Direct relationship between mutations in three cartilage-specific collagen genes (col2a1, col9a2 and col 10 a1) and hereditary skeletal disorders, that can predispose to osteo-arthritis, has been established in gain of function transgenic mice. The phenotypic consequences of the different mutations have been analized at molecular and cellular level.
Mutations in Col 2a1 can generate a broad spectrum of phenotypes in humans as in transgenic mice. A neonatal lethal phenotype was obtained with the delation of exon 48 in mice. Analysis of these mice shows depletion of collagen fibrils in cartilage matrix and sign of premature chondrocyte death. The ability of the mutant protein to affect chondrocyte proliferation and differentiation was also studied. Up to date no phenotype was observed with a glycine to a glutamic acid substitution at residue 853. However the time course of the osteoarthritic lesions makes the analysis of this phenotype very long.
For the same reasons the initially planned experiments with cultured chondrocytes derived from the affected transgenic animals were not performed. Transgenic mice carring the deletion of exon 25 to 27 in Col 9 a2 also show an increased susceptibility to osteoarthrosis at the age 9-12 months. The first lesions observed in these mice consist of fibrillation of articular cartilage followed by erosions, localized cell death, osteophytes formation, thickening and subcondral bone. The result is complete disappearance of articular cartilage and exposure of bone and joint surfaces.
Gain of function transgenic mice with 68 amino acid residues deletion in the triple helical domain of Col 10a1 did not show any phenotype in agreement with the previously generatd loss of function mice.
The transgenic mice produced show the possibility to mimick degenerative joint diseases in animal models and may become an important tool to design novel therapeutic interventions including gene therapy for osteoarthritis.
In conclusion the two year project on transgenic animal models for human osteoarthrosis and chondrodysplasias has been quite successful. Not only we have been able to confirm our hypothesis of the role of type II and IX collagens in the two types of cartilage diseases, but have learned more of the molecular mechanisms involved in the disease processes. Due to the long time required for the osteoarthritic lesions to develop some aspects remain to be completed later. We have also learned that transgenic mice are useful models for research on osteoporosis, craniofacial development and ophthalmological abnormalities. Finally, work on the type X, collagen genes suggests that mice are not always suitable for mimicking human disease due to differences in physiological parameters. The project has stimulated the groups connections with other European scientists and has triggered several new and promising subprojects which could lead into novel therapeutic applications, too.
Funding SchemeCSC - Cost-sharing contracts
20520 Turku / Abo