Axin1 and Axin2 are regulated by TGF- and mediate cross-talk between TGF- and Wnt signaling pathways.
Chondrocyte maturation during endochondral bone formation is regulated by a number of signals that either promote or inhibit maturation. Among these, two well-studied signaling pathways play crucial roles in modulating chondrocyte maturation: transforming growth factor-beta (TGF-beta)/Smad3 signaling slows the rate of chondrocyte maturation, while Wingless/INT-1-related (Wnt)/beta-catenin signaling enhances the rate of chondrocyte maturation. Axin1 and Axin2 are functionally equivalent and have been shown to inhibit Wnt/beta-catenin signaling and stimulate TGF-beta signaling. Here we show that while Wnt3a stimulates Axin2 in a negative feedback loop, TGF-beta suppresses the expression of both Axin1 and Axin2 and stimulates beta-catenin signaling. In Axin2 -/- chondrocytes, TGF-beta treatment results in a sustained increase in beta-catenin levels compared to wild-type chondrocytes. In contrast, overexpression of Axin enhanced TGF-beta signaling while overexpression of beta-catenin inhibited the ability of TGF-beta to induce Smad3-sensitive reporters. Finally, the suppression of the Axins is Smad3-dependent since the effect is absent in Smad3 -/- chondrocytes. Altogether these findings show that the Axins act to integrate signals between the Wnt/beta-catenin and TGF-beta/Smad pathways. Since the suppression Axin1 and Axin2 expression by TGF-beta reduces TGF-beta signaling and enhances Wnt/beta-catenin signaling, the overall effect is a shift from TGF-beta toward Wnt/beta-catenin signaling and an acceleration of chondrocyte maturation.
Dao
Debbie Y
DY
Department of Orthopaedics, Center for Musculoskeletal Research University of Rochester School of Medicine, Rochester, NY 14642, USA.
Yang
Xue
X
Chen
Di
D
Zuscik
Michael
M
O'Keefe
Regis J
RJ
D000818:Animals; D060466:Axin Protein; D001483:Base Sequence; D019902:Chondrocytes / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D060466:Axin Protein; C111729:Axin2 protein, mouse; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D051176:beta Catenin