Journal of Biochemistry Advance Access originally published online on February 22, 2007
Journal of Biochemistry 2007 141(5):653-660; doi:10.1093/jb/mvm067
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© 2007 The Japanese Biochemical Society.
Stimulation of Hepatocyte Growth Factor Production by Heparin-derived Oligosaccharides
1Division of Molecular Regenerative Medicine, Department of Biochemistry and Molecular Biology, Osaka University Graduate School of Medicine, 2-2-B7 Yamadaoka, Suita, Osaka 565-0871; 2Osaka Laboratory, Sawai Pharmaceutical, Co., Ltd., 8-14 Ikue 1-Chome, Asahi-Ku, Osaka 535-0004; and 3Saito Laboratory, Kringle Pharma, Inc., 7-7-15 Saitoasagi, Ibaraki, Osaka 567-0085, Japan
*To whom the correspondence should be addressed. Tel: +81-6-6879-3783, Fax: +81-6-6879-3789, E-mail: nakamura{at}onbich.med.osaka-u.ac.jp
Received December 31, 2006; Accepted February 14, 2007
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Abstract |
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We previously reported that heparin post-transcriptionally stimulates the production of hepatocyte growth factor (HGF). In this study, we addressed the size-dependency of heparin fragments on the HGF-inducing activity aiming to obtain fragments without antiblood coagulant activity. Heparin fragments, produced by digestion with heparinase, were size-fractionated and tested for HGF-inducing activity in cultured human fibroblasts. The HGF-inducing activity deceased with the reduction in oligosaccharide size. Decasaccharides exerted an activity comparable with undigested heparin, while smaller oligosaccharides showed lesser activities. The anticoagulant activity of heparin fragments also decreased with size and anticoagulant activity of decasaccharides was <13% that of undigested heparin. Further fractionation of decasaccharides by anion-exchange chromatography revealed that most of the decasaccharides had HGF-inducing activity and the extent of sulfation was roughly related to the activity. The lack of N-sulfation in heparin markedly reduced HGF-inducing activity, whereas 2-O-desulfation or 6-O-desulation had a lesser influence. Moreover, an N-sulfated disaccharide showed significant HGF-inducing activity, suggesting the involvement of N-sulfation in HGF-inducing activity. Because of the much reduced anticoagulant activity, potential applications of heparin-derived oligosaccharides such as decasaccharides is considerable as a therapeutic agent for many diseases.
Key Words: glycosaminoglycan, heparan sulfate, heparin, HGF, oligosaccharide
Abbreviations:
HGF, hepatocyte growth factor; HS, heparan sulfate; DMEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum; UA, hexuronic acid; 
UA, 4,5 unsaturated hexuronic acid; GlcN, N-unsubstituted glucosamine; GlcNS, N-sulfated glucosamine; GlcNAc, N-acetylglucosamine; 2S, 2-O-sulfate; 6S, 6-O-sulfate
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