IGF-I was originally discovered as a GH-dependent growth factor stimulating longitudinal growth. Currently, however, it has become evident that the biological activities of IGF-I extend well beyond those of a simple growth factor and impact such processes as insulin sensitivity, aging, cancer and cardiovascular disease.

The vast majority of IGF-I is tightly bound to IGF-binding proteins (IGFBPs), which renders IGF-I unable to stimulate the IGF-I receptor (IGF-IR) in vivo. This binding means that liberation of IGF-I from the IGFBPs is an important step controlling IGF-I action. In this context, IGFBP-cleaving enzymes appear to play a key role. Enzymatic cleavage of the IGFBPs markedly lowers their ligand affinity, and as a consequence, IGF-I becomes liberated and hence available for stimulation of the IGF-IR.

Two of the best-characterized IGFBP-cleaving enzymes are pregnancy-associated plasma protein-A (PAPP-A) and its paralog PAPP-A2. The two enzymes (often referred to as pappalysins) regulate the liberation of IGF-I in a highly controlled manner. PAPP-A is believed to act predominantly in tissues, serving to liberate IGF-I at the cell surface in close proximity to the IGF-IR. In keeping with this notion, mice lacking PAPP-A exhibit reduced body size, despite having normal circulating IGF-I concentrations. In contrast, human findings indicate that altered PAPP-A2 activity changes circulating IGF-I concentrations, although PAPP-A2 is also present in high concentrations in tissues. Thus, PAPP-A2 appears to impact circulating, as well as tissue, IGF-I activity. The enzymatic activity of PAPP-A and PAPP-A2 was recently discovered to be regulated by the protein Stanniocalcin-2 (STC2). By binding to the enzymatic sites of PAPP-A and PAPP-A2, STC2 inhibits their activity.

To date, the majority of findings demonstrating the ability of pappalysins and STC2 to regulate IGF-I action are from preclinical studies. However, clinical studies are now beginning to emerge. In this review, we will summarize our data on STC2, PAPP-A and PAPP-A2 in humans. These results indicate that pappalysins and STC2 constitute an important IGF-I activity-regulating system that warrants further investigation.

IGF-I 最初被发现是一种刺激纵向生长的 GH 依赖性生长因子。然而，目前，很明显 IGF-I 的生物活性远远超出了简单生长因子的生物活性，并影响胰岛素敏感性、衰老、癌症和心血管疾病等过程。

绝大多数 IGF-I 与 IGF 结合蛋白 (IGFBP) 紧密结合，这使得 IGF-I 无法在体内刺激 IGF-I 受体 (IGF-IR)。这种结合意味着从 IGFBP 中释放 IGF-I 是控制 IGF-I 作用的重要步骤。在这种情况下，IGFBP 裂解酶似乎起着关键作用。IGFBP 的酶促裂解显着降低了它们的配体亲和力，因此，IGF-I 被释放，因此可用于刺激 IGF-IR。

两种最具特征的 IGFBP 切割酶是妊娠相关血浆蛋白 A (PAPP-A) 及其旁系同源物 PAPP-A2。这两种酶（通常称为冠毛素）以高度受控的方式调节 IGF-I 的释放。PAPP-A 被认为主要在组织中起作用，用于在细胞表面释放 IGF-I，紧邻 IGF-IR。与这一观点一致，尽管具有正常的循环 IGF-I 浓度，但缺乏 PAPP-A 的小鼠表现出体型减小。相比之下，人类发现表明 PAPP-A2 活性的改变会改变循环 IGF-I 的浓度，尽管 PAPP-A2 在组织中也以高浓度存在。因此，PAPP-A2 似乎影响循环以及组织的 IGF-I 活性。最近发现 PAPP-A 和 PAPP-A2 的酶活性受蛋白质斯钙素-2 (STC2) 调节。通过与 PAPP-A 和 PAPP-A2 的酶促位点结合，STC2 抑制了它们的活性。

迄今为止，证明冠毛素和 STC2 调节 IGF-I 作用能力的大多数发现来自临床前研究。然而，临床研究现在开始出现。在这篇综述中，我们将总结我们关于人类 STC2、PAPP-A 和 PAPP-A2 的数据。这些结果表明，冠毛素和 STC2 构成了一个重要的 IGF-I 活性调节系统，值得进一步研究。