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

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

Objective The present study was conducted on transgenic Del1 (+/−) mice harboring six copies of a transgene with small deletion mutation engineered into mouse type II collagen gene. Incorporation of transgene into mouse genome was predicted to cause reduced mechanical strength of articular cartilage...

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Published in:Osteoarthritis and cartilage Vol. 8; no. 4; pp. 248 - 257
Main Authors: Säämänen, A.-M.K, Salminen, H.J, Dean, P.B, De Crombrugghe, B, Vuorio, E.I, Metsäranta, M.P.H
Format: Journal Article
Language:English
Published: England Elsevier Ltd 01-07-2000
Subjects:
Animals
Blotting, Northern
Collagen - genetics
Female
Gene Deletion
Knee Joint
Male
Mice
Mice, Transgenic
Osteoarthritis - genetics
Osteoarthritis - metabolism
Osteoarthritis - pathology
Ribonucleases - analysis
RNA, Messenger - analysis
Type II collagen, Chondrocyte, Osteoarthritis, Transgenic mice
Type II collagen, Chondrocyte, Osteoarthritis, Transgenic mice
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Summary:Objective The present study was conducted on transgenic Del1 (+/−) mice harboring six copies of a transgene with small deletion mutation engineered into mouse type II collagen gene. Incorporation of transgene into mouse genome was predicted to cause reduced mechanical strength of articular cartilage with deposition of structurally inferior collagen network and consequently to predispose the animal to early-onset joint degeneration. Design Progression of degenerative chances in the knee joints of Del1 (+/−) and control mice was followed by macroscopic and histologic analyses at 3–5 month intervals between 3 and 22 months of age. Expression and distribution of type II collagen was studied with Northern hybridization, RNase protection assay and immunohistochemistry. Results Articular cartilage degeneration began with superficial fibrillation at the age of 3 months in Del1 (+/−) mice. These changes coincided with a significant reduction in the expression of both endogenous and transgene-derived type II collagen mRNA. The defects gradually progressed into erosions penetrating the articular cartilage, bony sclerosis, degeneration of menisci, mineralization of various joint structures, cyst formation and exposure of subchondral bone. Nontransgenic controls also developed osteoarthritic lesions, but these appeared significantly later and were less severe. Increased transcription of type IIA procollagen mRNA, typical for chondroprogenitor cells and cartilage repair was also observed at six months in Del1 (+/−) mice. Conclusion These findings suggest that the impact of truncated type II collagen transgene, together with maturation-related reduction in type II collagen production significantly contribute to the early-onset degeneration of knee joints in Del1 (+/−) mice. These mice with osteoarthritis-like phenotype should provide a useful model for studies on the early pathogenic mechanisms involved in articular cartilage degeneration.
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ISSN:1063-4584
1522-9653
DOI:10.1053/joca.2000.0298