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
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
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 ?-catenin is increased in systemic sclerosis pulmonary fibrosis and promotes lung fibroblast migration and proliferation. Am J Respir Cell Mol Biol 45:915-22
Fertig, Noreen; Domsic, Robyn T; Rodriguez-Reyna, Tatiana et al. (2009) Anti-U11/U12 RNP antibodies in systemic sclerosis: a new serologic marker associated with pulmonary fibrosis. Arthritis Rheum 61:958-65
Yasuoka, Hidekata; Yamaguchi, Yukie; Feghali-Bostwick, Carol A (2009) The pro-fibrotic factor IGFBP-5 induces lung fibroblast and mononuclear cell migration. Am J Respir Cell Mol Biol 41:179-88
Veraldi, Kristen L; Gibson, Bethany T; Yasuoka, Hidekata et al. (2009) Role of insulin-like growth factor binding protein-3 in allergic airway remodeling. Am J Respir Crit Care Med 180:611-7
Yasuoka, Hidekata; Hsu, Eileen; Ruiz, Ximena D et al. (2009) The fibrotic phenotype induced by IGFBP-5 is regulated by MAPK activation and egr-1-dependent and -independent mechanisms. Am J Pathol 175:605-15
Hsu, Eileen; Feghali-Bostwick, Carol A (2008) Insulin-like growth factor-II is increased in systemic sclerosis-associated pulmonary fibrosis and contributes to the fibrotic process via Jun N-terminal kinase- and phosphatidylinositol-3 kinase-dependent pathways. Am J Pathol 172:1580-90
Feghali-Bostwick, Carol A; Gadgil, Aneal S; Otterbein, Leo E et al. (2008) Autoantibodies in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 177:156-63

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