In vivo involvement of heparan sulfate proteoglycan in the bioavailability, internalization, and catabolism of exogenous basic fibroblast growth factor

The in vivo bioavailability of exogenous fibroblast growth factor 2 (FGF2) was studied after i.v. injection of uniformly C-14-labeled FGF2 into young rats. C-14-FGF2 was rapidly accumulated in almost all solid organs within 5 min. After 30 min, more than 65% of FGF2 was retained in liver, 4.5% in ki dneys, 1.2% in spleen, 0.15% in adrenal glands, and trace amounts in bone m arrow, eyes, lungs,and heart. Suborgan distribution of C-14-FGF2 showed tha t for kidneys and adrenal glands, the labeling was mainly concentrated in t he cortical zone. Incubation of organ sections with 2 M NaCl or heparin elu ted all the radioactivity, indicating that labeling was due to FGF2-heparan sulfate proteoglycan (HSPG) interactions. Electrophoretic analysis show on ly native C-14-FGF2 in the blood and extracellular matrix; however, FGF2 is continuously catabolized in solid organs, indicating that all participate in the clearance of FGF2 by cellular internalization and subsequent catabol ism. All FGF2 catabolic fragments bound heparin, demonstrating the preserva tion of their HSPG-binding site during the in vivo intracellular catabolism of FGF2. Analysis of the high-affinity receptors of FGF2 (FGFR-1 and FGFR- 3) and the mitogen-activated protein kinase did not show any increase in ei ther FGFR tyrosine phosphorylation or in mitogen-activated protein kinase a ctivation. This study shows for the first time that exogenous FGF2 is cleav ed by HSPG cellular internalization and catabolism without inducing the act ivation of FGFRs within at least five organs in vivo, which strongly sugges ts that the HSPG-dependent internalization and catabolism pathway may contr ol the in vivo bioavailability of FGF2.