title: Receptor Protein Tyrosine Phosphatase α-Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice.
abstract: OBJECTIVE
  During rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) critically promote disease pathogenesis by aggressively invading the extracellular matrix of the joint. The focal adhesion kinase (FAK) signaling pathway is emerging as a contributor to the anomalous behavior of RA FLS. The receptor protein tyrosine phosphatase α (RPTPα), which is encoded by the PTPRA gene, is a key promoter of FAK signaling. The aim of this study was to investigate whether RPTPα mediates FLS aggressiveness and RA pathogenesis.
  
  
  METHODS
  Through RPTPα knockdown, we assessed FLS gene expression by quantitative polymerase chain reaction analysis and enzyme-linked immunosorbent assay, invasion and migration by Transwell assays, survival by annexin V and propidium iodide staining, adhesion and spreading by immunofluorescence microscopy, and activation of signaling pathways by Western blotting of FLS lysates. Arthritis development was examined in RPTPα-knockout (KO) mice using the K/BxN serum-transfer model. The contribution of radiosensitive and radioresistant cells to disease was evaluated by reciprocal bone marrow transplantation.
  
  
  RESULTS
  RPTPα was enriched in the RA synovial lining. RPTPα knockdown impaired RA FLS survival, spreading, migration, invasiveness, and responsiveness to platelet-derived growth factor, tumor necrosis factor, and interleukin-1 stimulation. These phenotypes correlated with increased phosphorylation of Src on inhibitory Y(527) and decreased phosphorylation of FAK on stimulatory Y(397) . Treatment of RA FLS with an inhibitor of FAK phenocopied the knockdown of RPTPα. RPTPα-KO mice were protected from arthritis development, which was due to radioresistant cells.
  
  
  CONCLUSIONS
  By regulating the phosphorylation of Src and FAK, RPTPα mediates proinflammatory and proinvasive signaling in RA FLS, correlating with the promotion of disease in an FLS-dependent model of RA.
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Stanford
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: Mattias N D
authors.initials: MN
authors.lastname: Svensson
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Sacchetti
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: Caila A
authors.initials: CA
authors.lastname: Pilo
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Wu
authors.affiliation: The Scripps Research Institute, La Jolla, California.
authors.forename: William B
authors.initials: WB
authors.lastname: Kiosses
authors.affiliation: Broegelmann Research Laboratory and University of Bergen, Bergen, Norway.
authors.forename: Annelie
authors.initials: A
authors.lastname: Hellvard
authors.affiliation: Broegelmann Research Laboratory and University of Bergen, Bergen, Norway.
authors.forename: Brith
authors.initials: B
authors.lastname: Bergum
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: German R Aleman
authors.initials: GR
authors.lastname: Muench
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: Christian
authors.initials: C
authors.lastname: Elly
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: Yun-Cai
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Hubrecht Institute-Koninklijke Nederlands Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands, and Institute of Biology, Leiden, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: den Hertog
authors.affiliation: Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ari
authors.initials: A
authors.lastname: Elson
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Jan
authors.initials: J
authors.lastname: Sap
authors.affiliation: Broegelmann Research Laboratory and University of Bergen, Bergen, Norway.
authors.forename: Piotr
authors.initials: P
authors.lastname: Mydel
authors.affiliation: University of California at San Diego School of Medicine, La Jolla.
authors.forename: David L
authors.initials: DL
authors.lastname: Boyle
authors.affiliation: University of California at San Diego School of Medicine, La Jolla.
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.affiliation: University of California at San Diego School of Medicine, La Jolla.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Firestein
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: Nunzio
authors.initials: N
authors.lastname: Bottini
mesh_terms: D000818:Animals; D000843:Ankle Joint; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D007375:Interleukin-1 / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013583:Synovial Membrane / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism*
chemical_list: D007375:Interleukin-1; D010982:Platelet-Derived Growth Factor; D014409:Tumor Necrosis Factor-alpha; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; C516843:Ptpra protein, mouse; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4