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© The Rockefeller University Press,
0021-9525/1997//1375 $5.00
The Journal of Cell Biology, Volume 136, Number 6,
, 1997 1375-1384
Article |
Transferrin Promotes Endothelial Cell Migration and Invasion: Implication in Cartilage Neovascularization
Dipartimento di Oncologia Clinica e Sperimentale, Università di Genova, Genova, Italy; Istituto Internazionale di Genetica e Biofisica, Consiglio Nazionale delle Ricerche, Napoli, Italy; and || Istituto di Anatomia Umana Normale, Istologia ed Embriologia, Università di Bari, Bari, Italy
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 synthesized by hypertrophic cartilage both in vivo and in vitro is transferrin. Here we show that transferrin is a major angiogenic molecule released by hypertrophic cartilage. Endothelial cell migration and invasion is stimulated by transferrins from a number of different sources, including hypertrophic cartilage. Checkerboard analysis demonstrates that transferrin is a chemotactic and chemokinetic molecule. Chondrocyte-conditioned media show similar properties. Polyclonal anti-transferrin antibodies completely block endothelial cell migration and invasion induced by purified transferrin and inhibit the activity produced by hypertrophic chondrocytes by 50–70% as compared with controls. Function-blocking mAbs directed against the transferrin receptor similarly reduce the endothelial migratory response. Chondrocytes differentiating in the presence of serum produce transferrin, whereas those that differentiate in the absence of serum do not. Conditioned media from differentiated chondrocytes not producing transferrin have only 30% of the endothelial cell migratory activity of parallel cultures that synthesize transferrin.
The angiogenic activity of transferrins was confirmed by in vivo assays on chicken egg chorioallantoic membrane, showing promotion of neovascularization by transferrins purified from different sources including conditioned culture medium.
Based on the above results, we suggest that transferrin is a major angiogenic molecule produced by hypertrophic chondrocytes during endochondral bone formation.
Abbreviations used in this paper: bFGF, basic FGF; CAM, choriallantoic membrane; CM, conditioned medium; KS, Kaposi sarcoma.
Address all correspondence to Fiorella Descalzi Cancedda, Centro di Biotecnologie Avanzate, Largo Rosanna Benzi, 10, 16132 Genova, Italy. Tel.: (39) 10-5737392. Fax: (39) 10-5737405. e-mail: Cancedda{at}sirio.cba.unige.it
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