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

Lookup NU author(s): Silvia Lecci, Beth Gibson, Dr Katarzyna Pirog

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

Author(s): Paganini C, Monti L, Costantini R, Besio R, Lecci S, Biggiogera M, Tian K, Schwartz JM, Huber C, Cormier-Daire V, Gibson BG, Pirog KA, Forlino A, Rossi A

Publication type: Article

Publication status: Published

Journal: Matrix Biology

Year: 2019

Volume: 81

Pages: 70-90

Print publication date: 01/08/2019

Online publication date: 12/11/2018

Acceptance date: 05/11/2018

Date deposited: 20/11/2018

ISSN (print): 0945-053X

ISSN (electronic): 1569-1802

Publisher: Elsevier BV

URL: https://doi.org/10.1016/j.matbio.2018.11.002

DOI: 10.1016/j.matbio.2018.11.002

PubMed id: 30439444


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