title: Colony-stimulating factor (CSF) 1 receptor blockade reduces inflammation in human and murine models of rheumatoid arthritis.
abstract: BACKGROUND
  CSF-1 or IL-34 stimulation of CSF1R promotes macrophage differentiation, activation and osteoclastogenesis, and pharmacological inhibition of CSF1R is beneficial in animal models of arthritis. The objective of this study was to determine the relative contributions of CSF-1 and IL-34 signaling to CSF1R in RA.
  
  
  METHODS
  CSF-1 and IL-34 were detected by immunohistochemical and digital image analysis in synovial tissue from 15 biological-naïve rheumatoid arthritis (RA) , 15 psoriatic arthritis (PsA) and 7 osteoarthritis (OA) patients . Gene expression in CSF-1- and IL-34-differentiated human macrophages was assessed by FACS analysis and quantitative PCR. RA synovial explants were incubated with CSF-1, IL-34, control antibody (Ab), or neutralizing/blocking Abs targeting CSF-1, IL-34, or CSF1R. The effect of a CSF1R-blocking Ab was examined in murine collagen-induced arthritis (CIA).
  
  
  RESULTS
  CSF-1 (also known as M-CSF) and IL-34 expression was similar in RA and PsA synovial tissue, but lower in controls (P < 0.05). CSF-1 expression was observed in the synovial sublining, and IL-34 in the sublining and the intimal lining layer. CSF-1 and IL-34 differentially regulated the expression of 17 of 336 inflammation-associated genes in macrophages, including chemokines, extra-cellular matrix components, and matrix metalloproteinases. Exogenous CSF-1 or IL-34, or their independent neutralization, had no effect on RA synovial explant IL-6 production. Anti-CSF1R Ab significantly reduced IL-6 and other inflammatory mediator production in RA synovial explants, and paw swelling and joint destruction in CIA.
  
  
  CONCLUSIONS
  Simultaneous inhibition of CSF1R interactions with both CSF-1 and IL-34 suppresses inflammatory activation of RA synovial tissue and pathology in CIA, suggesting a novel therapeutic strategy for RA.
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Laboratory of Translational Immunology and Department of Rheumatology and ClinicalImmunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Samuel
authors.initials: S
authors.lastname: Garcia
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Laboratory of Translational Immunology and Department of Rheumatology and ClinicalImmunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Hartkamp
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Laboratory of Translational Immunology and Department of Rheumatology and ClinicalImmunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Malvar-Fernandez
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Inge E
authors.initials: IE
authors.lastname: van Es
authors.affiliation: Five Prime Therapeutics, Inc., Two Corporate Drive, South San Francisco, CA, USA.
authors.forename: Haishan
authors.initials: H
authors.lastname: Lin
authors.affiliation: Five Prime Therapeutics, Inc., Two Corporate Drive, South San Francisco, CA, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Wong
authors.affiliation: Five Prime Therapeutics, Inc., Two Corporate Drive, South San Francisco, CA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Long
authors.affiliation: Five Prime Therapeutics, Inc., Two Corporate Drive, South San Francisco, CA, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Zanghi
authors.affiliation: Five Prime Therapeutics, Inc., Two Corporate Drive, South San Francisco, CA, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Rankin
authors.affiliation: Five Prime Therapeutics, Inc., Two Corporate Drive, South San Francisco, CA, USA.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Masteller
authors.affiliation: Five Prime Therapeutics, Inc., Two Corporate Drive, South San Francisco, CA, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Wong
authors.affiliation: Laboratory of Translational Immunology and Department of Rheumatology and ClinicalImmunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
authors.affiliation: Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Present address: GlaxoSmithKline, Stevenage, UK.|Present address: Cambridge University, Cambridge, UK.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. k.a.reedquist@umcutrecht.nl.|Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. k.a.reedquist@umcutrecht.nl.|Laboratory of Translational Immunology and Department of Rheumatology and ClinicalImmunology, University Medical Center Utrecht, Utrecht, The Netherlands. k.a.reedquist@umcutrecht.nl.
authors.forename: Kris A
authors.initials: KA
authors.lastname: Reedquist
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D001551:Benz(a)Anthracenes; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007378:Interleukins / Q000096:biosynthesis; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D060888:Real-Time Polymerase Chain Reaction; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism
chemical_list: D001551:Benz(a)Anthracenes; C529076:IL34 protein, human; D007378:Interleukins; C018913:dibenzoanthracene-5,6-dihydrodiol; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor