Growth factors have been isolated from rat chondrosarcoma and from bovine, human, and chicken cartilage. Both chondrosarcoma-derived growth factor (ChDGF) and cartilage-derived growth factor (CDGF) bind tightly to heparin. When applied to columns of heparin-sepharose, ChDGF and CDGF bind and are eluted with about 1.5 to 1.8 M NaCl. It appears that these growth factors have an affinity for heparin. First of all, they do not bind at all to other glycosaminoglycans such as chondroitin sulfate and hyaluronic acid. In addition, they bind much more tightly to heparin than does PDGF, even though ChDGF, CDGF, and PDGF are all highly cationic polypeptides with isoelectric points of about 10. The heparin affinity of these growth factors greatly facilitates their purification. By using a combination of cation exchange and heparin-sepharose chromatography, ChDGF has been purified to apparent homogeneity. ChDGF is an Mr = 18,000 polypeptide that is active at about 1 to 10 ng/ml. Bovine CDGF has also been purified by these methods and is a Mr = 19,000 polypeptide. Both ChDGF and CDGF are growth factors that stimulate the migration and proliferation of capillary endothelial cells. In addition, ChDGF has been shown to induce angiogenesis in the 9-day old chick embryo chorioallantoic membrane. Thus it appears that ChDGF and CDGF constitute a class of tumor and normal tissue-derived angiogenesis factors. The affinity of ChDGF and CDGF for heparin suggests a mechanism of growth factor action. Heparin-like molecules are the major glycosaminoglycan species on the endothelial cell surface and in the basement membrane of capillaries. It is possible that heparin-like molecules concentrate heparin-binding growth factors in the vicinity of the endothelium, resulting in endothelial cell proliferation. At present, the goals of the research are: (1) to sequence ChDGF and CDGF, the sequence information being used to generate synthetic peptides and to construct the growth factor gene; (2) to raise monoclonal antibodies to ChDGF and CDGF, antibodies to be used to detect and localize ChDGF and CDGF in vivo; (3) to administer ChDGF and CDGF in vivo via sustained release polymers; and (4) to determine the mechanism of action of these growth factors, in particular in regard to their interaction with endothelial cell heparin-like glycosaminoglycans. (J)
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