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（IGFBPs）结合，并推测IGFBPs可能调节IGF的作用。在这项研究中，我们研究了IGFBPs的病理意义如下。1)IGFBP-6的病理生理作用尚未阐明。最近我们用免疫印迹法（WIB）测定了血清IGFBP-6，发现血清IGFBP-6水平不依赖于GH，在慢性肾功能衰竭（CRF）患者中升高。本研究通过检测肾移植术后CRF患者血清IGFBP-6水平，进一步探讨其临床意义及调节机制。此外，我们还测量了IGFBP-2水平。所有CRF患者血清IGFBP-2、IGFBP-6水平均显著升高，透析后无明显变化。血清IGFBP-6水平在肾移植术后第1天显著下降，并随着肾功能的改善而进一步下降。与IGFBP-6相比，血清 ...更多信息 在肾移植后14天内，IGFBP-2水平没有下降。此外，我们证明了IGFBP-6在尿液中。提示IGFBP-6可能通过肾脏排泄，血清IGFBP-6水平可能与肾功能有关，血清IGFBP-6水平的调节与IGFBP-2不同。2）脐带血IGFBP-2、IGFBP-3水平分别高于和低于成人血清。脐血IGFBP-2水平与新生儿出生体重及胎儿IGFs游离水平呈负相关。新生儿出生体重与血清IGF-I、游离IGFs呈正相关。这些结果表明，胎儿血清中IGFBP-2的变化可能会调节游离IGFs的相对浓度，从而调节胎儿的生长。3)已经假设IGFBP-1在血糖的反调节中起作用。我们发现，胰岛素诱导低血糖后3小时内血清IGFBP-1没有升高。因此，我们无法支持该假设。4)据报道，成骨样细胞中IGFBPs受到多种因子的调节，但这些数据在物种之间存在差异。在本研究中，我们利用培养的人成骨细胞从松质骨获得的优势，并进行了各种药物的影响的研究。1，25-（OH）_2D_3能抑制成骨细胞的增殖，并能增加培养液中骨钙素的含量。1，25-（OH）_2D_3使IGFBP-3和IGFBP-4略有升高。E_2对细胞增殖和培养液中骨钙素含量无影响，但可使IGFBP-3、-4和-2升高。这些数据表明人成骨细胞的IGFBPs受骨代谢效应物的调节。然而，IGFBPs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