Study for pathological significance of insulin-like growth factor binding proteins.

胰岛素样生长因子（IGFs）与特异性结合蛋白（igfbp）结合，并推测igfbp可能调节IGF的作用。在本研究中，我们从以下方面探讨了igfbp的病理意义。1) IGFBP-6的病理生理作用尚未阐明。最近我们用免疫印迹法（Western immunoblot， WIB）检测血清IGFBP-6水平，发现慢性肾功能衰竭（CRF）患者血清IGFBP-6水平不依赖生长激素，且升高。在本研究中，为了进一步探讨血清IGFBP-6的临床意义和调节，我们测量了肾移植后CRF患者血清IGFBP-6水平。此外，我们还测量了IGFBP-2水平。所有CRF患者血清IGFBP-2和-6水平均显著升高。血液透析后血药浓度无变化。肾移植后1天血清IGFBP-6水平显著下降，并随着肾功能的改善进一步下降。与IGFBP-6相比，在肾移植后14天内，血清IGFBP-2水平没有下降。此外，我们还在尿液中发现了IGFBP-6。这些数据表明，IGFBP-6可能由肾脏排泄，血清IGFBP-6水平可能与肾功能有关，且血清IGFBP-6水平的调节与IGFBP-6不同。2.2脐带血清IGFBP-2和IGFBP-3水平分别高于和低于成人血清。脐血IGFBP-2水平与出生体重和游离igf水平呈负相关。出生体重与血清IGF-I和游离型igf呈正相关。这些发现表明，胎儿血清中IGFBP-2的变化可能会调节游离igf的相对浓度，进而调节胎儿的生长。3) IGFBP-1有反调节血糖的作用。我们发现胰岛素诱导的低血糖后3小时血清IGFBP-1没有升高。因此，我们不能支持这个假设。4)有报道称，成骨样细胞中igfbp受到多种药物的调控，但这些数据在物种之间存在差异。在本研究中，我们利用培养的人小梁骨成骨细胞，对各种药物的作用进行了研究。培养的人成骨细胞分泌igfbp，主要为IGFBP-3、-4和-2.1,25-(OH)_2D_3抑制成骨细胞的增殖，增加培养基中的骨钙素。1,25-(OH)_2D_3增加了IGFBP-3和IGFBP-4。E_2对培养液中细胞增殖和骨钙素没有影响，但升高了IGFBP-3、-4和-2。这些数据表明，人成骨细胞的igfbp受骨代谢效应物的调节。然而，igfbp如何调节IGF在骨代谢中的作用仍有待阐明。少

Insulin-like growth factors (IGFs) bind to specific binding proteins (IGFBPs), and it has been speculated that the IGFBPs might modulate IGF action. In this study, we have investigated pathological significance of IGFBPs as follows. 1) Pathophysiological roles of IGFBP-6 have not been elucidated. Recently we measured serum IGFBP-6 by Western immunoblot (WIB), and have found that serum IGFBP-6 levels are not GH dependent and increase in patients with chronic renal failure (CRF). In the present study, to investigate further clinical significance and regulation of serum IGFBP-6, we measured serum IGFBP-6 levels in patients with CRF after renal transplantation. Furthermore, we also measured IGFBP-2 levels. Serum IGFBP-2 and -6 levels remarkably increased in all patients with CRF.The levels did not change after hemodialysis. Serum IGFBP-6 levels dramatically decreased 1 day after renal transplantation and decreased further with the improvement of renal function. In contrast to IGFBP-6, seru … More m IGFBP-2 levels did not decrease during 14 days after renal transplantation. In addition, we demonstrated IGFBP-6 in urine. These data indicate that IGFBP-6 might be excreted by the kidneys and serum IGFBP-6 levels might be related with renal function, and that regulation of serum IGFBP-6 levels are different from that of IGFBP-2.2) Serum levels of IGFBP-2 and IGFBP-3 in cord sera were higher and lower than those in adult sera. Serum levels of IGFBP-2 in cord sera inversely correlated with birth weight and the levels of free from of IGFs. The birth weight positively correlated with serum IGF-I,and free form of IGFs. These findings suggest that changes in IGFBP-2 in fetal sera might modulate the relative concentrations of free IGFs, supposed to be active from of IGFs, and then modulate fetal growth. 3) It has been hypothesized that IGFBP-1 play a role in counter regulation of blood glucose. We found that serum IGFBP-1 did not increase in 3h after insulin-induced hypoglycemia. Therefore, we could not support the hypothesis. 4) It has been reported that IGFBPs were regulated by various agents in osteoblast-like cells, but these data were different among species. In the present study, we took advantage of cultured human osteoblasts obtained from trabecular bone, and undertook a study of effect of various agents. The cultured human osteoblasts secreted IGFBPs, mainly IGFBP-3, -4, and -2.1,25-(OH)_2D_3 inhibited the proliferation of osteoblasts, and increased osteocalcin in the media. 1,25-(OH)_2D_3 increased IGFBP-3 and slightly IGFBP-4. E_2 did not affect on the cell proliferation and osteocalcin in the media, but, increased IGFBP-3, -4 and -2. These data demonstrate that IGFBPs of human osteoblasts are regulated by effectors of bone metabolism. However, it remains to be elucidated how IGFBPs modulate IGF action in bone metabolism. Less