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Gadolinium-induced fibrosis is counter-regulated by CCN3 in human dermal fibroblasts: a model for potential treatment of nephrogenic systemic fibrosis

  • Bruce L. RiserEmail author
  • Narasimharao Bhagavathula
  • Patricia Perone
  • Kendra Garchow
  • Yiru Xu
  • Gary J. Fisher
  • Feridoon Najmabadi
  • Durga Attili
  • James Varani
Research Article

Abstract

We recently show that CCN3 is a counter-regulatory molecule for the pro-fibrotic protein CCN2, and a potentially novel fibrosis therapy. The goal of this study was to assess the role of CCN3 in fibroproliferative/fibrotic responses in human dermal fibroblasts exposed to Omniscan, one of the gadolinium-based contrast agents associated with development of nephrogenic systemic fibrosis (NSF) a rare but life-threatening disease thought to be complication of NMR diagnostics in renal impaired patients. Human dermal fibroblasts were exposed to Omniscan; or to platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) as controls. Proliferation was assessed along with matrix metalloproteinase-1, tissue inhibitor of metalloproteinases-1 and type 1 procollagen in the absence and presence of CCN3. In parallel, CCN3 production was assessed in control and Omniscan-treated cells. The results showed that PDGF stimulated fibroblast proliferation, production of Timp-1 and MMP-1 whereas exogenous CCN3 inhibited, in a dose response manner, cell proliferation (approx. 50 % max.) and production of MMP-1 (approx 35 % max.) but had little effect on TIMP-1. TGF-β stimulated type 1 procollagen production but not proliferation, Timp-1 or MMP-1 compared to non-TGF-ß treated control cells, and CCN3 treatment blocked (approx. 80 % max.) this up-regulation. Interestingly, untreated, control fibroblasts produced high constitutive levels of CCN3 and concentrations of Omniscan that induced fibroproliferative/fibrogenic changes in dermal fibroblasts correspondingly suppressed CCN3 production. The use of PDGF and TGF-β as positive controls, and the study of differential responses, including that to Omniscan itself, provide the first evidence for a role of fibroblast-derived CCN3 as an endogenous regulator of pro-fibrotic changes, elucidating possible mechanism(s). In conclusion, these data support our hypothesis of a role for fibroblast-derived CCN3 as an endogenous regulator of pro-fibrotic changes in these cells, and suggest that CCN3 may be an important regulatory molecule in NSF and a target for treatment in this and other fibrotic diseases.

Keywords

Nephroblastoma overexpressed gene (NOV) [CCN3] Gadolinium-based contrast agent (GBCA) Matrix metalloproteinase-1 (MMP-1) Platelet-derived growth factor (PDGF) Tissue inhibitor of metalloprotienases-1 (TIMP-1) Nephrogenic systemic fibrosis (NSF) 

Notes

Acknowledgments

This study was supported by a grant from Baxter Healthcare Corporation (BLR), and grants from the National Institutes of Health, Bethesda, MD (CA140760; JV), and from the Association for International Cancer Research, St. Andrews, Fife, Scotland (11–0577 JV).

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Copyright information

© The International CCN Society 2012

Authors and Affiliations

  • Bruce L. Riser
    • 1
    • 2
    Email author
  • Narasimharao Bhagavathula
    • 3
  • Patricia Perone
    • 3
  • Kendra Garchow
    • 1
  • Yiru Xu
    • 4
  • Gary J. Fisher
    • 4
  • Feridoon Najmabadi
    • 1
  • Durga Attili
    • 3
  • James Varani
    • 3
  1. 1.Department of Physiology and BiophysicsRosalind Franklin University of Science and MedicineNorth ChicagoUSA
  2. 2.Medical Products DivisionBaxter Healthcare CorporationRound LakeUSA
  3. 3.Department of PathologyThe University of Michigan Medical SchoolAnn ArborUSA
  4. 4.Department of DermatologyThe University of Michigan Medical SchoolAnn ArborUSA

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