title: Rheumatoid synovial fibroblasts differentiate into distinct subsets in the presence of cytokines and cartilage.
abstract: We investigated two distinct synovial fibroblast populations that were located preferentially in the lining or sub-lining layers and defined by their expression of either podoplanin (PDPN) or CD248, and explored their ability to undergo self-assembly and transmigration in vivo.
  
  
  
  Synovial fibroblasts (SF) were cultured in vitro and phenotypic changes following stimulation with interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1 were examined. To examine the phenotype of SF in vivo, a severe combined immunodeficiency (SCID) human-mouse model of cartilage destruction was utilised.
  
  
  
  SF in the lining layer in rheumatoid arthritis (RA) expressed high levels of PDPN compared to the normal synovium, whereas CD248 expression was restricted to sub-lining layer cells. TNF-α or IL1 stimulation in vitro resulted in an increased expression of PDPN. In contrast, stimulation with TGF-β1 induced CD248 expression. In the SCID human-mouse model, rheumatoid SF recapitulated the expression of PDPN and CD248. Fibroblasts adjacent to cartilage expressed PDPN, and attached to, invaded, and degraded cartilage. PDPN+CD248-SF preceded the appearance of PDPN-CD248+cells in contralateral implants.
  
  
  
  We have identified two distinct SF populations identified by expression of either PDPN or CD248 which are located within different anatomical compartments of the inflamed synovial membrane. These markers discriminate between SF subsets with distinct biological properties. As PDPN-expressing cells are associated with early fibroblast migration and cartilage erosion in vivo, we propose that PDPN-expressing cells may be an attractive therapeutic target in RA.
authors.affiliation: Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, B15 2WB, UK.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Croft
authors.affiliation: Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, B15 2WB, UK.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Naylor
authors.affiliation: Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, B15 2WB, UK.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Marshall
authors.affiliation: Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, B15 2WB, UK.
authors.forename: Debbie L
authors.initials: DL
authors.lastname: Hardie
authors.affiliation: Department of Internal Medicine and Rheumatology, Justus-Liebig-University Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Zimmermann
authors.affiliation: Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, B15 2WB, UK.
authors.forename: Jason
authors.initials: J
authors.lastname: Turner
authors.affiliation: Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, B15 2WB, UK.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Desanti
authors.affiliation: Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, B15 2WB, UK.
authors.forename: Holly
authors.initials: H
authors.lastname: Adams
authors.affiliation: Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, B15 2WB, UK.
authors.forename: Adrian I
authors.initials: AI
authors.lastname: Yemm
authors.affiliation: Department of Internal Medicine and Rheumatology, Justus-Liebig-University Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Müller-Ladner
authors.affiliation: Faculty of Medicine, Centre Médical Universitaire, Geneva, Switzerland.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dayer
authors.affiliation: Department of Internal Medicine and Rheumatology, Justus-Liebig-University Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Neumann
authors.affiliation: Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, B15 2WB, UK.|University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Filer
authors.affiliation: Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, B15 2WB, UK. c.d.buckley@bham.ac.uk.|Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK. c.d.buckley@bham.ac.uk.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
mesh_terms: D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D002358:Cartilage, Articular / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology*; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D013583:Synovial Membrane / Q000166:cytology*; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology; D000098853:Podoplanin
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D016207:Cytokines; D008562:Membrane Glycoproteins; C078203:CD248 protein, human; C117468:PDPN protein, human; D000098853:Podoplanin