RECOMBINANT HUMAN GROWTH-HORMONE (GH)-BINDING PROTEIN ENHANCES THE GROWTH-PROMOTING ACTIVITY OF HUMAN GH IN THE RAT

To address the role of the GH-binding protein (GHBP) in GH physiology, two forms of recombinant human GHBP (rhGHBP) were given alone or in c ombination with rhGH to hypophysectomized rats or GH-deficient dwarf r ats. Hypophysectomized rats were given daily sc injections of excipien t, hGH, rhGHBP, or rhGH plus rhGHBP (produced in Escherichia coli) for 7 days. Injections of rhGH induced dose-related body weight gain and bone growth that were increased by the coadministration of rhGHBP with rhGH; rhGHBP alone had no effect. Serum insulin-like growth factor in creased 24 h later when rhGH was given together with rhGHBP (P < 0.01) , but not when rhGH was given alone. E. coli-derived rhGHBP also enhan ced that bioactivity of coadministered rhGH in the GH-deficient dwarf rat. In contrast, the glycosylated rhGHBP, made in human A293 cells, i nhibited the growth-promoting activity of coadministered rhGH. The opp osite effects of these two forms of rhGHBP could be explained by clear ance studies that showed radiolabeled rhGH bound to A293 cell-derived rhGHBP to be cleared more rapidly from the blood than free rhGH. Natur al rabbit GHBP and E. coli-derived rhGHBP both prolonged the presence of rhGH in blood. It is proposed that by slowing the clearance of GH, GHBP increased the bioactivity of GH. In summary, codelivery of rhGHBP and rhGH caused a dose-dependent enhancement of the activity of rhGH in two rat models of GH deficiency. This suggests that endogenous circ ulating GHBP may increase the activity of blood-borne GH in a similar manner.