title: Vitamin D receptor regulates TNF-mediated arthritis.
abstract: OBJECTIVE
  Reduced vitamin D intake has been linked to increased susceptibility to develop rheumatoid arthritis (RA) and vitamin D deficiency is associated with increased disease activity in RA patients. The pathophysiological role of vitamin D in joint inflammation is, however, unclear.
  
  
  METHODS
  To determine the influence of absent vitamin D signalling in chronic arthritis, vitamin D receptor (VDR)-deficient mice were crossed with human tumour necrosis factor (TNF) transgenic mice (hTNFtg), which spontaneously develop chronic arthritis.
  
  
  RESULTS
  Clinical signs and symptoms of chronic arthritis were aggravated in hTNFtg mice lacking functional VDR signalling. Moreover, synovial inflammation was clearly increased in VDR(-/-)hTNFtg mice as compared to hTNFtg mice and was associated with an increased macrophage influx in inflamed joints. In vitro, VDR-deficient monocytes were proinflammatory and hyper-responsive to TNF stimulation associated with prolonged mitogen-activated protein kinase activation and cytokine secretion. Also, VDR(-/-) monocytes showed enhanced potential to differentiate into bone resorbing osteoclasts in vitro. In line, VDR(-/-)hTNFtg mice had significantly increased cartilage damage and synovial bone erosions.
  
  
  CONCLUSIONS
  VDR plays an important role in limiting the inflammatory phenotype in a mouse model of RA. Absent VDR signalling causes a proinflammatory monocyte phenotype associated with increased inflammation, cartilage damage and bone erosion.
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Zwerina
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baum
authors.forename: Roland
authors.initials: R
authors.lastname: Axmann
authors.forename: Gisela Ruiz
authors.initials: GR
authors.lastname: Heiland
authors.forename: Jörg H
authors.initials: JH
authors.lastname: Distler
authors.forename: Josef
authors.initials: J
authors.lastname: Smolen
authors.forename: Silvia
authors.initials: S
authors.lastname: Hayer
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D015519:Bone Density / Q000502:physiology; D001862:Bone Resorption / Q000378:metabolism / Q000503:physiopathology; D002358:Cartilage, Articular / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D008264:Macrophages / Q000473:pathology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000502:physiology; D011509:Proteoglycans / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013585:Synovitis / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D016207:Cytokines; D011509:Proteoglycans; D018167:Receptors, Calcitriol; D014409:Tumor Necrosis Factor-alpha