Article Text

other Versions

PDF
Extended report
Vitamin D receptor regulates TNF-mediated arthritis
  1. Karin Zwerina1,
  2. Wolfgang Baum1,
  3. Roland Axmann1,
  4. Gisela Ruiz Heiland1,
  5. Jörg H Distler1,
  6. Josef Smolen2,
  7. Silvia Hayer2,
  8. Jochen Zwerina1,3,
  9. Georg Schett1,2
  1. 1Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Division of Rheumatology, Department of Internal Medicine 3, Medical University of Vienna, Vienna, Austria
  3. 3Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
  1. Correspondence to Georg Schett, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany; georg.schett{at}uk-erlangen.de

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.

Statistics from Altmetric.com

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.

View Full Text

Footnotes

  • Funding This work was supported by: the Interdisziplinäres Zentrum für Klinische Forschung Erlangen Project A34 (to GS and JZ), Deutsche Forschungsgemeinschaft Grant FOR 661 (to GS), SFB 423 (to JZ and GS) and Focus Program SPP1468 Immunobone, the Bundesministerium für Bildung und Forschung (BMBF; project Ankyloss) and the European Union projects Masterswitch and BTCure..

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the University of Erlangen-Nuremberg Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.