Doctoral thesis (Dissertations and theses)
Analyse de l’ossification endochondrale dans le cadre de souris déficientes en 5-phosphatase SHIP2, un modèle potentiel pour l’opsismodysplasie humaine ?
Vande Catsyne, Charles-Andrew
2020
 

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Abstract :
[en] Opsismodysplasia is a rare recessive skeletal automosal chondrodysplasia characterized by dwarfism including shortened limbs, smaller hands and feet, macrocephaly and facial dysmorphism. The fate is variable, ranging from perinatal mortality to allow some individuals to exceed twenty. The radiographic abnormalities include shortened long bones with severely delayed epiphyseal mineralization, metaphyseal malformations, shortened metacarpals and phalanges, severe platyspondyly and a narrow chest. Histological studies performed on bones of opsismodysplastic patients are few but have nevertheless been able to highlight specific alterations in the growth plate. In the resting zone, germinal chondrocytes are more numerous and appear disorganized. Within the proliferative zone, there is nearly absence of columnar organization of proliferative chondrocytes. The hypertrophic area is reduced in size and has a significantly reduced number of hypertrophic cells. Finally, the bone trabeculae are described as thickened, shortened and irregular. These alterations were observed in all patients studied, but with great variability in intensity. In 2013, a group of researchers discovered that almost 60% of opsismodysplastic patients present homozygous or heterozygous mutations in the INPPL1 gene coding for the protein SHIP2. More than 25 different mutations have been identified in opsismodysplastic patients including nonsense, in-frame, missence, frame-shift and splice site mutations. Although most of them are predicted to severely alter or even completely inactivate the catalytic function of SHIP2, the underlying mechanism is currently unknown. In order to investigate the function of SHIP2 in endochondral ossification, we used in our study a SHIP2Δ/Δ mouse expressing a reduced level of catalytically inactive SHIP2 protein and an inhibitor of the protein 5-phosphatase activity. First, as seen in opsismodysplastic patients, catalytic inactivation of SHIP2 in mice induces a reduction in body size and in long bones, a craniofacial dysmorphism, reduction of the size of the hypertrophic zone and abnormalities of the mineralization of the growth plate. Second, the presence of the protein SHIP2 Δ is sufficient to induce in vitro intrinsic bone alterations of opsismodysplasia. Third, the expression of osteocalcin is increased when SHIP2 is inactivated in primary chondrocytes in culture and concomitantly with the decrease in the formation of mineralized nodules. Targeting osteocalcin mRNA with a specific shRNA increases the production of mineralized nodules. Fourth, phosphorylation levels of MEK and ERK1/2 are significantly increased when the catalytic activity of SHIP2 is inactivated in primary chondrocytes treated with serum and IGF1, but not with FGF2, compared to controls. Treatment of chondrocytes and metatarsals with an inhibitor of MEK phosphorylation partially restores the formation of mineralized nodules, the size of the hypertrophic zone and bone growth, allowing one day a potential treatment. Together, these results indicate that SHIP2Δ/Δ mice represent a relevant model for opsismodysplasia and that the majority of these abnormalities could be explained by dysregulation of the MAPK/ERK pathway. They underline the role of SHIP2 in chondrocytes differentiation during endochondral ossification, as an inhibitor of the MAPK/ERK pathway. Finally, this thesis opens up interesting work perspectives in therapeutic research in the context of human opsismodysplasia.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Vande Catsyne, Charles-Andrew ;  Université de Liège - ULiège > GIGA
Language :
French
Title :
Analyse de l’ossification endochondrale dans le cadre de souris déficientes en 5-phosphatase SHIP2, un modèle potentiel pour l’opsismodysplasie humaine ?
Alternative titles :
[en] Analysis of endochondral ossification process in SHIP2 deficient mice, a potential model for human opsismodysplasia ?
Defense date :
07 December 2020
Number of pages :
198
Institution :
ULiège - Université de Liège
Degree :
Docteur en Sciences Vétérinaires
Promotor :
Schurmans, Stéphane  ;  Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Functional Genetics
Funders :
FRIA - Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture [BE]
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since 22 February 2021

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