Transferrin promotes endothelial cell migration and invasion: implication in cartilage neovascularization

During endochondral bone formation, avascular cartilage differentiates to hypertrophic cartilage that then undergoes erosion and vascularization leading to bone deposition. Resting cartilage produces inhibitors of angiogenesis, shifting to production of angiogenic stimulators in hypertrophic cartilage. A major protein synthesizd by hypertrophic cartilage both in vivo and in vitro is transferrin, ttere we show that transferrin is a major angiogenic molecule released by hypertrophic cartilage, l-;ndoth(,lial ceil migration and invasion is stimulated by transferrins from a number of dif%rent sources, including hypertrophic cartilage. Checkerboard analysis demonstrates that transferrin is a chemotactic and chemokinetic molecule. ('bondrocyte conditioned media show similar properties. Polyclonal antitransferrin antibodies completely block endothelial ('ell migration and invasion induced by purified transferrin and substantially inhibit the activity produced by hypertrophic chondrocytes. Function blocking m. lbs directed against the transferrin receptor similarly reduce the endothelial migratory response. The angiogenic activity of transferrins was confirmed by in vivo assays on chicken egg chorioallantoic membrane, showing promotion of neovascularization by tran. -ferrins purified from ditferent sources including conditioned culture medium.