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Published on: January 31, 2014
Collagenolytic activity is suppressed in organ-cultured human skin exposed to a gadolinium-based MRI contrast agent
Patricia A Perone1, Stephanie L Weber, Marissa DaSilva
1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Objective:
Human skin produces increased amounts of matrix metalloproteinase-1 (MMP-1) when exposed in organ culture to Omniscan, one of the gadolinium-based MRI contrast agents (GBCA). MMP-1, by virtue of its ability to degrade structural collagen, contributes to collagen turnover in the skin. The objective of the present study was to determine whether collagenolytic activity was concomitantly up-regulated with increased enzyme.
Materials And Methods:
Skin biopsies from normal volunteers were exposed in organ culture to Omniscan. Organ culture fluids obtained from control and treated skin were examined for ability to degrade type I collagen. The same culture fluids were examined for levels of MMP-1, tissue inhibitor of metalloproteinases-1 (TIMP-1), and complexes of MMP-1 and TIMP-1.
Results:
Although MMP-1 was increased in culture fluid from Omniscan-treated skin, there was no increase in collagenolytic activity. In fact, collagenolytic activity declined. Increased production of TIMP-1 was also observed in Omniscan-treated skin, and the absolute amount of TIMP-1 was greater than the amount of MMP-1. Virtually all of the MMP-1 was present in MMP-1-TIMP-1 complexes, but the majority of TIMP-1 was not associated with MMP-1. When human dermal fibroblasts were exposed to TIMP-1 (up to 250 ng/mL), no increase in proliferation was observed, but an increase in collagen deposition into the cell layer was seen.
Conclusion:
Gadolinium-based MRI contrast agent exposure has recently been linked to a fibrotic skin condition in patients with impaired kidney function. The mechanism is unknown. The increase in TIMP-1 production and concomitant reduction in collagenolytic activity demonstrated here could result in decreased collagen turnover and increased deposition of collagen in lesional skin.
Insights
Gadolinium-based MRI contrast agents like Omniscan increase tissue inhibitor of metalloproteinases-1 (TIMP-1) in skin, reducing collagen breakdown. This may explain fibrotic skin conditions linked to these agents.
Area of Science:
- Dermatology
- Biochemistry
- Radiology
Background:
- Gadolinium-based contrast agents (GBCAs) are used in MRI scans.
- Human skin exposed to Omniscan, a GBCA, shows increased matrix metalloproteinase-1 (MMP-1).
- MMP-1 degrades collagen, impacting skin structure and turnover.
Purpose of the Study:
- To investigate if collagenolytic activity increases with elevated MMP-1 levels after Omniscan exposure.
- To determine the effect of Omniscan on collagen degradation in human skin organ cultures.
Main Methods:
- Human skin biopsies were cultured with and without Omniscan.
- Culture fluids were analyzed for collagenolytic activity, MMP-1, tissue inhibitor of metalloproteinases-1 (TIMP-1), and MMP-1/TIMP-1 complexes.
- Human dermal fibroblasts were exposed to TIMP-1 to assess proliferation and collagen deposition.
Main Results:
- Omniscan exposure increased MMP-1 but decreased collagenolytic activity.
- TIMP-1 production was elevated, with higher levels than MMP-1.
- Most MMP-1 existed as MMP-1/TIMP-1 complexes; excess TIMP-1 did not affect fibroblast proliferation but increased collagen deposition.
Conclusions:
- Increased TIMP-1 and reduced collagenolysis following GBCA exposure may lead to decreased collagen turnover.
- This mechanism could contribute to collagen deposition observed in fibrotic skin conditions associated with GBCAs.
- Further research is needed to understand the link between GBCAs and fibrotic skin reactions.
