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Rôle physiologique et physiopathologique de la xylosyltransférase I dans le développement ostéoarticulaire

Abstract : Proteoglycans (PGs) are proteins present in the extracellular matrix and on the surface of cells. They consist of a protein to which chains of glycosaminoglycans (GAGs) are attached. PGs play an essential role in many biological processes and in the homeostasis of different tissues including cartilage, bone and skin. Mutations in the genes encoding PG core proteins or the enzymes involved in GAG biosynthesis are associated with several syndromes and pathologies in human. Initiation of GAG synthesis is catalyzed by xylosyltransferase I (XT-I). XT-I plays a key role in the regulation of the synthesis of PGs in cartilage and it has been shown recently that hypomorphic mutations of XT-I are associated with the Desbuquois syndrome type II (DBQD2), characterized by skeletal abnormalities (osteochondrodysplasia). To elucidate the role of XT-I in skeletal development, we generated a conditional transgenic mouse, Col2α1-CreERTM; XylT1flox/flox allowing the invalidation of XT-I gene in the cartilage. Interestingly, the invalidation of XT-I induces skeletal developmental abnormalities characterized by significant dwarfism, and defects in many skeletal elements. Histological studies and SHG microscopy (second harmonic generation) of the growth plate showed the importance of XT-I in extracellular matrix formation, fibrillation of collagen type II, maturation of chondrocytes and their organization in column in the growth plate. The analysis of the molecular mechanisms involved indicates the disruption of the TGF-β signaling pathway in the growth plate. On the other hand, histomorphometric and histological studies of the bones revealed that the XT-I deficiency causes an acceleration of the ossification process with a stimulation of the osteoclasts activity in spongy bone leading to bone resorption, and increased ossification of the cortical bone. This work revealed the role of XT-I in skeletal development and in the maintenance of cartilage and bone homeostasis and highlighted the role of the TGF-β pathway in developmental abnormalities. This work also paves the way for the development of potential therapeutics for the treatment of patients with Desbuquois syndrome type II
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Submitted on : Thursday, April 18, 2019 - 9:38:00 AM
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Dima Ghannoum. Rôle physiologique et physiopathologique de la xylosyltransférase I dans le développement ostéoarticulaire. Biologie du développement. Université de Lorraine; Université libanaise, 2018. Français. ⟨NNT : 2018LORR0240⟩. ⟨tel-02103078⟩



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