Peters, Eric, Sipila, Kalle, Haag, Sabrina, Denessiouk, Konstantin, Kapyla, Jarmo, Denesyuk, Alexander, Hansen, Uwe, Konttinen, Yrjo, Johnson, Mark, Holmdahl, Rikard and Heino, Jyrki (2014) Citrullination of collagen II affects integrin-mediated cell adhesion in a receptor-specific manner. FASEB Journal, 28 (8). pp. 3758-3768. ISSN 1530-6860

Abstract

Citrullinated collagen II (CII) is a well-known autoantigen in rheumatoid arthritis (RA). However, the direct effects of CII citrullination on cell behavior have not been described. To study whether citrullination of CII could affect cellular functions, we measured the adhesion of 3 different cell types (human Saos2 osteosarcoma cells, human synovial fibroblasts, and rat mesenchymal stem cells) with impedance-based technology. The binding of different collagen receptor integrins to citrullinated collagen was studied by CHO cell lines, each overexpressing 1 of the 4 human collagen receptors on the cell surface, and with solid-phase binding assays, using the recombinant human integrin α1I, α2I, α10I, and α11I domains. Collagen citrullination decreased the adhesion of synovial fibroblasts ∼50% (P<0.05) and mesenchymal stem cells ∼40% (P<0.05) by specifically decreasing the binding of integrins α10β1 and α11β 1 to arginine-containing motifs, such as GFOGER. In contrast, citrullination had only a minor effect on the function of α 1β1 and α2β1 integrins, which have been reported to play a critical role in regulating leukocyte function. Molecular modeling was used to explain the detected functional differences at the structural level. Given that the integrins regulate cell metabolism, proliferation, and migration, we suggest that collagen citrullination modifies the pathogenesis of RA. Here, CII citrullination was shown to decrease the survival of mesenchymal stem cells. © FASEB.

Item Type:	Article
Additional Information:	This manuscripts arose from an official collaboration with the Holmdahl lab at the Karolinska Institute (legal has paperwork on file). Our contribution to the paper comes from the same experiments described in OAK submission #10568, except that they focus on a different epitope (C1). This epitope is well known/was discovered using overlapping arrays of synthetic citrullinated CII peptides, but we are the first to show its identification directly by LC/MS/MS methods from intact material.
Keywords:	PAD Rheumatoid arthritis
Date Deposited:	10 Mar 2018 00:45
Last Modified:	25 Jan 2019 00:46
URI:	https://oak.novartis.com/id/eprint/10570