Calcium activated nucleotidase 1 (CANT1) is critical for glycosaminoglycan biosynthesis in cartilage and endochondral ossification.
Acid Anhydride Hydrolases
/ genetics
Animals
Cartilage
/ cytology
Cell Proliferation
Cells, Cultured
Chondrocytes
/ cytology
Craniofacial Abnormalities
/ genetics
Disease Models, Animal
Dwarfism
/ genetics
Endoplasmic Reticulum
/ metabolism
Gene Knock-In Techniques
Gene Knockdown Techniques
Glycosaminoglycans
/ biosynthesis
Humans
Joint Instability
/ genetics
Mice
Nucleotidases
/ genetics
Ossification, Heterotopic
/ genetics
Osteogenesis
Polydactyly
/ genetics
Calcium activated nucleotidase 1
Cartilage
Glycosaminoglycan
Growth plate
Proteoglycan
Skeletal dysplasia
Journal
Matrix biology : journal of the International Society for Matrix Biology
ISSN: 1569-1802
Titre abrégé: Matrix Biol
Pays: Netherlands
ID NLM: 9432592
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
21
09
2018
revised:
05
11
2018
accepted:
05
11
2018
pubmed:
16
11
2018
medline:
12
5
2020
entrez:
16
11
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30439444
pii: S0945-053X(18)30397-4
doi: 10.1016/j.matbio.2018.11.002
pmc: PMC6598859
pii:
doi:
Substances chimiques
Glycosaminoglycans
0
Nucleotidases
EC 3.1.3.-
Acid Anhydride Hydrolases
EC 3.6.-
Cant1 protein, mouse
EC 3.6.1.6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
70-90Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
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