Investigation des mécanismes moléculaires impliqués dans les anomalies du développement ostéoarticulaire chez la souris invalidée pour le gène de la Xylosyltransférase I

Abstract : Proteoglycans (PGs) play an essential role in several major physiological processes such as cell signaling, proliferation and migration; this is mainly due to the interactions between their glycosaminoglycan chains (GAGs) with soluble mediators and their receptors. The initiation of the synthesis of GAG chains of PGs is catalyzed by Xylosyltransferase I (XT-I). Recently several studies have shown that mutations in XT-I gene are associated with Desbuquois syndrome type II which is characterized by skeletal abnormalities. To study the role of XT-I in skeletal development, we generated knockout mice for the XT-I gene (XT-I KO). XT-I KO mice show pronounced dwarfism and apparent frontonasal hypoplasia reflecting abnormalities in skeletal development. Evaluation of PG content revealed a strong decrease in PG synthesis in XT-I KO mice. Analysis of the different chondrocyte zones in the growth plate revealed a loss of columnar organization of proliferative chondrocyte and a significant reduction of the hypertrophic zone. To identify the mechanisms and factors underlying skeletal abnormalities in XT-I KO mice, the expression of several genes involved in skeletal development and in the regulation of chondrogenesis were analyzed by in situ hybridization using RNAscope technique. The results showed a strong expression of markers of chondrocyte hypertrophy thus suggesting early maturation of chondrocytes in XT-I KO mice. The XT-I KO embryos show also a premature formation of the secondary ossification center, indicating a precocious ossification which ultimately leads to the growth abnormalities showed in XT-I KO mice. The study of the signaling pathways involved in differentiation and chondrocyte maturation revealed an overexpression of the FGFR3 receptor and a significant activation of the downstream signaling pathways, thus suggesting disturbances of FGF signaling. Given the important role of FGFR3 in the regulation of chondrogenesis and endochondral ossification, these results strongly suggest the involvement of the FGF pathway in the development of skeletal abnormalities in XT-I KO mice and pave the way for the development of new therapeutics for the treatment of patients with Desbuquois syndrome type II.
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Taieb Mahdia. Investigation des mécanismes moléculaires impliqués dans les anomalies du développement ostéoarticulaire chez la souris invalidée pour le gène de la Xylosyltransférase I. Médecine humaine et pathologie. Université de Lorraine, 2019. Français. ⟨NNT : 2019LORR0032⟩. ⟨tel-02157545⟩

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