Abstract
Pulmonary fibrosis is a hallmark of diseases such as systemic sclerosis (SSc, scleroderma) and idiopathic pulmonary fibrosis (IPF). To date, the therapeutic options for patients with pulmonary fibrosis are limited, and organ transplantation remains the most effective option. Insulinlike growth factor-binding protein 5 (IGFBP-5) is a conserved member of the IGFBP family of proteins that is overexpressed in SSc and IPF. In this study, we demonstrate that both exogenous and adenovirally expressed IGFBP-5 promote fibrosis by increasing the production of extracellular matrix (ECM) genes and the expression of pro-fibrotic genes in primary human lung fibroblasts. IGFBP-5 increased expression of the pro-fibrotic growth factor CTGF and levels of the matrix crosslinking enzyme lysyl oxidase (LOX). Silencing of IGFBP-5 had different effects in lung fibroblasts from normal donors and patients with SSc or IPF. Moreover, we show that IGFBP-5 increases expression of ECM genes, CTGF, and LOX in human lung tissues maintained in organ culture. Together, our data extend our previous findings and demonstrate that IGFBP-5 exerts its pro-fibrotic activity by directly inducing expression of ECM and pro-fibrotic genes. Further, IGFBP-5 promotes its own expression, generating a positive feedback loop. This suggests that IGFBP-5 likely acts in concert with other growth factors to drive fibrosis and tissue remodeling.
Original language | English (US) |
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Article number | 00601 |
Journal | Frontiers in Endocrinology |
Volume | 9 |
Issue number | OCT |
DOIs | |
State | Published - Oct 15 2018 |
Funding
This publication was supported by the South Carolina Clinical and Translational Research (SCTR) Institute, with an academic home at the Medical University of South Carolina, through NIH/NCATS Grant Numbers TL1 TR001451 and UL1 TR001450, and by grants R01 HL121262 from NIH/NHLBI and K24 AR060297 and P30 AR072582 from NIH/NIAMS.
Keywords
- Extracellular matrix (ECM)
- Fibrosis
- Idiopathic pulmonary fibrosis (IPF)
- Insulin-like growth factor binding protein-5 (IGFBP-5)
- Systemic sclerosis (SSc)
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism