Article (Scientific journals)
Altered chondrocyte differentiation, matrix mineralization and MEK-Erk1/2 signaling in an INPPL1 catalytic knock-out mouse model of opsismodysplasia
Vande Catsyne, Charles-Andrew; Sayyed, Sufyan Ali; Molina Ortiz, Patricia et al.
2020In Advances in Biological Regulation, 76, p. 100651
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Keywords :
SHIP2; Inppl1; opsismodysplasia; Skeletal dysplasia; chondrocyte; osteocalcin; endochondral ossification; bone mineralization
Abstract :
[en] Opsismodysplasia (OPS) is a rare but severe autosomal recessive skeletal chondrodysplasia caused by inactivating mutations in the Inppl1/Ship2 gene. The molecular mechanism leading from Ship2 gene inactivation to OPS is currently unknown. Here, we used our Ship2∆/∆ mouse expressing reduced amount of a catalytically-inactive SHIP2 protein and a previously reported SHIP2 inhibitor to investigate growth plate development and mineralization in vivo, ex vivo and in vitro. First, as observed in OPS patients, catalytic inactivation of SHIP2 in mouse leads to reduced body length, shortening of long bones, craniofacial dysmorphism, reduced height of the hyperthrophic chondrocyte zone and to defects in growth plate mineralization. Second, intrinsic Ship2∆/∆ bone defects were sufficient to induce the characteristic OPS alterations in bone growth, histology and mineralization ex vivo. Third, expression of osteocalcin was significantly increased in SHIP2-inactivated chondrocyte cultures whereas production of mineralized nodules was markedly decreased. Targeting osteocalcin mRNA with a specific shRNA increased the production of mineralized nodules. Fourth, levels of p-MEK and p-Erk1/2 were significantly increased in SHIP2-inactivated chondrocytes in response to serum and IGF-1, but not to FGF2, as compared to control chondrocytes. Treatment of chondrocytes and bones in culture with a MEK inhibitor partially rescued the production of mineralized nodules, the size of the hypertrophic chondrocyte zone and bone growth, raising the possibility of a treatment that could partially reduce the phenotype of this severe condition. Altogether, our results indicate that Ship2∆/∆ mice represent a relevant model for human OPS. They also highlight the important role of SHIP2 in chondrocytes during endochondral ossification and its different differentiation steps. Finally, we identified a role of osteocalcin in mineralized nodules production and for the MEK-Erk1/2 signaling pathway in the OPS phenotype.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Vande Catsyne, Charles-Andrew ;  Université de Liège - ULiège > GIGA-R : Labo de génétique fonctionnelle
Sayyed, Sufyan Ali ;  Université de Liège > GIGA-Research
Molina Ortiz, Patricia ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Moës, Bastien ;  Université de Liège - ULiège > Molecular Biology of Diseases-Functional Genetics
Communi, David
Muller, Joséphine 
Heusschen, Roy ;  Université de Liège - ULiège > GIGA-R : Hématologie
CAERS, Jo  ;  Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'hématologie clinique
Azzi, Abdelhalim ;  Université de Liège - ULiège > Molecular Biology of Diseases-Functional Genetics
Erneux, Christophe
Schurmans, Stéphane  ;  Université de Liège - ULiège > Département des sciences fonctionnelles (DSF) > Biochimie métabolique vétérinaire
Language :
Title :
Altered chondrocyte differentiation, matrix mineralization and MEK-Erk1/2 signaling in an INPPL1 catalytic knock-out mouse model of opsismodysplasia
Publication date :
Journal title :
Advances in Biological Regulation
Publisher :
Elsevier, Netherlands
Volume :
Pages :
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 18 September 2019


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