Wnt/β-catenin Signaling Regulates Cranial Base Development and Growth

Abstract

Wnt proteins and beta-catenin signaling regulate major processes during embryonic development, and we hypothesized that they regulate cranial base synchondrosis development and growth. To address this issue, we analyzed cartilage-specific beta-catenin-deficient mice. Mutant synchondroses lacked typical growth plate zones, and endochondral ossification was delayed. In reciprocal transgenic experiments, cartilage overexpression of a constitutive active Lef1, a transcriptional mediator of Wnt/beta-catenin signaling, caused precocious chondrocyte hypertrophy and intermingling of immature and mature chondrocytes. The developmental changes seen in beta-catenin-deficient synchondroses were accompanied by marked reductions in Ihh and PTHrP as well as sFRP-1, an endogenous Wnt signaling antagonist and a potential Ihh signaling target. Thus, Wnt/beta-catenin signaling is essential for cranial base development and synchondrosis growth plate function. This pathway promotes chondrocyte maturation and ossification events, and may exert this important role by dampening the effects of Ihh-PTHrP together with sFRP-1.

miR-449a Regulates the Chondrogenesis of Human Mesenchymal Stem Cells Through Direct Targeting of Lymphoid Enhancer-Binding Factor-1

“…In perfect alignment with this theory, a study reported that the overexpression of LEF-1 in 3 separate cell sources, namely C3H10T1/2, ATDC5, and primary chondrocytes, showed induction of a key chondrogenic marker gene, Sox 9 [32]. However, upon the prolonged presence of LEF-1 induced by a constitutively active LEF-1 overexpression vector, hBM-MSCs rapidly went into hypertrophy [42]. Similarly, a study by Tamamura et al indicated that the transgenic overexpression of LEF-1 driven by the type II collagen promoter led to defective chondrocyte maturation, whereas an overexpression of mutated b-catenin in chick embryos resulted in the inhibition of both cartilage development and hypertrophy, suggesting that the canonical Wnt signaling has the unique effect of both hypertrophy and chondrogenic differentiation depending on the developmental stage [43].…”

A dynamic cell adhesion surface regulates tissue architecture in growth plate cartilage

“…Despite these differences, the PSS displays the tissue architecture, gene expression domains, and responses to morphogens consistent with growth plate cartilage in long bones (Fig. 1D) (Chen et al, 1999;Eswarakumar et al, 2002;Shum et al, 2003;Young et al, 2006;Koyama et al, 2007;Nagayama et al, 2008). …”

Developmental Regulation of the Growth Plate and Cranial Synchondrosis

“…This accelerated chondrocyte differentiation is associated with more accelerated endochondral bone formation. In contrast with the more localized expression of PTHrP in the resting zone of the growth plate with a gradient effect, PTHrP is expressed in both the resting and proliferative zones of the synchondrosis (Young et al 2006;Nagayama et al 2008). This may explain the phenotypic difference between the growth plate and synchondroses in PTHrP −/− mice.…”

“…Cartilage-specific deletion of β-catenin with Col2a-Cre in mice leads to similar but different abnormalities in cranial synchondroses compared with those in the growth plate (Day et al 2005;Nagayama et al 2008). In both locations, decreased bone formation is documented.…”

“…It is currently unknown how the expression levels of these signaling molecules are altered in the β-catenindeficient growth plate. In a reciprocal mouse model in which CA-LEF1 is expressed in chondrocytes, constitutive Wnt/β-catenin signaling is elicited (Nagayama et al 2008). Mutant synchondroses have accelerated chondrocyte maturation.…”