The development of the growth plate is a highly regulated process which involves several transcription factors, growth factors and extracellular matrix (ECM) compounds including PGs. resting zone, proliferative zone, prehypertrophic zone and hypertrophic zone forming a growth plate. After a period of cell proliferation, chondrocytes undergo maturation and become organized into four distinct zones i.e. It begins with the condensation of mesenchymal stem cells which differentiate into chondrocytes expressing type II collagen as well as cartilage specific PGs. Chondrogenesis is the earliest step for endochondral bone formation. Versican is expressed in early stages of chondrogenesis, inversely, aggrecan is expressed during establishment and maturation of the chondrogenic cells. During skeletal development, different PGs are expressed in a highly defined pattern that is regulated spatially and temporally. Once the linker is formed, GAG chains are extended by addition of repeating disaccharides units forming chondroitin-sulfate (CS) and heparan-sulfate (HS) GAG chains by CS and HS polymerizing enzymes. This process is initiated by Xylosyltransferase I (XylT-I) and II (XylT-II) which catalyze the transfer of xylose from UDP-xylose to a specific serine residue of the core protein. Biosynthesis of GAG chains is catalyzed by several glycosyltransferases and requires formation of common tetrasaccharide linker GlcA-β1-3-Gal-β1-3-Gal-β1-4-Xyl-Ser. PGs are involved in multiple pathological situations such as cancer, atherosclerosis, osteoarthritis and skeleton disorders and their biological activity is highly related to their GAG chains. They play an essential role in storage of growth factors and cytokines, and in establishing a morphogen gradient during tissue development. They are involved in various biological processes such as extracellular matrix deposition, cell proliferation, adhesion, migration and differentiation. Proteoglycans (PGs) are important bio-macromolecules composed of core protein and glycosaminoglycans (GAGs) chains. Our study revealed an uncovered role of XylT-I in the synthesis of proteoglycans and provides evidence that the structure of glycosaminoglycan chains of proteoglycans controls chondrocyte maturation and matrix organization. These cells characterized by higher expression of glycosaminoglycans exhibit circular organization then undergo hypertrophy and death creating a circular structure at the secondary ossification center location. Intriguingly, loss of XylT-I induced at embryonic stage E18.5 the migration of progenitor cells from the perichondrium next to the groove of Ranvier into the central part of epiphysis of E18.5 embryos. Histological and Second Harmonic Generation microscopy analysis revealed that deletion of XylT-I accelerated chondrocyte maturation and prevents chondrocytes columnar organization and arrangement in parallel of collagen fibers in the growth plate, suggesting that XylT-I controls chondrocyte maturation and matrix organization. Mechanistically, deletion of XylT-I impairs the synthesis of long glycosaminoglycan chains leading to the formation of proteoglycans with shorter glycosaminoglycan chains. We found that loss of XylT-I induces hypertrophic phenotype-like of chondrocytes associated with reduced interterritorial matrix. Here, we show that XylT-I is expressed and critical for the synthesis of proteoglycans in resting and proliferative but not in hypertrophic chondrocytes in the growth plate. However, the specific role of XylT-I in the growth plate is not completely understood. Genetic mutations in the Xylt1 gene are associated with Desbuquois dysplasia type II syndrome characterized by sever prenatal and postnatal short stature.
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