title: Blockade of the hedgehog pathway inhibits osteophyte formation in arthritis.
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.
authors.affiliation: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nurnberg, Erlangen, Germany.
authors.forename: Gisela
authors.initials: G
authors.lastname: Ruiz-Heiland
authors.forename: Angelika
authors.initials: A
authors.lastname: Horn
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.forename: Willy
authors.initials: W
authors.lastname: Hofstetter
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baum
authors.forename: Michael
authors.initials: M
authors.lastname: Stock
authors.forename: Jörg H
authors.initials: JH
authors.lastname: Distler
authors.forename: Falk
authors.initials: F
authors.lastname: Nimmerjahn
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D001842:Bone and Bones / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019902:Chondrocytes / Q000473:pathology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006984:Hypertrophy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D010006:Osteoblasts / Q000473:pathology; D054850:Osteophyte / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D010521:Periosteum / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000072086:Smoothened Receptor; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001713:Biphenyl Compounds; D053823:Hedgehog Proteins; C571088:LDE223; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor