Document Detail

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.
MedLine Citation:
PMID:  17907155     Owner:  NLM     Status:  MEDLINE    
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.
Galina S Bogatkevich; Anna Ludwicka-Bradley; Kristin B Highland; Faye Hant; Paul J Nietert; C Beth Singleton; Richard M Silver
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  56     ISSN:  0004-3591     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2007 Oct 
Date Detail:
Created Date:  2007-10-22     Completed Date:  2007-12-13     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3468-77     Citation Subset:  AIM; IM    
Medical University of South Carolina, Charleston, SC 29425, USA.
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MeSH Terms
Cell Culture Techniques
Collagen Type I / biosynthesis*
Connective Tissue Growth Factor
Enzyme-Linked Immunosorbent Assay
European Continental Ancestry Group
Fibroblasts / metabolism*
Hepatocyte Growth Factor / biosynthesis*
Immediate-Early Proteins / biosynthesis*
Intercellular Signaling Peptides and Proteins / biosynthesis*
Lung / metabolism
MAP Kinase Signaling System
Matrix Metalloproteinase 1 / metabolism
Mitogen-Activated Protein Kinase Kinases / metabolism
NF-kappa B / metabolism
Scleroderma, Systemic / metabolism*
Grant Support
K01-AR-051052/AR/NIAMS NIH HHS; P60-AR-049459-01/AR/NIAMS NIH HHS
Reg. No./Substance:
0/CTGF protein, human; 0/Collagen Type I; 0/Immediate-Early Proteins; 0/Intercellular Signaling Peptides and Proteins; 0/NF-kappa B; 139568-91-5/Connective Tissue Growth Factor; 67256-21-7/Hepatocyte Growth Factor; EC Protein Kinase Kinases; EC Metalloproteinase 1

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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