Clark R G, Mortensen D L, Carlsson L M, Spencer S A, McKay P, Mulkerrin M, Moore J, Cunningham B C
Genentech, Inc., South San Francisco, California 94080-4990, USA.
Endocrinology. 1996 Oct;137(10):4308-15. doi: 10.1210/endo.137.10.8828490.
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 combination with rhGH to hypophysectomized rats or GH-deficient dwarf rats. Hypophysectomized rats were given daily sc injections of excipient, 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 increased 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 enhanced the bioactivity of coadministered rhGH in the GH-deficient dwarf rat. In contrast, the glycosylated rhGHBP, made in human A293 cells, inhibited the growth-promoting activity of coadministered rhGH. The opposite effects of these two forms of rhGHBP could be explained by clearance studies that showed radiolabeled rhGH bound to A293 cell-derived rhGHBP to be cleared more rapidly from the blood than free rhGH. Natural 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 circulating GHBP may increase the activity of blood-borne GH in a similar manner.
为了探讨生长激素结合蛋白（GHBP）在生长激素（GH）生理学中的作用，将两种形式的重组人GHBP（rhGHBP）单独或与rhGH联合给予垂体切除的大鼠或生长激素缺乏的侏儒大鼠。给垂体切除的大鼠每日皮下注射赋形剂、hGH、rhGHBP或rhGH加rhGHBP（由大肠杆菌产生），持续7天。注射rhGH可诱导剂量相关的体重增加和骨骼生长，rhGHBP与rhGH共同给药可增强这种作用；单独注射rhGHBP则无作用。当rhGH与rhGHBP一起给药时，血清胰岛素样生长因子在24小时后增加（P<0.01），但单独给予rhGH时则无增加。大肠杆菌来源的rhGHBP也增强了共同给药的rhGH在生长激素缺乏的侏儒大鼠中的生物活性。相比之下，在人A293细胞中产生的糖基化rhGHBP抑制了共同给药的rhGH的促生长活性。这两种形式的rhGHBP的相反作用可以通过清除研究来解释，该研究表明，与游离rhGH相比，与A293细胞来源的rhGHBP结合的放射性标记rhGH从血液中清除得更快。天然兔GHBP和大肠杆菌来源的rhGHBP都延长了rhGH在血液中的存在时间。有人提出，通过减缓GH的清除，GHBP增加了GH的生物活性。总之，在两种生长激素缺乏的大鼠模型中，rhGHBP和rhGH的联合给药导致rhGH活性的剂量依赖性增强。这表明内源性循环GHBP可能以类似的方式增加血源性GH的活性。
