Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2007 Oct;56(10):3468-77.
doi: 10.1002/art.22874.

Down-regulation of collagen and connective tissue growth factor expression with hepatocyte growth factor in lung fibroblasts from white scleroderma patients via two signaling pathways

Galina S Bogatkevich  1 , Anna Ludwicka-Bradley, Kristin B Highland, Faye Hant, Paul J Nietert, C Beth Singleton, Richard M Silver
Affiliations
Free article

Down-regulation of collagen and connective tissue growth factor expression with hepatocyte growth factor in lung fibroblasts from white scleroderma patients via two signaling pathways

Galina S Bogatkevich et al. Arthritis Rheum. 2007 Oct.
Free article

Abstract

Objective: To study the mechanisms by which hepatocyte growth factor (HGF) down-regulates collagen and connective tissue growth factor (CTGF) in scleroderma (systemic sclerosis [SSc]) lung fibroblasts.

Methods: CTGF, type I collagen, and IkappaBalpha expression, together with MAPK phosphorylation, were studied by immunoblotting of lung fibroblasts derived from white SSc patients. Matrix metalloproteinase 1 (MMP-1) expression in cell culture medium samples was measured by enzyme-linked immunosorbent assay, MMP-1 activity was studied using an MMP-1 assay, and NF-kappaB DNA binding activity was determined using a transcription factor assay.

Results: In lung fibroblasts from white SSc patients, HGF activated MAPK (ERK-1/2) signaling pathways and MMP-1, while it inhibited NF-kappaB and significantly down-regulated CTGF and collagen in a time- and dose-dependent manner. Small interfering RNA (siRNA)-mediated depletion of Grb2 expression disrupted c-Met receptor downstream signaling, which resulted in diminished HGF-induced ERK-1/2 phosphorylation and the recovery of HGF-inhibited expression of MMP-1, NF-kappaB, collagen, and CTGF. The MAPK inhibitor, U0126, blocked MMP-1 activity and restored HGF-inhibited collagen and CTGF accumulation. Inhibition of MMP activity by MMP inhibitor GM1489 and inhibition of MMP-1 expression by siRNA did not prevent HGF-induced ERK-1/2 phosphorylation and NF-kappaB activity, but significantly restored HGF-inhibited collagen and CTGF accumulation. NF-kappaB inhibitor BAY 11-7082 did not interfere with MAPK phosphorylation or MMP-1 expression and activation, but significantly inhibited NF-kappaB DNA binding activity and acted synergistically with HGF to completely diminish the expression of CTGF.

Conclusion: In lung fibroblasts from white SSc patients, HGF down-regulates the accumulation of CTGF via MAPK/MMP-1 and NF-kappaB signaling pathways, whereas collagen down-regulation is mediated mainly by a MAPK/MMP-1-dependent pathway.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

Publication types

MeSH terms

Substances