Abstract
Chondroitin sulfate (CS) and dermatan sulfate (DS) interact with various extracellular molecules such as growth factors, cytokines/chemokines, neurotrophic factors, morphogens, and viral proteins, thereby playing roles in a variety of biological processes including cell adhesion, proliferation, tissue morphogenesis, neurite outgrowth, infections, and inflammation/leukocyte trafficking. CS/DS are modified with sulfate groups at C-2 of uronic acid residues as well as C-4 and/or C-6 of N-acetyl-D-galactosamine residues, yielding enormous structural diversity, which enables the binding with numerous proteins. We have demonstrated that highly sulfated CS-E from squid cartilage, for example, interacts with heparin-binding proteins including midkine, pleiotrophin, and fibroblast growth factors expressed in brain with high affinity (Kd values in the nM range). Here, we analyzed the binding of CS and DS, which have a relatively low degree of sulfation and have been widely used as a nutraceutical and a drug for osteoarthritis etc., with a number of heparin-binding neurotrophic factors/cytokines using surface plasmon resonance (SPR) and structurally characterized the CS/DS chains. SPR showed that relatively low sulfated CS-A, DS, and CS-C also bound with significant affinity to midkine, pleiotrophin, hepatocyte growth factor, monokine-induced by interferon-γ, and stromal cell derived factor-1β, although the binding was less intense than that with highly sulfated CS-D and CS-E. These findings suggest that even low sulfated CS and/or DS chains may contain binding domains, which include fine sugar sequences with specific sulfation patterns, and that sugar sequences, conformations and electrostatic potential are more important than the simple degree of sulfation represented by disaccharide composition.
Similar content being viewed by others
Abbreviations
- CS:
-
Chondroitin sulfate
- DS:
-
Dermatan sulfate
- FGF:
-
Fibroblast growth factor
- GAG:
-
Glycosaminoglycan
- HIV:
-
Human immunodeficiency virus
- HGF:
-
Hepatocyte growth factor
- MIG:
-
Monokine-induced by interferon-γ
- MK:
-
Midkine
- PG:
-
Proteoglycan
- PTN:
-
Pleiotrophin
- RANTES:
-
Regulated upon activation normal T cell express sequence
- SDB-1β:
-
Stromal cell derived factor-1β
- SPR:
-
Surface plasmon resonance
References
Mizumoto, S., Uyama, T., Mikami, T., Kitagawa, H., Sugahara, K.: Biosynthetic pathways for differential expression of functional chondroitin sulfate and heparan sulfate. In: Yarema, K.J. (ed.) Handbook of Carbohydrate Engineering, pp. 289–324. CRC Press, Boca Raton (2005)
Sugahara, K., Kitagawa, H.: Recent advances in the study of the biosynthesis and functions of sulfated glycosaminoglycans. Curr. Opin. Struct. Biol. 10, 518–527 (2000)
Sugahara, K., Mikami, T., Uyama, T., Mizuguchi, S., Nomura, K., Kitagawa, H.: Recent advances in the structural biology of chondroitin sulfate and dermatan sulfate. Curr. Opin. Struct. Biol. 13, 612–620 (2003)
Sugahara, K., Mikami, T.: Chondroitin/dermatan sulfate in the central nervous system. Curr. Opin. Struct. Biol. 17, 536–545 (2007)
Kawashima, H., Atarashi, K., Hirose, M., Hirose, J., Yamada, S., Sugahara, K., Miyasaka, M.: Oversulfated chondroitin/dermatan sulfates containing GlcAβ1/IdoAα1-3GalNAc(4,6-O-disulfate) interact with L- and P-selectin and chemokines. J. Biol. Chem. 277, 12921–12930 (2002)
Thiele, H., Sakano, M., Kitagawa, H., Sugahara, K., Rajab, A., Hohne, W., Leschik, G., Nurnberg, P., Mundlos, S.: Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement. Proc. Natl. Acad. Sci. U. S. A. 101, 10155–10160 (2004)
Bao, X., Muramatsu, T., Sugahara, K.: Demonstration of the pleiotrophin-binding oligosaccharide sequences isolated from chondroitin sulfate/dermatan sulfate hybrid chains of embryonic pig brains. J. Biol. Chem. 280, 35318–35328 (2005)
Uyama, T., Ishida, M., Izumikawa, T., Trybala, E., Tufaro, F., Bergström, T., Sugahara, K., Kitagawa, H.: Chondroitin 4-O-sulfotransferase-1 regulates E disaccharide expression of chondroitin sulfate required for herpes simplex virus infectivity. J. Biol. Chem. 281, 38668–38674 (2006)
Li, F., ten Dam, G.B., Murugan, S., Yamada, S., Hashiguchi, T., Mizumoto, S., Oguri, K., Okayama, M., van Kuppevelt, T.H., Sugahara, K.: Involvement of highly sulfated chondroitin sulfate in the metastasis of the Lewis lung carcinoma cells. J. Biol. Chem. 283, 34294–34304 (2008)
Mizumoto, S., Takahashi, J., Sugahara, K.: Receptor for advanced glycation end products (RAGE) functions as a receptor for specific sulfated glycosaminoglycans, and anti-RAGE antibody or the sulfated glycosaminoglycans delivered in vivo inhibit pulmonary metastasis of tumor cells. J. Biol. Chem. 287, 18985–18994 (2012)
Miyake, N., Kosho, T., Mizumoto, S., Furuichi, T., Hatamochi, A., Nagashima, Y., Arai, E., Takahashi, K., Kawamura, R., Wakui, K., Takahashi, J., Kato, H., Yasui, H., Ishida, T., Ohashi, H., Nishimura, G., Shiina, M., Saitsu, H., Tsurusaki, Y., Doi, H., Fukushima, Y., Ikegawa, S., Yamada, S., Sugahara, K., Matsumoto, N.: Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome. Hum. Mutat. 31, 966–974 (2010)
Deepa, S.S., Umehara, Y., Higashiyama, S., Itoh, N., Sugahara, K.: Specific interactions of oversulfated chondroitin sulfate E with various heparin- binding growth factors: implications as a physiological binding partner. J. Biol. Chem. 277, 43707–43716 (2002)
Maeda, N., Fukazawa, N., Hata, T.: The binding of chondroitin sulfate to pleiotrophin/heparin-binding growth-associated molecule is regulated by chain length and oversulfated structures. J. Biol. Chem. 281, 4894–4902 (2006)
Toida, T., Sakai, S., Akiyama, H., Linhardt, R.J.: Immunological activity of chondroitin sulfate. In: Volpi, N. (ed.) Advances in Pharmacology, vol. 53, pp. 403–415. Elsevier, San Diego (2006)
Uebelhart, D., Knols, K., de Bruin, E.D., Verbruggen, G.: Treatment of knee osteoarthritis with oral chondroitin sulfate. In: Volpi, N. (ed.) Advances in Pharmacology, vol. 53, pp. 523–539. Elsevier, San Diego (2006)
Johnson, Z., Proudfoot, A.E., Handel, T.M.: Interaction of chemokines and glycosaminoglycans: a new twist in the regulation of chemokine function with opportunities for therapeutic intervention. Cytokine Growth Factor Rev. 16, 625–636 (2005)
Kinoshita, A., Sugahara, K.: Microanalysis of glycosaminoglycan-derived oligosaccharides labeled with the fluorophore 2-aminobenzamide by high-performance liquid chromatography: application to disaccharide composition analysis and exo-sequencing of oligosaccharides. Anal. Biochem. 269, 367–378 (1999)
Conrad, H.E.: Degradation of heparan sulfate by nitrous acid. In: Iozzo, R.V. (ed.) Methods in Molecular Biology “Proteoglycan Protocols”, vol. 171, pp. 347–351. Humana Press, Totowa (2001)
Levy, J.A.: The unexpected pleiotropic activities of RANTES. J. Immunol. 182, 3945–3946 (2009)
Farouk, S.S., Rader, D.J., Reilly, M.P., Mehta, N.N.: CXCL12: a new player in coronary disease identified through human genetics. Trends Cardiovasc. Med. 20, 204–209 (2010)
Müller, M., Carter, S., Hofer, M.J., Campbell, I.L.: The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity—a tale of conflict and conundrum. Neuropathol. Appl. Neurobiol. 36, 368–387 (2010)
Mizumoto, S., Sugahara, K.: Glycosaminoglycan chain analysis and characterization (Glycosylation/Epimerization). In: Rédini, F. (ed.) Methods in Molecular Biology, “Proteoglycans: Methods and Protocols”, vol. 836, pp. 99–115. Humana Press, Springer, New York (2012)
Bao, X., Nishimura, S., Mikami, T., Yamada, S., Itoh, N., Sugahara, K.: Chondroitin sulfate/dermatan sulfate hybrid chains from embryonic pig brain, which contain a higher proportion of L-iduronic acid than those from the adult pig brain, exhibit neuritogenic and growth factor-binding activities. J. Biol. Chem. 279, 9765–9776 (2004)
Bitter, T., Muir, H.: A modified uronic acid carbazole reaction. Anal. Biochem. 4, 330–334 (1962)
Imada, K., Oka, H., Kawasaki, D., Miura, N., Sato, T., Ito, A.: Anti-arthritic action mechanisms of natural chondroitin sulfate in human articular chondrocytes and synovial fibroblasts. Biol. Pharm. Bull. 33, 410–414 (2010)
ten Dam, G.B., van de Westerlo, E.M., Purushothaman, A., Stan, R.V., Bulten, J., Sweep, F.C., Massuger, L.F., Sugahara, K., van Kuppevelt, T.H.: Antibody GD3G7 selected against embryonic glycosaminoglycans defines chondroitin sulfate-E domains highly up-regulated in ovarian cancer and involved in VEGF binding. Am. J. Pathol. 171, 1324–1333 (2007)
Lyon, M., Deakin, J.A., Rahmoune, H., Fernig, D.G., Nakamura, T., Gallagher, J.T.: Hepatocyte growth factor/scatter factor binds with high affinity to dermatan sulfate. J. Biol. Chem. 273, 271–278 (1998)
Friand, V., Haddad, O., Papy-Garcia, D., Hlawaty, H., Vassy, R., Hamma-Kourbali, Y., Perret, G.Y., Courty, J., Baleux, F., Oudar, O., Gattegno, L., Sutton, A., Charnaux, N.: Glycosaminoglycan mimetics inhibit SDF-1/CXCL12-mediated migration and invasion of human hepatoma cells. Glycobiology 19, 1511–1524 (2009)
Shimazaki, Y., Nagata, I., Ishii, M., Tanaka, M., Marunouchi, T., Hata, T., Maeda, N.: Developmental change and function of chondroitin sulfate deposited around cerebellar Purkinje cells. J. Neurosci. Res. 82, 172–183 (2005)
Ishii, M., Maeda, N.: Spatiotemporal expression of chondroitin sulfate sulfotransferases in the postnatal developing mouse cerebellum. Glycobiology 18, 602–614 (2008)
Conrad, H.E.: Heparin-Binding Proteins. Academic, San Diego (1998)
Zhang, F., McLellan, J.S., Ayala, A.M., Leahy, D.J., Linhardt, R.J.: Kinetic and structural studies on interactions between heparin or heparan sulfate and proteins of the hedgehog signaling pathway. Biochemistry 46, 3933–3941 (2007)
Casu, B.: In: Garg, H.G., Linhardt, R.J., Hales, C.A. (eds.) Structure and Active Domains of Heparin: Chemistry and Biology of Heparin and Heparan Sulfate, pp. 1–28. Elsevier, Oxford (2005)
Ai, X., Do, A.T., Lozynska, O., Kusche-Gullberg, M., Lindahl, U., Emerson Jr., C.P.: QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling. J. Cell Biol. 162, 341–351 (2003)
Nandini, C.D., Mikami, T., Ohta, M., Itoh, N., Akiyama-Nambu, F., Sugahara, K.: Structural and functional characterization of oversulfated chondroitin sulfate/dermatan sulfate hybrid chains from the notochord of hagfish: neuritogenic activity and binding activities toward growth factors and neurotrophic factors. J. Biol. Chem. 279, 50799–50809 (2004)
Li, F., Shetty, A.K., Sugahara, K.: Neuritogenic activity of chondroitin/dermatan sulfate hybrid chains of embryonic pig brain and their mimicry from shark liver: involvement of the pleiotrophin and hepatocyte growth factor signaling pathways. J. Biol. Chem. 282, 2956–2966 (2007)
Hashiguchi, T., Kobayashi, T., Fongmoon, D., Shetty, A.K., Mizumoto, S., Miyamoto, N., Nakamura, T., Yamada, S., Sugahara, K.: Demonstration of the hepatocyte growth factor signaling pathway in the in vitro neuritogenic activity of chondroitin sulfate from ray fish cartilage. Biochim. Biophys. Acta 1810, 406–413 (2011)
Miyata, S., Komatsu, Y., Yoshimura, Y., Taya, C., Kitagawa, H.: Persistent cortical plasticity by upregulation of chondroitin 6-sulfation. Nat. Neurosci. 15, 414–422 (2012)
Fukui, S., Feizi, T., Galustian, C., Lawson, A.M., Chai, W.: Oligosaccharide microarrays for high-throughput detection and specificity assignments of carbohydrate-protein interactions. Nat. Biotechnol. 20, 1011–1017 (2002)
Yamaguchi, K., Tamaki, H., Fukui, S.: Detection of oligosaccharide ligands for hepatocyte growth factor/scatter factor (HGF/SF), keratinocyte growth factor (KGF/FGF-7), RANTES and heparin cofactor II by neoglycolipid microarrays of glycosaminoglycan-derived oligosaccharide fragments. Glycoconj. J. 23, 513–523 (2006)
Li, F., Nandini, C.D., Hattori, T., Bao, X., Murayama, D., Nakamura, T., Fukushima, N., Sugahara, K.: Structure of pleiotrophin- and hepatocyte growth factor-binding sulfated hexasaccharide determined by biochemical and computational approaches. J. Biol. Chem. 285, 27673–27685 (2010)
Maeda, N., He, J., Yajima, Y., Mikami, T., Sugahara, K., Yabe, T.: Heterogeneity of the chondroitin sulfate portion of phosphacan/6B4 proteoglycan regulates its binding affinity for pleiotrophin/HB-GAM. J. Biol. Chem. 278, 35805–35811 (2003)
Ito, Y., Hikino, M., Yajima, Y., Mikami, T., Sirko, L., von Holst, A., Faissner, A., Fukui, S., Sugahara, K.: Structural characterization of the epitopes of the monoclonal antibodies 473HD, CS-56 and MO-225 specific for chondroitin sulfate D-type using the oligosaccharide library. Glycobiology 15, 593–603 (2005)
Mitsunaga, C., Mikami, T., Mizumoto, S., Fukuda, J., Sugahara, K.: Chondroitin sulfate/dermatan sulfate hybrid chains in the development of cerebellum: Spatiotemporal regulation of the expression of critical disulfated disaccharides by specific sulfotransferases. J. Biol. Chem. 281, 18942–18952 (2006)
Handel, T.M., Johnson, Z., Crown, S.E., Lau, E.K., Proudfoot, A.E.: Regulation of protein function by glycosaminoglycans—as exemplified by chemokines. Annu. Rev. Biochem. 74, 385–410 (2005)
Hileman, R.E., Fromm, J.R., Weiler, J.M., Linhardt, R.J.: Glycosaminoglycan-protein interactions: definition of consensus sites in glycosaminoglycan binding proteins. Bioessays 20, 156–167 (1998)
Appay, V., Rowland-Jones, S.L.: RANTES: a versatile and controversial chemokine. Trends Immunol 22, 83–87 (2001)
Proudfoot, A.E., Fritchley, S., Borlat, F., Shaw, J.P., Vilbois, F., Zwahlen, C., Trkola, A., Marchant, D., Clapham, P.R., Wells, T.N.: The BBXB motif of RANTES is the principal site for heparin binding and controls receptor selectivity. J. Biol. Chem. 276, 10620–10626 (2001)
Martin, L., Blanpain, C., Garnier, P., Wittamer, V., Parmentier, M., Vita, C.: Structural and functional analysis of the RANTES-glycosaminoglycans interactions. Biochemistry 40, 6303–6318 (2001)
Farber, J.M.: A macrophage mRNA selectively induced by gamma-interferon encodes a member of the platelet factor 4 family of cytokines. Proc. Natl. Acad. Sci. U. S. A. 87, 5238–5242 (1990)
Sgadari, C., Farber, J.M., Angiolillo, A.L., Liao, F., Teruya-Feldstein, J., Burd, P.R., Yao, L., Gupta, G., Kanegane, C., Tosato, G.: Mig, the monokine induced by interferon-gamma, promotes tumor necrosis in vivo. Blood 89, 2635–2643 (1997)
Schwartz, G.N., Liao, F., Gress, R.E., Farber, J.M.: Suppressive effects of recombinant human monokine induced by IFN-γ (rHuMig) chemokine on the number of committed and primitive hemopoietic progenitors in liquid cultures of CD34+ human bone marrow cells. J. Immunol. 159, 895–904 (1997)
Oberlin, E., Amara, A., Bachelerie, F., Bessia, C., Virelizier, J.L., Arenzana-Seisdedos, F., Schwartz, O., Heard, J.M., Clark-Lewis, I., Legler, D.F., Loetscher, M., Baggiolini, M., Moser, B.: The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382, 833–835 (1996)
Omata, T., Segawa, Y., Itokazu, Y., Inoue, N., Tanaka, Y.: Effects of chondroitin sulfate-C on bradykinin-induced proteoglycan depletion in rats. Arzneimittelforschung 49, 577–581 (1999)
Beren, J., Hill, S.L., Diener-West, M., Rose, N.R.: Effect of pre-loading oral glucosamine HCl/chondroitin sulfate/manganese ascorbate combination on experimental arthritis in rats. Exp. Biol. Med. 226, 144–151 (2001)
Kahan, A., Uebelhart, D., De Vathaire, F., Delmas, P.D., Reginster, J.Y.: Long-term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: the study on osteoarthritis progression prevention, a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 60, 524–533 (2009)
Clegg, D.O., Reda, D.J., Harris, C.L., Klein, M.A., O’Dell, J.R., Hooper, M.M., Bradley, J.D., Bingham 3rd, C.O., Weisman, M.H., Jackson, C.G., Lane, N.E., Cush, J.J., Moreland, L.W., Schumacher Jr., H.R., Oddis, C.V., Wolfe, F., Molitor, J.A., Yocum, D.E., Schnitzer, T.J., Furst, D.E., Sawitzke, A.D., Shi, H., Brandt, K.D., Moskowitz, R.W., Williams, H.J.: Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N. Engl. J. Med. 354, 795–808 (2006)
Cho, S.Y., Sim, J.S., Jeong, S.C., Chang, S.Y., Choi, D.W., Toida, T., Kim, Y.S.: Effects of low molecular weight chondroitin sulfate on type II collagen-induced arthritis in DBA/1 J mice. Biol. Pharm. Bull. 27, 47–51 (2004)
Lamari, F.N., Theocharis, A.D., Asimakopoulou, A.P., Malavaki, C.J., Karamanos, N.K.: Metabolism and biochemical/physiological roles of chondroitin sulfates: analysis of endogenous and supplemental chondroitin sulfates in blood circulation. Biomed. Chromatogr. 20, 539–550 (2006)
Jain, A., Gupta, Y., Jain, K.: Perspectives of biodegradable natural polysaccharides for site-specific drug delivery to the colon. J. Pharm. Pharm. Sci. 10, 86–128 (2007)
Theoharides, T.C., Patra, P., Boucher, W., Letourneau, R., Kempuraj, D., Chiang, G., Jeudy, S., Hasse, L., Athanasiou, A.: Chondroitin sulphate inhibits connective tissue mast cells. Br. J. Pharmacol. 131, 1039–1049 (2000)
McCarty, M.F., Russell, A.L., Seed, M.P.: Sulfated glycosaminoglycans and glucosamine may synergize in promoting synovial hyaluronic acid synthesis. Med. Hypotheses 54, 798–802 (2000)
Sakai, S., Akiyama, H., Sato, Y., Yoshioka, Y., Linhardt, R.J., Goda, Y., Maitani, T., Toida, T.: Chondroitin sulfate intake inhibits the IgE-mediated allergic response by down-regulating Th2 responses in mice. J. Biol. Chem. 281, 19872–19880 (2006)
Acknowledgments
This work was supported in part by Grants-in-aid for Scientific Research on Innovative Areas (24110501) (to K.S.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT), Japan–Thailand Research Cooperative Program (to K. S.), Young Scientists (B) 23790066 (to S. M.) from the Japan Society for the Promotion of Science (JSPS), and the endowment from Zeria Pharmaceutical Co., Ltd.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mizumoto, S., Fongmoon, D. & Sugahara, K. Interaction of chondroitin sulfate and dermatan sulfate from various biological sources with heparin-binding growth factors and cytokines. Glycoconj J 30, 619–632 (2013). https://doi.org/10.1007/s10719-012-9463-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10719-012-9463-5