title: The Wnt antagonist Wif-1 interacts with CTGF and inhibits CTGF activity.
abstract: Wnt inhibitory factor 1 (Wif-1) is a secreted antagonist of Wnt signalling. We recently demonstrated that this molecule is expressed predominantly in superficial layers of epiphyseal cartilage but also in bone and tendon. Moreover, we showed that Wif-1 is capable of binding to several cartilage-related Wnt ligands and interferes with Wnt3a-dependent Wnt signalling in chondrogenic cells. Here we provide evidence that the biological function of Wif-1 may not be confined to the modulation of Wnt signalling but appears to include the regulation of other signalling pathways. Thus, we show that Wif-1 physically binds to connective tissue growth factor (CTGF/CCN2) in vitro, predominantly by interaction with the C-terminal cysteine knot domain of CTGF. In vivo such an interaction appears also likely since the expression patterns of these two secreted proteins overlap in peripheral zones of epiphyseal cartilage. In chondrocytes CTGF has been shown to induce the expression of cartilage matrix genes such as aggrecan (Acan) and collagen2a1 (Col2a1). In this study we demonstrate that Wif-1 is capable to interfere with CTGF-dependent induction of Acan and Col2a1 gene expression in primary murine chondrocytes. Conversely, CTGF does not interfere with Wif-1-dependent inhibition of Wnt signalling. These results indicate that Wif-1 may be a multifunctional modulator of signalling pathways in the cartilage compartment.
authors.affiliation: Department of Experimental Medicine I, Nikolaus-Fiebiger-Zentrum für Molekulare Medizin, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Cordula
authors.initials: C
authors.lastname: Surmann-Schmitt
authors.forename: Takako
authors.initials: T
authors.lastname: Sasaki
authors.forename: Takako
authors.initials: T
authors.lastname: Hattori
authors.forename: Nicole
authors.initials: N
authors.lastname: Eitzinger
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Klaus
authors.initials: K
authors.lastname: von der Mark
authors.forename: Michael
authors.initials: M
authors.lastname: Stock
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D053674:Aggrecans / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002356:Cartilage / Q000166:cytology / Q000378:metabolism; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053674:Aggrecans; C499177:COL2A1 protein, human; D024043:Collagen Type II; D012097:Repressor Proteins; C485569:WIF1 protein, human; D051153:Wnt Proteins; D055513:Connective Tissue Growth Factor