Background/Purpose:

The Insulin-like growth factor (IGF) system plays an important role in cellular growth, proliferation, differentiation, apoptosis and transformation; IGF binding proteins (IGFBP) exert cell and tissue-specific effects in an IGF-dependent and independent manner. For example, IGFBP-3 and -5 are increased in dermal and pulmonary fibrosis associated with systemic sclerosis (SSc), induce extracellular matrix (ECM) production, and promote fibrosis in vitro and in vivo. We sought to examine the effects of another member of the IGFBP family, IGFBP-4, on ECM production and fibrosis.

Methods:

Primary human fibroblasts were cultured from lung tissues of patients with SSc-associated lung fibrosis and from normal donors. Lung fibrosis was induced in C57BL/6J mice using bleomycin. Quantitative real time PCR was used to measure mRNAs levels in lung tissues of patients with SSc and normal donors. Immunoblotting was used to examine proteins levels. Suppression of IGFBP-4 in primary fibroblasts using gene-specific siRNA was used to examine the effects of loss of function. A replication-deficient adenovirus expressing IGFBP-4 was used for gain of function studies.

Results:

IGFBP-4 mRNA levels were significantly decreased in pulmonary fibroblasts of patients with SSc compared to those of normal donors. Production of ECM components including fibronectin, collagen and tenascin C, was significantly reduced by endogenous expression of IGFBP-4 and exogenous recombinant IGFBP-4 in a dose-dependent manner. The anti-fibrotic activity of IGFBP-4 also blocked TGFβ-induced ECM production. Expression of IGFBP-4 inhibited ECM production ex vivo in human lung and skin in organ culture. In vivo, IGFBP-4 reduced bleomycin-induced collagen production and histologic evidence of fibrosis. Silencing IGFBP-4 expression to mimic levels observed in SSc lung fibroblasts resulted in increased ECM production. Gene expression array analysis of IGFBP-4-treated primary human lung fibroblasts showed a reduction in the levels of the chemokine receptor CXCR4 and the pro-fibrotic factor CTGF. IGFBP-4 also reduced CXCR4 and CTGF protein levels.

Conclusion:

IGFBP-4 exerts anti-fibrotic effects by reducing the levels of the chemokine receptor CXCR4 and the levels of the pro-fibrotic factor CTGF. Thus reduced IGFBP-4 levels in SSc lung fibroblasts may contribute to the fibrotic phenotype via loss of IGFBP-4 anti-fibrotic activity. Our findings suggest that IGFBP-4 is an anti-fibrotic factor whose effects can be harnessed for the development of therapies to reduce fibrosis in SSc.

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/insulin-like-growth-factor-binding-protein-4-exerts-anti-fibrotic-effects-and-its-levels-are-reduced-in-ssc-associated-lung-fibrosis/