Axin2 regulates chondrocyte maturation and axial skeletal development

Abstract

Axis inhibition proteins 1 and 2 (Axin1 and Axin2) are scaffolding proteins that modulate at least two signaling pathways that are crucial in skeletogenesis: the Wnt/b-catenin and TGF-b signaling pathways. To determine whether Axin2 is important in skeletogenesis, we examined the skeletal phenotype of Axin2-null mice in a wild-type or Axin1 þ/À background. Animals with disrupted Axin2 expression displayed a runt phenotype when compared to heterozygous littermates. Whole-mount and tissue b-galactosidase staining of Axin2 LacZ/LacZ mice revealed that Axin2 is expressed in cartilage tissue, and histological sections from knockout animals showed shorter hypertrophic zones in the growth plate. Primary chondrocytes were isolated from Axin2-null and wild-type mice, cultured, and assayed for type X collagen gene expression. While type II collagen levels were depressed in cells from Axin2-deficient animals, type X collagen gene expression was enhanced. There was no difference in BrdU incorporation between null and heterozygous mice, suggesting that loss of Axin2 does not alter chondrocyte proliferation. Taken together, these findings reveal that disruption of Axin2 expression results in accelerated chondrocyte maturation. In the presence of a heterozygous deficiency of Axin1, Axin2 was also shown to play a critical role in craniofacial and axial skeleton development. ß

Dual function of β-catenin in articular cartilage growth and degeneration at different stages of postnatal cartilage development

“…By this approach, we found that collagen X and MMP-13 expressions were significantly increased following LiCl-induced β-catenin activation. It is well known that articular chondrocytes undergo maturation during early OA pathogenesis, after which the characteristic maturational marker genes collagen X [28][29][30] and MMP-13 [31,32] are expressed. MMP-13 is a potent enzyme that preferentially targets type II collagen in the cartilage matrix for degradation; interestingly, MMP-13 expression has been found to be increased in human OA joints [33].…”

A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

“…Further assessment of these mice revealed an important role of axin-2 in mature bone: significant differences in bone volume and BMD are seen at 6 and 12 months when compared with wild-type mice, but no differences in bone volume or BMD are observed at 2 months of age (129). These mice also show an abnormal chondrocyte phenotype due to expedited maturation, resulting in a shorter hypertrophic zone in the growth plate of long bones (128). An Axin2 mutation was also identified in the canopus (canp) mouse: mice that were homozygous for the V26D missense mutation in Axin2 were arrested at midgestation with abnormal heart development and shortened or doubled tails.…”

Wnt Signaling in Bone Development and Disease: Making Stronger Bone with Wnts

“…Removal of the Wnt antagonist secreted Frizzled-related protein 1 (sFRP1) in mice led to a diminished growth plate and increased calcification in the hypertrophic zone, and accelerated differentiation of hypertrophic chondrocytes (Gaur et al 2006). A similar phenotype is seen in Axin2-null mice that were runted and showed evidence of accelerated chondrocyte maturation (Dao et al 2010). Constitutive activation of b-catenin in chondrocytes and skeletal mesenchyme also caused neonatal lethality with severe chondrodysplasia (Akiyama et al 2004;Guo et al 2004;Hill et al 2005).…”

“…This phenotype can be rescued by reducing levels of b-catenin (Liu et al 2007). Compound Axin2 2/2 ; Axin1 þ/2 mice have recently been shown to develop severe craniofacial and axial skeleton defects (Dao et al 2010), again highlighting the important pro-osteogenic functions of the Wnt/b-catenin signaling pathway in skeletal development.…”