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Antonio Rossi, Ph.D. - "In vivo models of chondrodysplasias caused by defects in proteoglycan biosynthesis: phenotyping and pharmacological approaches"

Department of Molecular Medicine Unit of Biochemistry, University of Pavia, Italy
When Nov 21, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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Heritable skeletal disorders are connective tissue diseases that primarily affect the development and homeostasis of the skeleton; unfortunately, in general no resolutive treatments are available for these painful conditions. Thus, the goal in this research area is the deep phenotyping of relevant in vivo and in vitro models in order to identify and test novel targets for innovative therapies.
In this respect among the skeletal disorders that are being studied in our group, Diastrophic Dysplasia (DTD) and Desbuquois Dysplasia (DBQD) are paradigmatic. Both dysplasias, with similar clinical features, are caused by defects in the biosynthesis of glycosaminoglycan (GAG) chains of proteoglycans (PGs).
DBQD type 1 is caused by mutations in the Calcium-Activated Nucleotidase 1 (CANT1) a Golgi/ER resident enzyme. To define the role of CANT1 in the etiology of DBQD, we generated Cant1 knock-in and knock-out mice. Morphological and clinical observations in the murine strains confirmed the skeletal defects described in the patients. PG synthesis was studied in rib knock-out chondrocytes; mutant cells showed GAG chains with reduced hydrodynamic size, GAG oversulfation, reduced PG synthesis and impaired secretion. This latter observation was confirmed by transmission electron microscopy of mutant vs. wild type cartilage showing the presence of dilated vacuoli suggesting a role of CANT1 in protein secretion.
Nowadays animal models are useful tools to elucidate the molecular mechanisms underlying genetic diseases as described above, but also to develop therapeutic strategies. The dtd mouse is a murine model of Diastrophic Dysplasia (DTD) a skeletal dysplasia caused by mutations in the sulfate-chloride antiporter (SLC26A2), crucial for sulfate uptake and GAG sulfation. Deep phenotyping of the model suggested that N-acetyl-L-cysteine (NAC) might play a role as an intracellular sulfate source for macromolecular sulfation. Because of the important prenatal phase of skeletal development and growth, we administered NAC in the drinking water to pregnant mice to explore a possible transplacental effect on the foetuses. A marked increase of proteoglycan sulfation was observed in dtd newborns from NAC treated pregnancies compared to the placebo group paralleled by a partial rescue of the abnormal bone morphology.
In conclusion, these different mouse models have recapitulated key aspects of disease pathology and identified new fundamental mechanisms paving the way for developing potential therapeutic approaches.

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