Abstract
Multiple osteochondromas (MO) is a hereditary disorder associated with benign cartilaginous tumors, known to be characterized by absence or highly reduced amount of heparan sulfate (HS) in the extracellular matrix of growth plate cartilage, which alters proper signaling networks leading to improper bone growth. Although recent studies demonstrated accumulation of HS in the cytoplasm of MO chondrocytes, nothing is known on the structural alterations which prevent HS from undergoing its physiologic pathway. In this work, osteochondroma (OC), peripheral chondrosarcoma, and healthy cartilaginous human samples were processed following a procedure previously set up to structurally characterize and compare HS from pathologic and physiologic conditions, and to examine the phenotypic differences that arise in the presence of either exostosin 1 or 2 (EXT1 or EXT2) mutations. Our data suggest that HS chains from OCs are prevalently below 10 kDa and slightly more sulfated than healthy ones, whereas HS chains from peripheral chondrosarcomas (PCSs) are mostly higher than 10 kDa and remarkably more sulfated than all the other samples. Although deeper investigation is still necessary, the approach here applied pointed out, for the first time, structural differences among OC, PCS, and healthy HS chains extracted from human cartilaginous excisions, and could help in understanding how the structural features of HS are modulated in the presence of pathological situations also involving different tissues.
Highlights
Heparan sulfate proteoglycans (HSPGs) are amongst the most biologically important glycoconjugates, playing an essential role in a variety of events at the molecular level [1]
Two groups of human cartilage excisions were analyzed for their heparan sulfate (HS) content: healthy samples from fetal growth plate (FT) and prepubescent growth plate (GRP), and pathologic samples from multiple osteochondromas patients, including both osteochondromas (OC) and their malignant degeneration, chondrosarcomas (CS)
All samples were freeze-dried after each step of purification and analyzed by NMR to verify the efficacy of the purification step and possibly the appearance of signals typical of HS
Summary
Heparan sulfate proteoglycans (HSPGs) are amongst the most biologically important glycoconjugates, playing an essential role in a variety of events at the molecular level [1]. Their expression and structural characteristics vary depending on tissue and cell type, and they undergo dramatic changes during development and in disease processes [2,3,4]. (EXT1, MIM608177) and exostosin-2 (EXT2, MIM608210) genes play a key role in HSPG biosynthesis, as they encode for two ubiquitously expressed transmembrane Golgi glycosyltransferases, EXT1 and EXT2, which catalyze HS polymerization forming a heterodimeric complex [6,7,8,9,10]. After the polymerization, an important modification process follows, involving the sequential action of a series of enzymes: N-deacetylase-N-sulfotransferase (NDST), which removes the N-acetyl group from
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