Stromal transcriptional profiles reveal hierarchies of anatomical site, serum response and disease and identify disease specific pathways

Andrew Filer*, Philipp Antczak, Greg N. Parsonage, Holly M. Legault, Margot O'Toole, Mark J. Pearson, Andrew M. Thomas, Dagmar Scheel-Toellner, Karim Raza, Christopher D. Buckley, Francesco Falciani

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Synovial fibroblasts in persistent inflammatory arthritis have been suggested to have parallels with cancer growth and wound healing, both of which involve a stereotypical serum response programme. We tested the hypothesis that a serum response programme can be used to classify diseased tissues, and investigated the serum response programme in fibroblasts from multiple anatomical sites and two diseases. To test our hypothesis we utilized a bioinformatics approach to explore a publicly available microarray dataset including rheumatoid arthritis (RA), osteoarthritis (OA) and normal synovial tissue, then extended those findings in a new microarray dataset representing matched synovial, bone marrow and skin fibroblasts cultured from RA and OA patients undergoing arthroplasty. The classical fibroblast serum response programme discretely classified RA, OA and normal synovial tissues. Analysis of low and high serum treated fibroblast microarray data revealed a hierarchy of control, with anatomical site the most powerful classifier followed by response to serum and then disease. In contrast to skin and bone marrow fibroblasts, exposure of synovial fibroblasts to serum led to convergence of RA and OA expression profiles. Pathway analysis revealed three inter-linked gene networks characterising OA synovial fibroblasts: Cell remodelling through insulin-like growth factors, differentiation and angiogenesis through -3 integrin, and regulation of apoptosis through CD44. We have demonstrated that Fibroblast serum response signatures define disease at the tissue level, and that an OA specific, serum dependent repression of genes involved in cell adhesion, extracellular matrix remodelling and apoptosis is a critical discriminator between cultured OA and RA synovial fibroblasts.

Original languageEnglish
Article numbere0120917
JournalPLoS ONE
Volume10
Issue number3
DOIs
Publication statusPublished - 25 Mar 2015

Bibliographical note

© 2015 Filer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

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    Filer, A., Antczak, P., Parsonage, G. N., Legault, H. M., O'Toole, M., Pearson, M. J., Thomas, A. M., Scheel-Toellner, D., Raza, K., Buckley, C. D., & Falciani, F. (2015). Stromal transcriptional profiles reveal hierarchies of anatomical site, serum response and disease and identify disease specific pathways. PLoS ONE, 10(3), [e0120917]. https://doi.org/10.1371/journal.pone.0120917