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

Research output: Contribution to journalArticle

  • External authors:
  • Chiara Paganini
  • Luca Monti
  • Rossella Costantini
  • Roberta Besio
  • Silvia Lecci
  • Marco Biggiogera
  • Kun Tian
  • Céline Huber
  • Valérie Cormier-Daire
  • Beth G Gibson
  • Katarzyna A Pirog
  • Antonella Forlino
  • Antonio Rossi

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.

Bibliographical metadata

Original languageEnglish
Pages (from-to)70-90
JournalMatrix biology : journal of the International Society for Matrix Biology
Volume81
Early online date12 Nov 2018
DOIs
Publication statusE-pub ahead of print - 12 Nov 2018