title: Stromal transcriptional profiles reveal hierarchies of anatomical site, serum response and disease and identify disease specific pathways.
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.
authors: Rheumatology Research Group, Centre for Muscoloskeletal Ageing Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, B15 2WD, UK; University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Birmingham, B15 2WB, UK.
authors: Andrew
authors: A
authors: Filer
authors: Centre of Computational Biology and Modelling (CCBM), Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, UK.
authors: Philipp
authors: P
authors: Antczak
authors: School of Cancer Sciences, College of Medical and Dental Sciences, The University of Birmingham, B15 2TT, UK.
authors: Greg N
authors: GN
authors: Parsonage
authors: Biological Technologies, Wyeth Research, Cambridge, Massachusetts 02140, USA.
authors: Holly M
authors: HM
authors: Legault
authors: Biological Technologies, Wyeth Research, Cambridge, Massachusetts 02140, USA.
authors: Margot
authors: M
authors: O'Toole
authors: MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, B15 2WD, UK.
authors: Mark J
authors: MJ
authors: Pearson
authors: The Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK.
authors: Andrew M
authors: AM
authors: Thomas
authors: Rheumatology Research Group, Centre for Muscoloskeletal Ageing Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, B15 2WD, UK.
authors: Dagmar
authors: D
authors: Scheel-Toellner
authors: Rheumatology Research Group, Centre for Muscoloskeletal Ageing Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, B15 2WD, UK; Sandwell and West Birmingham Hospitals NHS Trust, Dudley Road, Birmingham, B18 7QH, UK.
authors: Karim
authors: K
authors: Raza
authors: Rheumatology Research Group, Centre for Muscoloskeletal Ageing Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, B15 2WD, UK; Sandwell and West Birmingham Hospitals NHS Trust, Dudley Road, Birmingham, B18 7QH, UK.
authors: Christopher D
authors: CD
authors: Buckley
authors: Centre of Computational Biology and Modelling (CCBM), Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, UK.
authors: Francesco
authors: F
authors: Falciani
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology*; D001854:Bone Marrow Cells / Q000166:cytology; D002478:Cells, Cultured; D016208:Databases, Factual; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D039661:Integrin beta3 / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology*; D025341:Principal Component Analysis; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000166:cytology; D013002:Somatomedins / Q000494:pharmacology; D013583:Synovial Membrane / Q000166:cytology; D059467:Transcriptome
chemical_list: D039661:Integrin beta3; D013002:Somatomedins