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Abstract Number: 124

M10, a Small Fragment of the Hepatocyte Growth Factor Receptor, Attenuates Fibrotic Changes in a Murine Model of Scleroderma Lung Disease and in Human Lung Fibroblasts

Tanjina Akter1, Ilia Atanelishvili1, Atsushi Noguchi2, Galina S. Bogatkevich1 and Rick Silver3, 1Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, 2Division of Rheumatology, Endocrinology and Nephrology,, Hokkaido University Graduate School of Medicine, Sapporo, Japan, 3Rheumatology, Medical University of SC, Charleston, SC

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Scleroderma

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Session Information

Date: Sunday, October 21, 2018

Title: Systemic Sclerosis and Related Disorders – Basic Science Poster I

Session Type: ACR Poster Session A

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

Background/Purpose: Interstitial lung disease (ILD) is the major cause of mortality among scleroderma (systemic sclerosis, SSc) patients. Extracellular matrix (ECM) deposition is a hallmark of this and other fibrotic lung diseases. TGFβ plays a crucial role in ECM gene expression via regulation of Ca2+/calmodulin-dependent protein kinases and matrix metalloproteinases (MMPs). We recently demonstrated that M10 peptide, naturally derived from the cytosolic fragment of the hepatocyte growth factor receptor, blocks the TGFβ-mediated canonical pathway via interaction with SMAD2 and reduces fibrosis in vivo. In this study, we investigate the efficacy of M10 in the regulation of intracellular Ca2+ levels, ECM proteins, and in the bleomycin-induced therapeutic mouse model of SSc-ILD.

Methods: Lung fibroblasts were derived from lung tissues of SSc patients and from matched normal lungs obtained at autopsy. Antifibrotic in vivo effects of M10 (10 mg/kg, intraperitoneal, every 48h) were studied in the bleomycin-induced therapeutic mouse model of SSc-ILD. Ca2+ was measured by FLIPR Tetra cellular screening system equipped with Molecular Devices ScreenWorks® software. Expression levels of collagen, connective tissue growth factor (CTGF, CCN2), fibronectin and tenascin were measured by immunoblotting and real-time PCR. Expression levels of matrix metalloproteinases (MMPs) were determined by human MMP antibody array. Statistical analysis was performed using GraphPad Prism 7 software.

Results: In both normal lung fibroblasts and SSc-ILD lung fibroblasts, an acute increase of intracellular Ca2+ was observed 15sec following TGFβ administration, with a second peak of delayed Ca2+ efflux at 60sec. A high level of Ca2+ was maintained throughout the 10 min of the cellular screening process. In the presence of M10 peptide, TGFβ-mediated Ca2+ was significantly (p < 0.001) reduced in both acute and delayed states maintaining overall lower amplitude. M10 peptide suppressed TGFβ-mediated mRNA and protein expression of collagen I, CCN2, fibronectin, and tenascin. M10 peptide significantly induced the expression of MMP-10 in normal lung fibroblasts, whereas M10 peptide inhibited MMP-3 in SSc-ILD lung fibroblasts. In the bleomycin-induced therapeutic mouse model of SSc-ILD, M10 noticeably reduced collagen in lung parenchyma. A semi-quantitative evaluation of histopathology using the Ashcroft scale demonstrated a significant decrease in bleomycin-induced fibrosis in M10-treated mice as compared to mice treated with control (scrambled) peptide.

Conclusion: M10 peptide reduces ECM proteins, inhibits TGFβ-mediated Ca2+ efflux and regulates MMPs demonstrating strong antifibrotic effects in vitro and in vivo in an animal model of lung fibrosis and should be considered as a potential therapeutic agent for systemic sclerosis and other fibrosing diseases.


Disclosure: T. Akter, None; I. Atanelishvili, None; A. Noguchi, None; G. S. Bogatkevich, None; R. Silver, None.

To cite this abstract in AMA style:

Akter T, Atanelishvili I, Noguchi A, Bogatkevich GS, Silver R. M10, a Small Fragment of the Hepatocyte Growth Factor Receptor, Attenuates Fibrotic Changes in a Murine Model of Scleroderma Lung Disease and in Human Lung Fibroblasts [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/m10-a-small-fragment-of-the-hepatocyte-growth-factor-receptor-attenuates-fibrotic-changes-in-a-murine-model-of-scleroderma-lung-disease-and-in-human-lung-fibroblasts/. Accessed .
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