
2017[May]; 18
(5
): ? PMID28498357
show ga
Adiponectin, an adipocyte-derived hormone, exerts pleiotropic biological effects
on metabolism, inflammation, vascular homeostasis, apoptosis and immunity.
Recently, adiponectin has been suggested to attenuate the progression of human
dermal fibrosis. Connective tissue growth factor (CTGF) is induced in keloids and
is thought to be participated in the formation of keloid fibrosis. However, the
roles played by adiponectin in keloids remain unclear. In this study, we explored
the effects of adiponectin on CTGF-induced cell proliferation, migration and the
deposition of extracellular matrix (ECM) and their associated intracellular
signalling pathways in keloid fibroblasts (KFs). We also explored possible
mechanisms of keloid pathogenesis. Primary fibroblast cultures were established
from foreskin biopsies and skin biopsies from patients with keloids. The
expression of adiponectin and adiponectin receptors (adipoRs) was evaluated by
reverse transcription-PCR (RT-PCR), quantitative real-time RT-PCR,
immunofluorescence staining, and immunohistochemical analysis. Next, KFs and
normal dermal fibroblasts (NFs) were treated with CTGF in the presence or absence
of adiponectin. A cell counting kit-8 (CCK-8) and the Transwell assay were used
to examine cell proliferation and migration. The level of the collagen I,
fibronectin (FN) and ?-smooth muscle actin (?-SMA) mRNAs and proteins were
determined by quantitative real-time RT-PCR and western blotting. The effects of
RNA interference (RNAi) targeting the adipoR genes were detected. Phosphorylation
of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK),
mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase-protein
kinase (PI3K-Akt) were examined by western blotting to further investigate the
signalling pathways. Furthermore, inhibitors of signal transduction pathways were
investigated. The expression levels of adiponectin and adipoRs were significantly
decreased in keloids compared with those in normal skin tissue. Adiponectin
suppressed the CTGF-induced KFs, but not NFs, proliferation, migration and ECM
production. Moreover, adiponectin inhibited the phosphorylation of AMPK, p38 and
extracellular-regulated kinase (ERK), but not that of Jun N-terminal kinase (JNK)
or Akt, in CTGF-treated KFs. The activity of adiponectin-mediated signalling
pathways was attenuated by small interfering RNAs (siRNAs) targeting adipoR1 (but
not siRNAs targeting adipoR2, T-cadherin or calreticulin), AMPK (Compound C), p38
(SB203580) inhibitors, and mitogen-activated protein kinase kinase (MEK)
inhibitor (PD98059). Based on our results, adiponectin suppresses CTGF-induced
KFs proliferation, migration and ECM overproduction. One of the underlying
mechanisms is the activation of the adipoR1, AMPK, p38, and ERK signalling
pathways. Therefore, adiponectin may play an important role in the progression of
keloids, suggesting a potential novel target for keloid treatment.
free
free
free
