Insulin-like growth factor binding protein 5 induces skin fibrosis: A novel murine model for dermal fibrosis

Hidekata Yasuoka, Drazen M. Jukic, Zhihong Zhou, Augustine M.K. Choi, Carol A. Feghali-Bostwick

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

Objective. To determine the role of insulin-like growth factor binding protein 5 (IGFBP-5) in the development of skin fibrosis in vivo, by examining the effect of overexpression of IGFBP-5 in mouse skin. Methods. Wild-type C57BL/6J mice were injected subcutaneously with replication-deficient serotype 5 adenovirus expressing human IGFBP-3 (Ad3), IGFBP-5 (Ad5), or no complementary DNA (cAd). Mice were killed 3, 8, or 22 days postinjection. The dermal thickness and dermal collagen bundle thickness in skin sections were measured. The deposition of collagen in the extracellular matrix (ECM) was quantified using the Sircol assay. Expression of proliferating cell nuclear antigen (PCNA) and fibronectin, as determined by immunohistochemical analysis, was used to evaluate fibroblast activation, and vimentin and α-smooth muscle actin (α-SMA) were used to evaluate the fibroblast phenotype. Results. Adenovirally expressed IGFBP was detected in dermal fibroblasts, endothelial cells, epithelial cells, and muscle bundles in Ad3- and Ad5-injected mice. Increased collagen deposition, denser dermal connective tissue, and increased collagen bundle thickness were observed in IGFBP-5-overexpressing mice. Dermal thickness and collagen bundle thickness were significantly increased in Ad5-injected mice compared with cAd- and Ad3-injected mice. Treatment with Ad5 resulted in a dose-dependent increase in dermal and collagen bundle thickness. Increased deposition of collagen and fibronectin, increased numbers of PCNA-positive fibroblasts, as well as increased numbers of vimentin- and α-SMA-double-positive fibroblasts were detected in the dermis of IGFBP-5-overexpressing mouse skin. Conclusion. IGFBP-5 is a key mediator of fibrosis. IGFBP-5 mediates its profibrotic effects through fibroblast activation, increased ECM deposition, and myofibroblastic transformation of dermal fibroblasts. Overexpression of IGFBP-5 provides a novel model for studying the pathogenesis of skin fibrosis in systemic sclerosis.

Original languageEnglish
Pages (from-to)3001-3010
Number of pages10
JournalArthritis and Rheumatism
Volume54
Issue number9
DOIs
Publication statusPublished - 2006 Sep

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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