Systemic sclerosis (SSc) is an idiopathic connective tissue disease of unknown etiology that leads to debilitating and life-threatening fibrosis. Currently, no effective therapeutic or curative measures are available. We have recently made the novel observation of a significant increase in Insulin-Like Growth Factor Binding Protein-5 (IGFBP-5) expression in skin fibroblasts from patients with systemic sclerosis. We have further demonstrated increased IGFBP-5 in lung tissues of patients with pulmonary fibrosis and in primary fibroblasts cultured from these tissues. Furthermore, we have shown that IGFBP-5 is pro- fibrotic both in vitro and in vivo, suggesting that IGFBP-5 can initiate and perpetuate the fibrotic response. Collectively, our findings establish IGFBP-5 as a novel pro-fibrotic factor. We now demonstrate that IGFBP-5 induces reactive oxygen species (ROS) generation in primary fibroblasts. We also demonstrate trafficking of IGFBP-5 to caveolar and nuclear compartments. Furthermore, we show that IGFBP-5 induces expression and nuclear translocation of a novel DOK/IRS protein. We hypothesize that IGFBP-5 is a novel mediator of fibrosis that exerts its effects via a redox-sensitive signaling cascade. Moreover, IGFBP-5 trafficking and its pro-fibrotic activity are caveolin-dependent and involve induction of DOK5/IRS6 and nucleocytoplasmic shuttling of IGFBP-5 and DOK5/IRS6.
Our specific aims are designed to test our hypothesis. We plan to 1) determine the role of redox-sensitive and -insensitive pathways in mediating the fibrotic effects of IGFBP-5, 2) determine whether the new DOK/IRS protein, DOK5/IRS6, induced by IGFBP-5, mediates its fibrotic effects, and 3) examine the role of nuclear compartmentalization of IGFBP-5 in its fibrotic activity. It is thus our goal to determine the mechanism by which IGFBP-5 induces fibrosis using a combination of in vitro, in vivo, and organ culture approaches. Completion of these aims will define the mechanism for the pro-fibrotic effects of IGFBP-5, and potentially identify novel therapeutic targets for the treatment of SSc and other fibrosing diseases.

Public Health Relevance

The proposed studies will yield new insights into the mechanism of action of IGFBP-5, a novel mediator of fibrosis. Our studies will also generate new targets for the development of future therapies for the treatment of systemic sclerosis and other fibrotic diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Tseng, Hung H
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Su, Yunyun; Nishimoto, Tetsuya; Feghali-Bostwick, Carol (2015) IGFBP-5 Promotes Fibrosis Independently of Its Translocation to the Nucleus and Its Interaction with Nucleolin and IGF. PLoS One 10:e0130546
Fan, Ming-Hui; Feghali-Bostwick, Carol A; Silver, Richard M (2014) Update on scleroderma-associated interstitial lung disease. Curr Opin Rheumatol 26:630-6
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