Collagen triple helix repeat containing 1 is a new promigratory marker of arthritic pannus.

Askhat Myngbay,Toni S. Forde,Mohamed Ramez,Altynai Adilbayeva,Yergali Bexeitov,Volkhard Lindner,Vyacheslav A. Adarichev,Mohammed Talha Shekhani

doi:10.1186/s13075-016-1067-1

Abstract

BackgroundThe formation of destructive hypercellular pannus is critical to joint damage in rheumatoid arthritis (RA). The collagen triple helix repeat containing 1 (CTHRC1) protein expressed by activated stromal cells of diverse origin has previously been implicated in tissue remodeling and carcinogenesis. We recently discovered that the synovial Cthrc1 mRNA directly correlates with arthritis severity in mice. This study characterizes the role of CTHRC1 in arthritic pannus formation.MethodsSynovial joints of mice with collagen antibody-induced arthritis (CAIA) and human RA-fibroblast-like synoviocytes (FLS) were immunostained for CTHRC1, FLS and macrophage-specific markers. CTHRC1 levels in plasma from patients with RA were measured using sandwich ELISA. The migratory response of fibroblasts was studied with a transwell migration assay and time-lapse microscopy. Velocity and directness of cell migration was analyzed by recording the trajectories of cells treated with rhCTHRC1.ResultsImmunohistochemical analysis of normal and inflamed synovium revealed highly inducible expression of CTHRC1 in arthritis (10.9-fold). At the tissue level, CTHRC1-expressing cells occupied the same niche as large fibroblast-like cells positive for α-smooth muscle actin (α-SMA) and cadherin 11 (CDH11). CTHRC1 was produced by activated FLS predominantly located at the synovial intimal lining and at the bone-pannus interface. Cultured RA-FLS expressed CDH11, α-SMA, and CTHRC1. Upon treatment with exogenous rhCTHRC1, embryonic fibroblasts and RA-FLS significantly increased migration velocity, directness, and cell length along the front-tail axis (1.4-fold, p < 0.01).ConclusionCTHRC1 was established as a novel marker of activated synoviocytes in murine experimental arthritis and RA. The pro-migratory effect of CTHRC1 on synoviocytes is considered one of the mechanisms promoting hypercellularity of the arthritic pannus.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1067-1) contains supplementary material, which is available to authorized users.

Highlights

The formation of destructive hypercellular pannus is critical to joint damage in rheumatoid arthritis (RA)
collagen triple helix repeat containing 1 (CTHRC1) expression is strongly inducible in murine arthritis Earlier we reported low levels of Cthrc1 mRNA in the paws of naïve mice, but substantial upregulation of mRNA during inflammation [9]
To characterize which tissue express CTHRC1, we used immunohistochemical analysis (IHC) staining of synovial joints

Summary

Introduction

The formation of destructive hypercellular pannus is critical to joint damage in rheumatoid arthritis (RA). In addition to the increased proliferation and production of a wide spectrum of cartilage-degrading proteases, activated FLS demonstrate a high level of invasiveness and motility within the affected joint, and FLS are even capable of spreading the disease to as yet unaffected cartilage using. Invasive properties of activated FLS from patients with rheumatoid arthritis (RA) and from murine arthritis models directly correlate with the rate of joint destruction and deformities, and poor disease outcome [4]. One of the relatively unique surface markers for RA-FLS is cadherin-11 (CDH11), which plays an essential role in the acquisition of the invasive phenotype of activated FLS in arthritis [2, 6]. CDH11 is expressed in many other mesenchymal-type cells and is involved in the regulation of invasiveness of, for instance, prostate and glioblastoma tumors, and promotes bone metastasis [7, 8]

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