Characterization of the function of type XIII collagen in mice; specific roles during cardiovascular development and posnatally in bone modeling
1University of Oulu, Faculty of Medicine, Department of Medical Biochemistry and Molecular Biology
2University of Oulu, Collagen Research Unit
3University of Oulu, Biocenter Oulu
|Online Access:||PDF Full Text (PDF, 1 MB)|
|Persistent link:|| http://urn.fi/urn:isbn:9514279441
|Publish Date:|| 2005-11-23
|Thesis type:||Doctoral Dissertation
|Defence Note:||Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in Auditorium F101 of the Department of Physiology (Aapistie 7), on December 2nd, 2005, at 10 a.m.
Doctor David Rice
Research Assistant Professor Katri Selander
Type XIII collagen is a type II transmembrane protein which is expressed in many tissues throughout development and adult life. It is located in focal adhesions of cultured cells and in the adhesive structures of tissues such as the myotendinous junctions in muscle, intercalated discs in the heart and the cell-basement membrane interphases. To further characterize the function of this protein, we generated transgenic mice overexpressing it in normal and mutant forms.
A large in-frame deletion in the COL2 domain of type XIII collagen led to synthesis of truncated α1(XIII) chains in transgenic mice, disrupting the assembly of normal type XIII collagen trimers. Fibroblasts derived from the mutant mice expressed shortened α1(XIII) chains, and no intracellular accumulation of the mutant protein was detected, suggesting that the mutant molecules were expressed on the cell surface. Transgene expression led to an embryonally lethal phenotype in offspring from heterozygous mating at two distinct stages of development. The early phenotype fetuses died due to the lack of chorioallantoic fusion and functioning placenta at 10.5 dpc, while the death of the late phenotype fetuses was caused by cardiac and placental defects around 13.5 dpc. The phenotype resembles closely several other cell adhesion molecule mutants, indicating that type XIII collagen has an essential role in certain adhesive interactions that are necessary for normal development.
Mice overexpressing type XIII collagen with or without a point mutation developed postnatally an unexpected skeletal phenotype marked by a massive increase in bone mass. The cortical bone cross-sectional area and volumetric bone mineral density were highly increased, but trabecular bone volume was not significantly altered. The bone formation rate was several times higher in the mutant mice than in their normal littermates, while the osteoclast number and resorption activity were normal. Type XIII collagen was expressed highly in primary osteoblasts derived from the transgenic mice. Overexpression of type XIII collagen in osteoblasts enhanced both cell proliferation and differentiation while lack of it had opposite effects. Furthermore, mutant cells responded to mechanical strain differently than wild-type cells. The findings suggest that type XIII collagen has an important role in bone modeling, and it may in particular have a function in coupling the regulation of bone mass to mechanical usage.
Acta Universitatis Ouluensis. D, Medica
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