Regulation of collagen turnover in human skin fibroblasts exposed to a gadolinium-based contrast agent.
OBJECTIVE
Nephrogenic systemic fibrosis is a clinical syndrome linked with exposure in renal failure patients to gadolinium-based contrast agents (GBCAs) during magnetic resonance imaging. Recently, we demonstrated that GBCA exposure led to increased matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels in human skin fibroblasts. The goals of the present work were to assess the relationship between altered MMP-1/TIMP-1 expression and collagen production/deposition, and the intracellular signaling events that lead from GBCA stimulation to altered MMP-1 and TIMP-1 production.


METHODS
Human dermal fibroblasts were treated with one of the currently used GBCAs (Omniscan). Proliferation was quantified as were levels of MMP-1, TIMP-1, procollagen type I, and collagen type I. Signaling events were concomitantly assessed, and signaling inhibitors were used.


RESULTS
Fibroblasts exposed to Omniscan had increases in both MMP-1 and TIMP-1 levels. Omniscan treatment interfered with collagen turnover, leading to increased type I collagen deposition without an increase in type I procollagen production. U0126, an inhibitor of mitogen-activated protein kinase signaling, and LY294002, a phosphatidylinositol-3 kinase inhibitor, reduced MMP-1 levels. U0126 also reduced TIMP-1 levels, but LY294002 increased TIMP-1.


CONCLUSIONS
These data provide evidence for complex regulation of collagen deposition in Omniscan-treated skin. They suggest that the major effect of Omniscan exposure is on an enzyme/inhibitor system that regulates collagen breakdown rather than on collagen production, per se.
Bhagavathula
Narasimharao
N
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
DaSilva
Marissa
M
Aslam
Muhammad N
MN
Dame
Michael K
MK
Warner
Roscoe L
RL
Xu
Yiru
Y
Fisher
Gary J
GJ
Johnson
Kent J
KJ
Swartz
Richard
R
Varani
James
J
D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D003287:Contrast Media / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D019786:Gadolinium DTPA / Q000008:administration & dosage*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*
D003287:Contrast Media; D019715:Tissue Inhibitor of Metalloproteinase-1; C064925:gadodiamide; D003094:Collagen; D020781:Matrix Metalloproteinase 1; D019786:Gadolinium DTPA