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. 2013 Nov 15;38(24):2079-84.
doi: 10.1097/01.brs.0000435024.57940.8d.

Chondrocyte-specific inhibition of β-catenin signaling leads to dysplasia of the caudal vertebrae in mice

Bing Shu  1 , Tian-Fang Li, Xiao-Feng Li, De-Zhi Tang, Yejia Zhang, Qi Shi, Yong-Jun Wang, Di Chen
Affiliations
Free PMC article

Chondrocyte-specific inhibition of β-catenin signaling leads to dysplasia of the caudal vertebrae in mice

Bing Shu et al. Spine (Phila Pa 1976). .
Free PMC article

Abstract

Study design: To inhibit β-catenin specifically signaling in chondrocytes Col2-ICAT transgenic mice were generated. Anomalies in caudal vertebrae were detected during embryonic and postnatal stages of Col2-ICAT transgenic mice.

Objective: To determine the role of canonical β-catenin signaling in caudal vertebral development.

Summary of background data: β-catenin signaling plays a critical role in skeletal development. Col2-ICAT transgenic mice were generated to selectively block β-catenin signaling by overexpression of the ICAT gene in chondrocytes.

Methods: Tails of E16.5 transgenic embryos and adult Col2-ICAT transgenic mice and their wild-type littermates were collected and analyzed. Skeletal preparation, 3-dimensional micro-computed tomographic and histological analyses were performed to evaluate changes in the structure of caudal vertebrae. Bromodeoxyuridine labeling was performed to evaluate changes in chondrocyte proliferation in caudal vertebrae.

Results: Skeletal preparation and 3-dimensional micro-computed tomographic analyses revealed bone deformation and angulated deformities in tail tissue in Col2-ICAT transgenic mice. Histological studies revealed abnormal bone development and dysplastic caudal vertebrae in Col2-ICAT transgenic mice. Inhibition of β-catenin signaling in cartilage resulted in vertebral dysplasia leading to aberrant resegmenting process. Thus, 2 poorly developed sclerotomes failed to fuse to form a complete vertebrae. BrdU labeling revealed a decreased chondrocyte proliferation in both cartilageous templates of transgenic embryos and the growth plate of adult Col2-ICAT transgenic mice.

Conclusion: Wnt/β-catenin signaling plays an important role in vertebral development. Inhibition of β-catenin signaling in chondrocytes results in caudal vertebra deformity in mice, which may occur as early as in the stage of sclerotome formation.

Level of evidence: N/A.

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Figures

Figure 1.
Figure 1.
Col2-ICAT transgenic mice display an aberrant vertebral development resulting in angulated deformity in tails as evidenced by macroscopic observation (A) and radiographic analysis (B). The results of whole-mount Alizarin red/Alcian blue staining showed abnormal bone formation in the tails of the Col2-ICAT transgenic mice (C). The results were further confirmed by micro-CT analysis (D). The quantitative data showed that numbers of caudal vertebrae of the Col2-ICAT transgenic mice were significantly reduced compared with the WT littermates (E). P < 0.05, unpaired Student t test (n = 6). WT indicates wild-type; CT, computed tomographic.
Figure 2.
Figure 2.
Tail-tissue deformity of adult Col2-ICAT transgenic mice. Histological analysis with H&E (A) and safranin O/fast green (B) staining demonstrated the dysplasia of caudal vertebrae in Col2-ICAT transgenic mice compared with their WT littermates. Disorganized bone due to vertebral dysplasia exhibits a typical cartilage endplate, endochondral ossification, and IVD-like structure between the abnormal bone and the adjacent vertebra. Sparse cartilaginous tissue was also found opposite to the abnormal vertebra with limited bone formation inside (black arrow). Right and left panels, ×100, middle panels, ×40. The results of BrdU labeling demonstrated that chondrocyte proliferation in growth plate of caudal vertebrae from the Col2-ICAT transgenic mice was significantly reduced compared with their WT littermates (×200, C). H&E indicates hematoxylin/eosin; IVD, intervertebral disc; BrdU, bromodeoxyuridine; WT, wild-type.
Figure 3.
Figure 3.
Defects in the development of caudal vertebrae at early embryonic stage. Macroscopic deformities (the white arrows) in tails were observed in E16.5 Col2-ICAT transgenic embryos (A). The results of Alizarin red/Alcian blue staining showed angulated tail and ectopic caudal vertebrae of E16.5 Col2-ICAT transgenic embryos (B) (×100). Cell proliferation was reduced in cartilaginous template of caudal vertebrae of E16.5 Col2-ICAT transgenic embryos compared with WT embryos (×400, C). The BrdU positive cells were significantly decreased in Col2-ICAT transgenic embryos compared with wild-type controls (D). *P < 0.05, unpaired Student t test (n = 6). BrdU indicates bromodeoxyuridine; WT, wild-type.
Figure 4.
Figure 4.
Ectopic resegmentation and formation of caudal vertebrae were observed in Col2-ICAT transgenic embryos. Histological analyses showed that ectopic resegmentation (arrows), axis excursion (A) as well as poorly formed dysplastic caudal vertebrae were observed in Col2-ICAT transgenic embryos (B). A, ×100; B, upper panel, ×100; lower panel, ×400. H&E indicates hematoxylin/eosin; WT, wild-type.
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