Chondrodysplasias Caused by Defects in the Col2a1 Gene
Professor Markku Hakala, Rheumatism Foundation Hospital, Heinola, Finland
Professor Hannu Aro, University of Turku
Professor Juha Peltonen, University of Turku
Docent Mikko Lammi, University of Kuopio, Finland
Professor Heikki Helminen, University of Kuopio, Finland
Docent Kaija Puustjärvi, Helsinki University Hospital, Finland
Professor Heikki Kröger, Kuopio University Hospital, Finland
Articles of the thesis
Mutations in COL2A1 gene encoding for type II collagen have been shown to cause a variety of chondrodysplasias and osteoarthrosis. They also play a role in the pathogenesis of disc degeneration. In this study, we investigated mice with defects in the Col2a1 gene. Due to the great homology of the human and murine genomes, the hypothesis was that the mice might manifest a similar phenotype as the human patients. It has been shown previously that substitution of arginine at position 519 to cysteine (Arg519Cys) in human type II procollagen a1(II) gene causes an early generalized OA with mild chondrodysplasia. Del1(+/-) mice, heterozygous for a transgene harboring a 150 bp deletion mutation in Col2a1 gene for type II collagen, have also been shown to suffer from progressive osteoarthrosis. The heterozygous knockout of COL2A1 gene causes Stickler’s syndrome in human patients.
In this study, three lines of mouse models were investigated. First, male mice with heterozygous inactivation of Col2a1 gene were compared with the control mice. In addition, voluntary running activity was monitored in half of these mice. Secondly, the mice harboring an arginine to cysteine substitution at position 519 of COL2A1 gene were compared with the control mice. Finally, Del1(+/-) mice were investigated for the skeletal abnormalities.
Heterozygous inactivation of the Col2a1 caused a growth delay in young mice. They also had irregular vertebral endplates, which calcified prematurely. The proteoglycan concentration in the spinal tissues was decreased. These features were compensated by the age of 15 months. The bone mineral density of the mice with the gene defect did not increase when the mice used running wheels as it did in normal mice. Arg519Cys mutation caused dysplastic changes in the long bones of young mice, flattened vertebral bodies, and osteoarthritic changes in joints. The intervertebral discs of the transgenic animals were degenerated, and their histological structure was disturbed. The changes were more severe in mice with no murine Col2a1 allele. The 150 bp deletion mutation in Col2a1 gene caused a decrease in the breaking strength and ultimate stress of femoral bone, despite the fact that femoral size, morphology and mineral density of the 15-month-old transgenic mice were the same as in controls. No differences in hydroxyproline or calcium content, or dry mass of the humeri could be observed between the groups. In polarized light microscopic analysis, the parallelism of the femoral bone collagen network was 4% lower in the transgenic mice. Also in the vertebral bone, the birefringence was 33% and in the annulus fibrosus of the intervertebral disc 57% lower in the transgenic 15-month-old female mice than in the age-matched controls. Femoral cortical bone had islets positive for type II collagen both in the control and transgenic mice.
Mice with heterozygous knockout of Col2a1 gene show phenotype similar to that seen in patients with Stickler’s syndrome. Also, the Arg519Cys mutation in COL2A1 gene produced phenotype typical for patients suffering from progressive osteoarthrosis and mild chondrodysplasia. The transgene in Col2a1 gene harboring a 150 bp deletion mutation led to decreased collagen fibril organization in bone and lower bone breaking strength.
We conclude that the defects or alterations in the Col2a1 gene or genetic background result in a phenotype in mice bearing resemblance to alterations in humans. In future, specific treatments of the disorders caused by defects in the human COL2A1 gene may be tested in mice.
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Last updated January 29, 2019