Supplemental Figure 2 from Oncofetal Chondroitin Sulfate Glycosaminoglycans Are Key Players in Integrin Signaling and Tumor Cell Motility
Thomas Mandel ClausenMarina Ayres PereiraNader Al NakouziHtoo Zarni OoMette Ø. AgerbækSherry LeeMaj Sofie Ørum-MadsenAnders Riis KristensenAmal M. El-NaggarPaul M. GrandgenettJean L. GremMichael A. HollingsworthPeter Johannes HolstThor G. TheanderPoul H. SorensenMads DaugaardAli Salanti
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Chondroitin sulfate proteoglycans are the primary constituents of the macrophage glycosaminoglycan and extracellular microenvironment. To examine their potential role in atherogenesis, we investigated the biological importance of one of the chondroitin sulfate glycosaminoglycan biosynthesis gene, ChGn-2 (chondroitin sulfate N-acetylgalactosaminyltransferase-2), in macrophage foam cell formation. Approach and Results: ChGn-2-deficient mice showed decreased and shortened glycosaminoglycans. ChGn-2-/-/LDLr-/- (low-density lipoprotein receptor) mice generated less atherosclerotic plaque after being fed with Western diet despite exhibiting a metabolic phenotype similar to that of the ChGn-2+/+/LDLr-/- littermates. We demonstrated that in macrophages, ChGn-2 expression was upregulated in the presence of oxLDL (oxidized LDL), and glycosaminoglycan was substantially increased. Foam cell formation was significantly altered by ChGn-2 in both mouse peritoneal macrophages and the RAW264.7 macrophage cell line. Mechanistically, ChGn-2 enhanced oxLDL binding on the cell surface, and as a consequence, CD36-an important macrophage membrane scavenger receptor-was differentially regulated.ChGn-2 alteration on macrophages conceivably influences LDL accumulation and subsequently accelerates plaque formation. These results collectively suggest that ChGn-2 is a novel therapeutic target amenable to clinical translation in the future. Graphic Abstract: A graphic abstract is available for this article.
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Synthesis and distribution of glycosaminoglycans in the developing facial region of mouse embryos were investigated during stages of development when the embryonic facial processes form and expand. Facial regions of 11th and 12th day embryos were either 1) labeled with 3H-glucosamine and newly synthesized glycosaminoglycans determined on the basis of specific enzyme sensitivity, or 2) sectioned and stained with Alcian Blue coupled with enzyme digestion in order to localize glycosaminoglycans. On the basis of enzyme sensitivity over half of the newly synthesized glycosaminoglycans during this time period were identified as hyaluronate, with only 12-15% representing chondroitin sulfate. Hyaluronate was found to be the primary component of the extracellular matrix. Basal laminae exhibited prominent chondroitin sulfate staining and also appeared to contain hyaluronate and heparan sulfate. It is suggested that hyaluronate may play a structural role in maintaining the shape and orientation of the facial processes.
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Abstract: Isolated glycosaminoglycans (GAGs) were quantified biochemically in the cerebella of 6‐day‐old rats. 14 C‐Labeled hyaluronic acid (HA) and chondroitin‐4‐sulfate (C‐4‐S), added prior to isolation of GAGs from tissue, served as internal standards to allow correction for unknown losses during the purification procedure and exact quantification of GAGs in the intact tissue. Three main constituents—HA, chondroitin sulfate (CS), and heparan sulfate (HS)—were found at concentrations of 1.82, 1.52, and 0.76 μg/mg protein amounting to 44%, 37%, and 19% of the total GAG fraction, respectively. Incorporation of [ 3 H]glucosamine precursor into GAGs was higher for HS (56% of incorporated precursor) and lower for HA (29%) and CS (15%). The specific activities of individual GAGs were 64.7 nCi/μg for HS, 14.2 for HA, and 8.3 for CS.
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Previous data from our laboratory suggest that the transitional epithelium of the urinary bladder secretes and binds to its surface a glycosaminoglycan. The presence of this substance at the bladder surface markedly reduces the ability of microorganisms to adhere to the mucosa. Furthermore, this glycosaminoglycan can be removed (with acid) and replaced by intravesical instillation of a synthetic sulfonated glycosaminoglycan (heparin), whose presence is as effective as that of the natural glycosaminoglycan in reducing adherence. We conducted the current study with a different sulfonated glycosaminoglycan to determine whether the antiadherence activity is generalized to heparin congeners and whether the antiadherence effect of heparin is independent of its known anticoagulant activity. In this study we examined the sulfonated glycosaminoglycan, sodium pentosanpolysulfate, which lacks significant anticoagulant activity, and found it to have a mechanism of antiadherence analogous to that of heparin and almost equally as active on a weight basis.
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The existence and pathophysiological role of glycosaminoglycans in the tear fluid in humans was investigated using quantitative analyses of hyaluronic acid and chondroitin sulfate in the tear fluid. The subjects were 42 eyes of 31 normal controls, 9 eyes of 9 patients with superficial punctate keratitis (SPK), and 13 eyes of 13 patients with epithelial defect. After an instillation of 100 microliters saline solution in the conjunctival sac, as much tear fluid as possible was collected from the lower cul-de-sac. The glycosaminoglycans in the tears were then treated with chondroitinase ABC to make fractions of unsaturated disaccharides. The quantities of disaccharides were determined by high-performance liquid chromatography. Concentrations were expressed as nanomoles of unsaturated disaccharides per protein in the tears. The concentrations of hyaluronic acid and chondroitin sulfate in the normal controls were 0.07 +/- 0.12(n mol/mg protein) and 6.91 +/- 3.63 (n mol/mg protein), respectively. The mean concentration of hyaluronic acid was significantly higher in patients with epithelial erosion than in normal controls, whereas the mean concentration of chondroitin sulfate was significantly lower in patients with epithelial erosion than in normal controls. There was no significant difference in the concentration of glycosaminoglycans between the patients with SPK and normal controls. The results of our study suggest that glycosaminoglycans are synthesized and endogenously secreted into the tear fluids and, especially in the case of hyaluronic acid, may play an important role in corneal epithelial wound healing in patients with epithelial erosion.
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Abstract Transitions in glycosaminoglycan content occur during early cartilage development in 5–8 week human embryos. With increasing embryonic age, there is an increase in chondroitin 6‐sulfate relative to chondroitin 4‐sulfate, and a large decrease in heparan sulfate. Keratan sulfate is detectable after 8 weeks. Mesonephros and limb buds show distinct differences from all other tissues.
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