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

Debbie Y Dao1, Xue Yang, Di Chen

  • 1Department of Orthopaedics, Center for Musculoskeletal Research University of Rochester School of Medicine, Rochester, NY 14642, USA.

Annals of the New York Academy of Sciences
|December 18, 2007
PubMed

Insights

Transforming growth factor-beta (TGF-beta) suppresses Axin expression, shifting signaling towards Wingless/INT-1-related (Wnt)/beta-catenin and accelerating chondrocyte maturation during bone formation.

Area of Science:

  • Skeletal Biology and Development
  • Cell Signaling Pathways
  • Endochondral Ossification

Background:

  • Chondrocyte maturation is a tightly regulated process crucial for endochondral bone formation.
  • Transforming growth factor-beta (TGF-beta) signaling inhibits chondrocyte maturation, while Wingless/INT-1-related (Wnt)/beta-catenin signaling promotes it.
  • Axin1 and Axin2 are key regulators that inhibit Wnt signaling and can stimulate TGF-beta signaling.

Purpose of the Study:

  • To investigate the interplay between TGF-beta, Wnt/beta-catenin, and Axin proteins in chondrocyte maturation.
  • To elucidate the role of Axin1 and Axin2 in integrating these signaling pathways.
  • To determine the effect of TGF-beta on Axin expression and its downstream consequences on beta-catenin signaling.

Main Methods:

  • Analysis of Axin1 and Axin2 expression in response to Wnt3a and TGF-beta stimulation.
  • Assessment of beta-catenin levels in wild-type and Axin2 knockout (Axin2-/-) chondrocytes following TGF-beta treatment.
  • Investigation of the effects of Axin and beta-catenin overexpression on TGF-beta signaling.
  • Examination of Smad3-dependent regulation of Axin suppression by TGF-beta.

Main Results:

  • TGF-beta suppresses the expression of both Axin1 and Axin2, while Wnt3a stimulates Axin2 in a feedback loop.
  • TGF-beta treatment leads to a sustained increase in beta-catenin levels in Axin2-/- chondrocytes compared to wild-type.
  • Overexpression of Axin enhances TGF-beta signaling, whereas beta-catenin overexpression inhibits TGF-beta's induction of Smad3-sensitive reporters.
  • The suppression of Axin expression by TGF-beta is dependent on Smad3 signaling.

Conclusions:

  • Axin proteins act as crucial integrators of Wnt/beta-catenin and TGF-beta/Smad signaling pathways.
  • TGF-beta-induced suppression of Axin expression shifts the balance from TGF-beta to Wnt/beta-catenin signaling.
  • This signaling shift accelerates chondrocyte maturation, providing new insights into skeletal development regulation.

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