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Blockade of the hedgehog pathway inhibits osteophyte formation in arthritis
  1. Gisela Ruiz-Heiland1,
  2. Angelika Horn1,
  3. Pawel Zerr1,
  4. Willy Hofstetter2,
  5. Wolfgang Baum1,
  6. Michael Stock1,
  7. Jörg H Distler1,
  8. Falk Nimmerjahn3,
  9. Georg Schett1,
  10. Jochen Zwerina1,4
  1. 1Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nurnberg, Erlangen, Germany
  2. 2Group for Bone Biology, Department of Clinical Research, University of Bern, Bern, Switzerland
  3. 3Department of Genetics, University of Erlangen-Nurnberg, Erlangen, Germany
  4. 4Ludwig Boltzmann Institute of Osteology, Hanusch Hospital, Vienna, Austria
  1. Correspondence to Jochen Zwerina, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Krankenhausstrasse 12, D-91054 Erlangen, Germany; jochen.zwerina{at}uk-erlangen.de

Abstract

Background Osteophyte formation is a common phenomenon in arthritis. Bone formation by endochondral ossification is considered a key pathophysiological process in the formation of osteophytes.

Objective To examine the hypothesis that inhibition of smoothened (Smo), a key component of the hedgehog pathway inhibits osteophyte formation as the hedgehog pathway mediates endochondral ossification.

Methods Arthritis was induced in 8-week-old C57/BL6 mice by serum transfer (K/BxN model). Mice were then treated by daily administration of either vehicle or LDE223, a specific small molecule inhibitor for Smo, over 2 weeks starting at the onset of disease. Clinical course of arthritis, histological and molecular changes of bone in the affected joints as well as systemic bone changes were assessed.

Results Serum transfer-induced arthritis led to severe osteophyte formation within 2 weeks of onset. Blockade of Smo inhibited hedgehog signalling in vivo and also significantly inhibited osteophyte formation, whereas the clinical and histopathological signs of arthritis were not affected. Also, systemic bone mass did not change. Smo inhibitor particularly blocked the formation of hypertrophic chondrocytes and collagen type X expression.

Conclusions The data indicate that blockade of hedgehog signalling by targeting Smo specifically inhibits osteophyte formation in arthritis without affecting inflammation and without eliciting bone destruction at the local and systemic level. Blockade of Smo may thus be considered as a strategy to specifically influence the periosteal bone response in arthritis associated with bone apposition.

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Footnotes

  • Funding This study was supported by the Deutsche Forschungsgemeinschaft (FG 661/TP4 and SPP1468-IMMUNOBONE; to AH, GS and JZ), the Bundesministerium für Bildung und Forschung (ANCYLOSS and IMMUNOPAIN; to GS, JZ and AH), the MASTERSWITCH, KINACEPT and ADIPOA projects of the European Union (to GS), the Interdisciplinary Centre for Clinical Research and the ELAN fund of the University of Erlangen-Nuremberg.

  • Competing interest None.

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

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