Type XIII Collagen Strongly Affects Bone Formation in Transgenic Mice

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Abstract
To characterize the function of type XIII collagen, a transmembrane protein occurring at cell adhesion sites, we generated transgenic mice overexpressing it. High transgene expression was detected in cartilage and bone. The overexpression mice developed an unexpected skeletal phenotype marked by a massive increase in bone mass caused by increased bone formation rather than impaired resorption. Type XIII collagen is a type II transmembrane protein that is expressed in many tissues throughout development and adult life. It is located in focal adhesions of cultured fibroblasts and other cells and in the adhesive structures of tissues. To further characterize the function of this protein, we generated transgenic mice overexpressing it. High transgene expression was detected in cartilage and bone in locations also containing the endogenous protein. Col13a1 5'-flanking sequences were tested for their efficiencies to drive gene expression. Skeletal tissues of transgenic mice and wildtype littermates were compared using histological, immunohistochemical, and bone histomorphometrical analyses. Bone formation rate was measured by tetracycline double-labeling. Osteoclast number and resorption activity were determined using standard methods. RNA samples from transgenic and wildtype femurs were analyzed by Northern blotting and quantitative RT-PCR. There was no defect in early skeletal development, but the high bone mass phenotype became apparent in heterozygous mice at the age of 3-4 weeks. The changes were most noticeable in proximal long bones but were also detectable in calvarial bones. The cortical bone cross-sectional area and the volumetric BMD were highly increased, but the bone marrow was well formed. Histological and histomorphometric analysis showed that trabecular bone volume was not significantly altered. Because of the normal epiphyseal growth plates, the longitudinal growth was not affected. Bone formation rate was several times higher in the overexpression mice than in their normal littermates, whereas the osteoclast number and resorption activity were normal. RNA analysis revealed increased expression in the transcription factor Runx2 and IGF-II, both known to be involved in bone biology. Overexpression of type XIII collagen in skeletal tissues leads postnatally to an abnormally high bone mass caused by increased bone formation rather than impaired resorption. The findings suggest that type XIII collagen has an important role in bone modeling, and in particular, it may have a function in coupling the regulation of bone mass to mechanical use.

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