Axin1 and Axin2 are regulated by TGF-β and mediate cross-talk between TGF-β and Wnt signaling pathways

Debbie Y. Dao, Xue Yang, Di Chen, Michael Zuscik, Regis J. O'Keefe

Research output: Chapter in Book/Report/Conference proceedingConference contributionpeer-review

50 Scopus citations

Abstract

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-β)/Smad3 signaling slows the rate of chondrocyte maturation, while Wingless/INT-1-related (Wnt)/β-catenin signaling enhances the rate of chondrocyte maturation. Axin1 and Axin2 are functionally equivalent and have been shown to inhibit Wnt/β-catenin signaling and stimulate TGF-β signaling. Here we show that while Wnt3a stimulates Axin2 in a negative feedback loop, TGF-β suppresses the expression of both Axin1 and Axin2 and stimulates β-catenin signaling. In Axin2 -/- chondrocytes, TGF-β treatment results in a sustained increase in β-catenin levels compared to wild-type chondrocytes. In contrast, overexpression of Axin enhanced TGF-β signaling while overexpression of β-catenin inhibited the ability of TGF-β 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/β-catenin and TGF-β/Smad pathways. Since the suppression Axin1 and Axin2 expression by TGF-β reduces TGF-β signaling and enhances Wnt/β-catenin signaling, the overall effect is a shift from TGF-β toward Wnt/β-catenin signaling and an acceleration of chondrocyte maturation.

Original languageEnglish
Title of host publicationSkeletal Biology and Medicine, Part A
Subtitle of host publicationAspects of Bone Morphogenesis and Remodeling
PublisherBlackwell Publishing Inc.
Pages82-99
Number of pages18
ISBN (Print)9781573316842
DOIs
StatePublished - Nov 2007

Publication series

NameAnnals of the New York Academy of Sciences
Volume1116
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • Axin
  • Axin1
  • Axin2
  • Chondrogenesis
  • TGF-β
  • Wnt
  • β-catenin

Fingerprint

Dive into the research topics of 'Axin1 and Axin2 are regulated by TGF-β and mediate cross-talk between TGF-β and Wnt signaling pathways'. Together they form a unique fingerprint.

Cite this