Abstract
The Wnt/beta-catenin signaling pathway is essential for normal skeletal development because conditional gain or loss of function of beta-catenin in cartilage results in embryonic or early postnatal death. To address the role of beta-catenin in postnatal skeletal growth and development, Col2a1-ICAT transgenic mice were generated. Mice were viable and had normal size at birth, but became progressively runted. Transgene expression was limited to the chondrocytes in the growth plate and articular cartilages and was associated with decreased beta-catenin signaling. Col2a1-ICAT transgenic mice showed reduced chondrocyte proliferation and differentiation, and an increase in chondrocyte apoptosis, leading to decreased widths of the proliferating and hypertrophic zones, delayed formation of the secondary ossification center, and reduced skeletal growth. Isolated primary Col2a1-ICAT transgenic chondrocytes showed reduced expression of chondrocyte genes associated with maturation, and demonstrated that VEGF gene expression requires cooperative interactions between BMP2 and beta-catenin signaling. Altogether the findings confirm a crucial role for Wnt/beta-catenin in postnatal growth.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Animals, Newborn
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Bone Development / drug effects
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Proteins / pharmacology
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Cartilage / abnormalities*
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Cartilage / drug effects
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Cartilage / growth & development*
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Cartilage / pathology
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Cell Cycle Proteins / metabolism
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Cell Differentiation / drug effects
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Cell Proliferation / drug effects
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Chondrocytes / drug effects
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Chondrocytes / metabolism
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Chondrocytes / pathology
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Chondrogenesis* / drug effects
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Embryo, Mammalian / abnormalities
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Embryo, Mammalian / drug effects
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Embryo, Mammalian / metabolism
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Gene Expression Regulation, Developmental / drug effects
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Growth Plate / drug effects
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Growth Plate / pathology
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Mice
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Mice, Transgenic
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Neovascularization, Physiologic / drug effects
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Promoter Regions, Genetic / genetics
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Repressor Proteins
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Signal Transduction* / drug effects
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Transcription Factors / metabolism
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Transcription, Genetic / drug effects
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Transforming Growth Factor beta / pharmacology
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Transgenes
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Wnt Proteins / metabolism
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beta Catenin / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Bmp2 protein, mouse
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Proteins
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Cell Cycle Proteins
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Ctnnbip1 protein, mouse
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Repressor Proteins
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Transcription Factors
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Transforming Growth Factor beta
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Vascular Endothelial Growth Factor A
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Wnt Proteins
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beta Catenin