β-d-Xylosides Stimulate GAG Synthesis in Chondrocyte Cultures Due to Elevation of the Extracellular GAG Domains, Accompanied by the Depletion of the Intra–pericellular GAG Pools, with Alterations in the GAG Profiles

Abstract

The familial disease of hereditary multiple exostoses is characterized by abnormal skeletal deformities requiring extensive surgical procedures. In hereditary multiple exostoses patients there is a shortage in the pericellular glycosaminoglycan (GAG) of heparan sulfate (HS), related to defective activity of HS glycosyltransferases, mainly in the pericellular regions of chondrocytes. This study searched for a novel approach employing xylosides with different aglycone groups priming a variety of GAG chains, in attempting to alter the GAG compositional profile. Cell cultures of patients with osteochondroma responded to p-nitrophenyl β-D-xyloside by a significant increase in total GAG synthesis, expressed mainly in the extracellular domains, limited to chondroitin sulfate). The different β-D-xylosides, in addition to increasing the synthesis of extracellular GAGs, led to a significant depletion of the intracellular GAG domains. In mouse chondrocyte cultures, β-D-xylosides with different aglycones created a unique distribution of the GAG pools. Of special interest was the finding that the naphthalene methanol β-D-xyloside showed the highest absolute levels of HS-GAGs in both extracellular and intra-pericellular moieties compared with other β-D-xylosides and with controls without xyloside. In summary, β-D-xylosides can be utilized in chondrocyte cultures to modify the distribution of GAGs between the extracellular and intracellular compartments. In addition, xylosides may alter the profile of specific GAG chains in each moiety.

Heparan sulfate proteoglycans mediate renal carcinoma metastasis

“…Currently however, limited therapeutics exist that target degradation of the glycocalyx. To remove HS, naphthalene methanol‐ d ‐xyloside (NX), a drug that blocks the assembly of HS side chains of proteoglycans has been described . To deplete hyaluronans, pegylated human recombinant hyaluronidase (PEGPH20) has been used in preclinical and clinical studies to enhance perfusion and drug delivery .…”

“…To remove HS, naphthalene methanol-D-xyloside (NX), a drug that blocks the assembly of HS side chains of proteoglycans has been described. 40 To deplete hyaluronans, pegylated human recombinant hyaluronidase (PEGPH20) has been used in preclinical and clinical studies to enhance perfusion and drug delivery. [41][42][43] Unfortunately, systemic delivery of such drugs can have serious side effects by depleting the endothelial cell glycocalyx, which provides a barrier to vascular leakage and inflammatory cell adhesion and sustains flow-induced release of nitric oxide.…”

The glycocalyx and its significance in human medicine

“…It acts to promote GCX reconstitution and control GCX degrading enzymes and has antiinflammatory, anti-apoptotic and antisenescence effects on ECs. Frati Munari [103] noted that treatment with sulodexide improved chronic venous disease and promoted healing of chronic Pentosan polysulphate Reduces MMP activity [104] Wheat germ agglutinin Lectin that binds to HS and HA [60] Rhamnan sulphate Enhances HS synthesis [105][106][107] Hawthorn extract WSS 1442 Enhances HS (indirect evidence) [108,110] Cationic copolymers Bind to the GCX [111] MicroRNAs Restore PGs and their biosynthetic enzymes [129] Degrade the glycocalyx PEGPH20 Depletes HA [112][113][114][115] 4-MU/4-ME Suppresses HA synthesis [92,[116][117][118][119][120][121][122][123] A6 monoclonal antibody Blocks CD44 [124] Naphthalene methanol-D-xyloside Blocks HS assembly [125] Peracetylated 6-fluoro-GalNAc Inhibits sulphated GAG synthesis [126] siRNAs Block GAG synthetic enzymes Unpublished data PEGPH20, pegylated human recombinant hyaluronidase; 4-MU, 4-methylumbelliferone; 4-ME, 4-methlesculetin; GAG, glycosaminoglycan; MMP, matrix metalloproteinase; HS, heparan sulphate; HA, hyaluronic acid; GCX, glycocalyx; PG, proteoglycan.…”

“…Naphthalene methanol-D-xyloside, a drug that blocks the assembly of HS side chains on proteoglycans, has been utilized to remove HS pharmacologically [125]. Van Wijk et al [126] tested 11 sugar analogues for their capacity to interfere with GAG chain elongation or GAG sulphation and discovered that peracetylated 6-fluoro-GalNAc was particularly effective in inhibiting the biosynthesis of sulphated GAGs.…”

Odiparcil, a potential glycosaminoglycans clearance therapy in mucopolysaccharidosis VI—Evidence from in vitro and in vivo models

“…β-D-xyloside derivatives are found to be more efficient than D-xylose as substrates for β4GalT7, thus eliminating the need for core protein and xylosyltransferase but still engaging the downstream GAG synthesis machinery [19][20][21][22]. The newly synthesized β-D-xyloside-bound GAG (in case of odiparcil mainly CSGAG) are soluble and readily releasable into the circulatory system [25] and, therefore, might lead to a net reduction of cellular GAG [26][27][28]. Since MPS VI pathologies are caused by the cellular accumulation of CSGAG, it could be hypothesised that a reduction in CS/DS levels could provide relief from disease symptoms.…”