Calcium activated nucleotidase 1 (CANT1) is critical for glycosaminoglycan biosynthesis in cartilage and endochondral ossification.

Autor: Paganini C; Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, Pavia, Italy; Scuola Universitaria Superiore IUSS, Pavia, Italy., Monti L; Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, Pavia, Italy., Costantini R; Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, Pavia, Italy., Besio R; Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, Pavia, Italy., Lecci S; Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, Pavia, Italy., Biggiogera M; Department of Biology & Biotechnology, University of Pavia, Pavia, Italy., Tian K; Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Schwartz JM; Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Huber C; Department of Genetics, INSERM UMR1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, AP-HP, Hôpital Necker Enfants Malades, Paris, France., Cormier-Daire V; Department of Genetics, INSERM UMR1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, AP-HP, Hôpital Necker Enfants Malades, Paris, France., Gibson BG; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK., Pirog KA; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK., Forlino A; Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, Pavia, Italy., Rossi A; Department of Molecular Medicine, Unit of Biochemistry, University of Pavia, Pavia, Italy. Electronic address: antrossi@unipv.it.
Jazyk: angličtina
Zdroj: Matrix biology : journal of the International Society for Matrix Biology [Matrix Biol] 2019 Aug; Vol. 81, pp. 70-90. Date of Electronic Publication: 2018 Nov 12.
DOI: 10.1016/j.matbio.2018.11.002
Abstrakt: Desbuquois dysplasia type 1 (DBQD1) is a chondrodysplasia caused by mutations in CANT1 gene encoding an ER/Golgi calcium activated nucleotidase 1 that hydrolyses UDP. Here, using Cant1 knock-in and knock-out mice recapitulating DBQD1 phenotype, we report that CANT1 plays a crucial role in cartilage proteoglycan synthesis and in endochondral ossification. Specifically, the glycosaminoglycan synthesis was decreased in chondrocytes from Cant1 knock-out mice and their hydrodynamic size was reduced, whilst the sulfation was increased and the overall proteoglycan secretion was delayed. Interestingly, knock-out chondrocytes had dilated ER cisternae suggesting delayed protein secretion and cellular stress; however, no canonical ER stress response was detected using microarray analysis, Xbp1 splicing and protein levels of BiP and ATF4. The observed proteoglycan defects caused deregulated chondrocyte proliferation and maturation in the growth plate resulting in the reduced skeletal growth. In conclusion, the pathogenic mechanism of DBQD1 comprises deregulated chondrocyte performance due to defective intracellular proteoglycan synthesis and altered proteoglycan properties in the extracellular matrix.
(Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: