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Janne Sahlman

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

Abstract 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.

  1. Sahlman J, Inkinen R, Hirvonen T, Lammi MJ, Lammi PE, Nieminen J, Lapveteläinen T, Prockop DJ, Arita M, Li SW, Hyttinen MM, Helminen HJ, Puustjärvi K: Premature vertebral endplate ossification and mild dics degeneration in mice after inactivation of one allele of the Col2a1 gene for type II collagen. Spine 26(23):2558-2565, 2001 [Pubmed] [Full text]

  2. Sahlman J, Pitkänen MT, Prockop DJ, Arita M, Li SW, Helminen HJ, Långsjö TK, Puustjärvi K, Lammi MJ: A human COL2A1 gene with an Arg519Cys mutation causes osteochondrodysplasia in transgenic mice. Arthritis Rheum 50(10):3153-3160, 2004 [Pubmed] [Full text]

  3. Nieminen J, Sahlman J, Hirvonen T, Jämsä T, Tuukkanen J, Kovanen V, Kröger H, Jurvelin J, Arita M, Li SW, Prockop DJ, Hyttinen MM, Helminen HJ: Abnormal response to physical activity in femurs after heterozygous inactivation of one allele of the Col2a1 gene for type II collagen in mice. Calcif Tissue Int 77(2): 104-112, 2005 [Pubmed] [Full text]

  4. Sahlman J, Nieminen J, Morko J, Rieppo J, Jämsä T, Tuukkanen J, Arokoski JPA, Salminen H, Säämänen AM, Vuorio E, Helminen HJ, Puustjärvi K, Lammi MJ: Reduced bone strength and collagen organization in female mice harboring deletion in Col2a1 gene.

Related articles

  1. Lapveteläinen T, Hyttinen MM, Säämänen AM, Långsjö T, Sahlman J, Felszeghy S, Vuorio E, Helminen HJ: Lifelong voluntary joint loading increases osteoarthritis in mice housing a deletion mutation in type II procollagen gene, and slightly also in non-transgenic mice. Ann Rheum Dis 61(9): 810-817, 2002 [Pubmed] [Full text]

  2. Kaarniranta K, Ihanamäki T, Sahlman J, Pulkkinen H, Uusitalo H, Arita M, Tammi R, Lammi MJ, Helminen HJ: A mouse model for Stickler's syndrome: ocular phenotype of a mice carrying a targeted heterozygous inactivation of type II (pro)collagen gene (Col2a1). Exp Eye Res 83(2):297-303, 2006 [Pubmed] [Full text]

  3. Nieminen J, Sahlman J, Hirvonen T, Lapveteläinen T, Miettinen M, Arnala I, Malluche HH, Helminen HJ: Disturbed synthesis of type II collagen interferes with rate of bone formation and growth and increases bone resorption in transgenic mice. Calcif Tissue Int 82(3): 229-237, 2008 [Pubmed] [Full text]

Last updated January 29, 2019

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