Wnt proteins are expressed during limb morphogenesis, yet their role and mechanism of action remains unclear during long bone growth. Wnt expression, effects and modulation of signaling events by BMP and transforming growth factor-beta (TGF-β) were evaluated in chick embryonic chondrocytes. Chondrocyte cell cultures underwent spontaneous maturation with increased expression of colX and this was associated with an increase in the expression of multiple Wnts, including Wnt 4, 5a, 8c, and 9a. Both parathyroid hormone related peptide (PTHrP) and TGF-β inhibited colX, but had disparate effects on Wnt expression. While TGF-β strongly inhibited all Wnts, PTHrP did not inhibit either Wnt8c or Wnt9a and had lesser effects on the expression of the other Wnts. BMP-2 induced colX expression, and also markedly increased Wnt8c expression. Overexpression of β-catenin and/or T cell factor (TCF)-4 also induced the type X collagen promoter. Overexpression of Wnt8c induced maturation, as did overexpression of β-catenin. The Wnt8c/β-catenin maturational effects were enhanced by BMP-2 and inhibited by TGF-β. TGF-β also inhibited activation of the Topflash reporter by β-catenin, suggesting a direct inhibitory effect since the Topflash reporter contains only β-catenin binding sequences. In turn β-catenin inhibited activation of the p3TP-Luc reporter by TGF-β, although the effect was partial. Thus, Wnt/β-catenin signaling is a critical regulator of the rate of chondrocyte differentiation. Moreover, this pathway is modulated by members of the TGF-β family and demonstrates the highly integrated nature of signals controlling endochondral ossification. © 2005 Wiley-Liss, Inc.
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