CANT1 deficiency in a mouse model of Desbuquois dysplasia impairs glycosaminoglycan synthesis and chondrocyte differentiation in growth plate cartilage

Abstract

Desbuquois dysplasia (DD) type 1 is a rare skeletal dysplasia characterized by a short stature, round face, progressive scoliosis, and joint laxity. The causative gene has been identified as calcium‐activated nucleotidase 1 (CANT1), which encodes a nucleotidase that preferentially hydrolyzes UDP to UMP and phosphate. In this study, we generated Cant1 KO mice using CRISPR/Cas9‐mediated genome editing. All F0 mice possessing frameshift deletions at both Cant1 alleles exhibited a dwarf phenotype. Germline transmission of the edited allele was confirmed in an F0 heterozygous mouse, and KO mice were generated by crossing of the heterozygous breeding pairs. Cant1 KO mice exhibited skeletal defects, including short stature, thoracic kyphosis, and delta phalanx, all of which are observed in DD type 1 patients. The glycosaminoglycan (GAG) content and extracellular matrix space were reduced in the growth plate cartilage of mutants, and proliferating chondrocytes lost their typical flat shape and became round. Chondrocyte differentiation, especially terminal differentiation to hypertrophic chondrocytes, was impaired in Cant1 KO mice. These findings indicate that CANT1 is involved in the synthesis of GAG and regulation of chondrocyte differentiation in the cartilage and contribute to a better understanding of the pathogenesis of DD type 1.

Integration of Proteomics and Metabonomics in Exploring the Protecting Mechanism of Gushukang Capsule in Osteoporosis Rats

“…Higher serum UA levels appear to be protective for bone loss in peri-and postmenopausal women [21]. Cant1, a calcium-activated nucleotide, is essential for glycosaminoglycan synthesis in cartilage [22]. In this study, the key differential protein Cant1 was involved in purine metabolism and was down-regulated after GSK treatment.…”

Experimental animal models of scoliosis for understanding the etiology of idiopathic scoliosis

“…В основном прозрачные тела рыбок делают их все более ценными объектами для изучения постэмбрионального развития скелета и заболеваний позвоночника [60][61][62]. ; sagittal profile (б) and top view of adult male with deformity (в) [57] лиз результатов на моделях сколиоза у мышей и рыб показал, что нарушения в формировании костной ткани позвоночника на стадии хряща могут способствовать развитию сколиоза [64][65][66][67][68][69].…”

“…Модели сколиоза со специфической инактивацией или отключением генов или белков, связанных с регуляцией хряща, предполагают, что дефекты аномального энхондрального окостенения, хондрогенной дифференцировки и апоптоза хондроцитов приводят к искривлению позвоночника [52,65,67,69]. Основные механизмы генетических факторов, приводящих к искривлению позвоночника, еще предстоит подтвердить.…”

Mechanosensory and mechanotransductive processes mediated by ion channels in articular chondrocytes: Potential therapeutic targets for osteoarthritis

“…These effects require Ca 2+ influx induced by mechanical activation of the TRPV4 ion channel [ 33 , 108 ]. The ECM of articular cartilage is a key factor in the development and progression of OA and HA plays a key role in articular cartilage lubrication and preventing ECM loss in articular cartilage in addition to its other excellent physicochemical properties, such as regulation of cell adhesion and cell motility, and manipulation of cell differentiation and proliferation [ 109 , 110 ]. Excessive cyclic tensile strain enhances the expression of ADAM10, which induces cleavage of CD44 a transmembrane protein that serves as an HA receptor [ 81 ].…”