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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050840-09
Application #
8265727
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Tseng, Hung H
Project Start
2003-09-30
Project End
2013-09-30
Budget Start
2012-06-01
Budget End
2013-09-30
Support Year
9
Fiscal Year
2012
Total Cost
$316,768
Indirect Cost
$107,680
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
Yasuoka, Hidekata; Yamaguchi, Yukie; Feghali-Bostwick, Carol A (2014) The membrane-associated adaptor protein DOK5 is upregulated in systemic sclerosis and associated with IGFBP-5-induced fibrosis. PLoS One 9:e87754
Aida-Yasuoka, Keiko; Peoples, Christine; Yasuoka, Hidekata et al. (2013) Estradiol promotes the development of a fibrotic phenotype and is increased in the serum of patients with systemic sclerosis. Arthritis Res Ther 15:R10
Ruiz, Ximena D; Mlakar, Logan R; Yamaguchi, Yukie et al. (2012) Syndecan-2 is a novel target of insulin-like growth factor binding protein-3 and is over-expressed in fibrosis. PLoS One 7:e43049
Yamaguchi, Yukie; Takihara, Takahisa; Chambers, Roger A et al. (2012) A peptide derived from endostatin ameliorates organ fibrosis. Sci Transl Med 4:136ra71
Brissett, Monique; Veraldi, Kristen L; Pilewski, Joseph M et al. (2012) Localized expression of tenascin in systemic sclerosis-associated pulmonary fibrosis and its regulation by insulin-like growth factor binding protein 3. Arthritis Rheum 64:272-80
Yamaguchi, Yukie; Yasuoka, Hidekata; Stolz, Donna B et al. (2011) Decreased caveolin-1 levels contribute to fibrosis and deposition of extracellular IGFBP-5. J Cell Mol Med 15:957-69
Lam, Anna P; Flozak, Annette S; Russell, Susan et al. (2011) Nuclear β-catenin is increased in systemic sclerosis pulmonary fibrosis and promotes lung fibroblast migration and proliferation. Am J Respir Cell Mol Biol 45:915-22
Hsu, Eileen; Shi, Haiwen; Jordan, Rick M et al. (2011) Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension. Arthritis Rheum 63:783-94

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