Mechanisms of Insulin-like Growth Factor-II-Mediated Fibrosis

Sara Garrett¹, Justin Thomas², Eileen Hsu³ and Carol A. Feghali-Bostwick⁴, ¹Medicine/Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, ²Eisenhower Medical Center, Rancho Mirage, CA, ³Kaiser Permanente Medical Group, Mclean, VT, ⁴Division of Rheumatology and Immunology, Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, United States, Charleston, SC

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Fibroblasts, fibrosis, Insulin-like growth factor, matrix metalloproteinase (MMP) and scleroderma

Session Information

Date: Sunday, November 5, 2017

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's – Pathogenesis, Animal Models and Genetics Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Previous work has shown that insulin-like growth factor (IGF)-II is increased in fibrosing lung diseases, including idiopathic pulmonary fibrosis (IPF) and scleroderma/systemic sclerosis (SSc)-associated pulmonary fibrosis. Our goal was to identify the mechanism by which upregulated IGF-II expression contributes to fibrosis in these conditions.

Methods: Fibroblasts derived from lung tissues of normal donors (NL), patients with IPF, and patients with SSc-associated pulmonary fibrosis were used. Gene expression, protein expression, phosphorylation, and secretion were analyzed with qRT-PCR, immunoprecipitation, immunoblotting, and ELISA, respectively, in early passage primary fibroblasts. Antibody, siRNA, and inhibitors were used to neutralize, knockdown, or block endogenous IGF-II and the IGF-II receptors: IGF-1 receptor (IGF1R), IGF2R, and/or insulin receptor (IR).

Results: The IGF1R, IGF2R, and IR receptors showed lower basal gene expression in SSc fibroblasts. Extracellular matrix (ECM) transcripts, though unchanged in NL, were dramatically increased in IPF and SSc with IGF-II (200 ng/mL) stimulation. Activation of IGF1R, assessed via receptor phosphorylation, occurred 5 min following IGF-II. Phosphorylation decreased by 10 min in NL, but persisted through 10 min in SSc fibroblasts. Phosphorylation was abrogated by antibody-mediated neutralization of endogenous IGF-II. Dual siRNA knockdown of IGF1R and IR decreased ECM components collagen and fibronectin in NL and SSc fibroblasts, as did treatment with an IGF1R tyrosine kinase inhibitor. IGF-II decreased IGF1R and IR transcripts at 6 hr in NL, IPF, and SSc and decreased IGF2R in NL from 1-48 hr. MMP3 transcript was decreased with IGF-II stimulation in IPF and SSc, whereas TIMP1 transcript and secretion were increased.

Conclusion: Decreased basal receptor pools, ECM component upregulation, and longer receptor activation render fibroblasts from pathologic lung more sensitive to IGF-II-stimulated fibrosis. Inhibitor studies indicate IGF-II signaling is mediated by IGF1R and IR, which can form a hybrid receptor. IGF-II causes disruption of steady-state ECM deposition and breakdown through altered MMP:TIMP levels, promoting a pro-fibrotic milieu in IPF and SSc.

Disclosure: S. Garrett, None; J. Thomas, None; E. Hsu, None; C. A. Feghali-Bostwick, None.

To cite this abstract in AMA style:

Garrett S, Thomas J, Hsu E, Feghali-Bostwick CA. Mechanisms of Insulin-like Growth Factor-II-Mediated Fibrosis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/mechanisms-of-insulin-like-growth-factor-ii-mediated-fibrosis/. Accessed .

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