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.
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.
|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|
Showing the most recent 10 out of 17 publications