Regulation of collagen turnover in human skin fibroblasts exposed to a gadolinium-based contrast agent.

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Bhagavathula N, DaSilva M, Aslam MN, Dame MK, Warner RL, Xu Y, Fisher GJ, Johnson KJ, Swartz R, Varani J

Regulation of collagen turnover in human skin fibroblasts exposed to a gadolinium-based contrast agent.

Invest Radiol. 2009 Aug;44(8):433-9. doi: 10.1097/RLI.0b013e3181a4d7e9.

PubMed ID
19561517 [ View in PubMed
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Abstract

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. MATERIALS AND 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. CONCLUSION: 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.