Skeletal development in transgenic mice expressing a mutation at Gly574Ser of type II collagen

We have generated transgenic mice by microinjection of a 39-kb mouse pro alpha 1(II) collagen gene construct containing a deletion of exon 7 and intron 7. This mutation was expected to disturb the assembly and processing of the homotrimeric type II collagen molecule in cartilage. Expression of transgene mRNA at levels equivalent or higher than the endogenous mRNA in the offspring of two founder animals resulted in a severe chondrodysplastic phenotype with short limbs, hypoplastic thorax, abnormal craniofacial development, and other skeletal deformities. The affected pups died at birth due to respiratory distress. Light microscopy of epiphyseal growth plates of transgenic pups demonstrated a marked reduction in cartilaginous extracellular matrix and disruption of the normal organization of the growth plate. The zone of proliferating chondrocytes was greatly reduced whereas the zone of hypertrophic chondrocytes was markedly increased extending deep into the diaphysis suggestive of a defect in endochondral ossification. Electron microscopic examination revealed chondrocytes with extended RER, a very severe reduction in the amount of cartilage collagen fibrils, and abnormalities in their structure. We postulate that the deletion in the alpha 1(II) collagen acts as a dominant negative mutation disrupting the assembly and secretion of type II collagen molecules. The consequences of the mutation include interference with normal endochondral ossification. These mice constitute a valuable model to study the mechanisms underlying human chondrodysplasias and normal bone formation.

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Osteoarthritis-like lesions in transgenic mice harboring a small deletion mutation in type II collagen gene

Osteoarthritis and Cartilage ◽

10.1053/joca.2000.0298 ◽

2000 ◽

Vol 8 (4) ◽

pp. 248-257 ◽

Cited By ~ 47

Author(s):

A.-M.K Säämänen ◽

H.J Salminen ◽

P.B Dean ◽

B De Crombrugghe ◽

E.I Vuorio ◽

...

Keyword(s):

Transgenic Mice ◽

Type Ii Collagen ◽

Deletion Mutation ◽

Collagen Gene ◽

Type Ii ◽

Small Deletion

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Definition of MHC and T cell receptor contacts in the HLA-DR4restricted immunodominant epitope in type II collagen and characterization of collagen-induced arthritis in HLA-DR4 and human CD4 transgenic mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.95.13.7574 ◽

1998 ◽

Vol 95 (13) ◽

pp. 7574-7579 ◽

Cited By ~ 97

Author(s):

E. C. Andersson ◽

B. E. Hansen ◽

H. Jacobsen ◽

L. S. Madsen ◽

C. B. Andersen ◽

...

Keyword(s):

T Cell ◽

Transgenic Mice ◽

T Cell Receptor ◽

Type Ii Collagen ◽

Cell Receptor ◽

Type Ii ◽

Immunodominant Epitope ◽

Collagen Induced Arthritis ◽

Definition Of

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Skeletal Malformations Caused by Overexpression of Cbfa1 or Its Dominant Negative Form in Chondrocytes

The Journal of Cell Biology ◽

10.1083/jcb.153.1.87 ◽

2001 ◽

Vol 153 (1) ◽

pp. 87-100 ◽

Cited By ~ 267

Author(s):

Chisato Ueta ◽

Masahiro Iwamoto ◽

Naoko Kanatani ◽

Carolina Yoshida ◽

Yang Liu ◽

...

Keyword(s):

Transgenic Mice ◽

Endochondral Ossification ◽

Skeletal Development ◽

Type Ii Collagen ◽

Dominant Negative ◽

Chondrocyte Maturation ◽

Skeletal Malformations ◽

Dominant Negative Form ◽

Cellular Phenotypes

During skeletogenesis, cartilage develops to either permanent cartilage that persists through life or transient cartilage that is eventually replaced by bone. However, the mechanism by which cartilage phenotype is specified remains unclarified. Core binding factor α1 (Cbfa1) is an essential transcription factor for osteoblast differentiation and bone formation and has the ability to stimulate chondrocyte maturation in vitro. To understand the roles of Cbfa1 in chondrocytes during skeletal development, we generated transgenic mice that overexpress Cbfa1 or a dominant negative (DN)-Cbfa1 in chondrocytes under the control of a type II collagen promoter/enhancer. Both types of transgenic mice displayed dwarfism and skeletal malformations, which, however, resulted from opposite cellular phenotypes. Cbfa1 overexpression caused acceleration of endochondral ossification due to precocious chondrocyte maturation, whereas overexpression of DN-Cbfa1 suppressed maturation and delayed endochondral ossification. In addition, Cbfa1 transgenic mice failed to form most of their joints and permanent cartilage entered the endochondral pathway, whereas most chondrocytes in DN-Cbfa1 transgenic mice retained a marker for permanent cartilage. These data show that temporally and spatially regulated expression of Cbfa1 in chondrocytes is required for skeletogenesis, including formation of joints, permanent cartilages, and endochondral bones.

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