title: Wnt inhibitory factor 1 deficiency uncouples cartilage and bone destruction in tumor necrosis factor α-mediated experimental arthritis.
abstract: OBJECTIVE
  Wnt signaling plays a pivotal role in skeletal development and in the control of cartilage and bone turnover. We have recently shown that the secreted Wnt antagonist Wnt inhibitory factor 1 (WIF-1) is mainly expressed in the upper layers of epiphyseal and articular cartilage and, to a lesser extent, in bone. Nevertheless, WIF-1(-/-) mice develop normally. In light of these findings, we undertook this study to analyze the role of WIF-1 in arthritis.
  
  
  METHODS
  Expression analyses for WIF-1 were performed by real-time reverse transcription-polymerase chain reaction (RT-PCR). WIF-1(-/-) and tumor necrosis factor (TNF)-transgenic mice were crossbred, and the progression of arthritis in TNF-transgenic WIF-1(-/-) mice and littermate controls was evaluated. Structural joint damage was analyzed by histologic staining, histomorphometry, and micro-computed tomography. Wnt/β-catenin signaling was investigated by real-time RT-PCR and immunofluorescence on primary chondrocytes.
  
  
  RESULTS
  WIF-1 expression was repressed by TNFα in chondrocytes and osteoblasts and down-regulated in experimental arthritis and in articular cartilage from patients with rheumatoid arthritis. WIF-1 deficiency partially protected TNF-transgenic mice against bone erosion and loss of trabecular bone, probably as a result of less osteoclast activity. In contrast, arthritis-related cartilage damage was aggravated by WIF-1 deficiency, while overexpression of WIF-1 attenuated cartilage degradation in TNF-transgenic mice. In chondrocytes, TNFα stimulated canonical Wnt signaling, which could be blocked by WIF-1, indicating a direct effect of TNFα and WIF-1 on Wnt signaling in this system.
  
  
  CONCLUSIONS
  These data suggest that WIF-1 may take part in the fine-tuning of cartilage and bone turnover, promoting the balance of cartilage versus bone anabolism.
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stock
authors.forename: Christina
authors.initials: C
authors.lastname: Böhm
authors.forename: Carina
authors.initials: C
authors.lastname: Scholtysek
authors.forename: Matthias
authors.initials: M
authors.lastname: Englbrecht
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Fürnrohr
authors.forename: Patricia
authors.initials: P
authors.lastname: Klinger
authors.forename: Kolja
authors.initials: K
authors.lastname: Gelse
authors.forename: Svitlana
authors.initials: S
authors.lastname: Gayetskyy
authors.forename: Klaus
authors.initials: K
authors.lastname: Engelke
authors.forename: Ulrike
authors.initials: U
authors.lastname: Billmeier
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.forename: Wim
authors.initials: W
authors.lastname: van den Berg
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D002356:Cartilage / Q000378:metabolism* / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016326:Extracellular Matrix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; C118544:Wif1 protein, mouse