Assessment of the in vitro and in vivo biological activities of the human follicle-stimulating isohormones
Assessment of the in vitro and in vivo biological activities of the human follicle-stimulating isohormones
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DOI：
10.1016/s0303-7207(01)00657-8
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发表时间：
2002-01-25
影响因子：
4.1
通讯作者：
Ulloa-Aguirre, A
中科院分区：
文献类型：
--
作者：
Barrios-De-Tomasi, J;Timossi, C;Ulloa-Aguirre, A
促性腺激素以不同的分子形式合成和释放。在本文中，我们提供的证据表明，人垂体 FSH 的糖基化变体在靶细胞水平上表现出差异性和不同的作用，并且唾液酸化程度较低、寿命较短的变体可能在体内条件下发挥显着的作用。与酸性更强的类似物（pH < 4.76）相比，酸性/唾液酸化糖型（通过前部糖蛋白提取物的高分辨率色谱聚焦揭示的洗脱 pH 值 6.60-4.60）诱导培养的大鼠颗粒细胞中更高的 cAMP 释放、雌激素产生和组织型纤溶酶原激活剂（tPA）酶活性以及细胞色素 P450 芳香酶和 tPA mRNA 表达。相比之下，酸性/唾液酸化糖型比酸性/唾液酸化糖型诱导更高的α-抑制素亚基 mRNA 表达。在从小鼠卵巢中分离出的卵丘封闭的卵母细胞中，添加酸性较低的亚型比酸性较高的类似物更有效地诱导减数分裂的恢复。有趣的是，酸性最低的亚型（pH > 7.10）可作为多种 FSH 介导作用的强拮抗剂。对未成熟大鼠卵泡中同种型对颗粒细胞增殖的体内影响的评估表明，在垂体切除术后立即施用时，短命同种型在维持颗粒细胞增殖方面与酸性更强的同种型同等甚至更有效。这些结果表明，天然存在的人类 FSH 亚型可能在靶细胞水平上表现出差异甚至独特的作用，并且分子代谢清除率以外的因素（包括受体结合亲和力和配体激活其受体并触发细胞内信号传导的能力）也在确定特定 FSH 变体的体内净效应中发挥重要作用。 (C) 2002 Elsevier Science Ireland Ltd. 保留所有权利。
Gonadotropins are synthesized and released in different molecular forms. In this article, we present evidence that the glycosylation variants of human pituitary FSH exhibit differential and divergent effects at the target cell level and that less sialylated, short-lived variants may exert significant effects in in vivo conditions. Less acidic/sialylated glycoforms (elution pH value 6.60-4.60 as disclosed by high resolution chromatofocusing of anterior glycoprotein extracts), induced higher cAMP release, estrogen production and tissue-type plasminogen activator (tPA) enzyme activity as well as cytochrome P450 aromatase and tPA mRNA expression in cultured rat granulosa cells than the more acidic analogs (pH < 4.76). By contrast, the more acidic /sialylated glycoforms induced higher a-inhibin subunit mRNA expression than their less acidic counterparts. In cumulus enclosed oocytes isolated from mice ovaries, addition of less acidic isoforms induced resumption of meiosis more efficiently than the more acidic analogs. Interestingly, the least acidic isoform (pH > 7.10) behave as a strong antagonist of several FSH-mediated effects. Assessment of the in vivo effects of the isoforms on granulosa cell proliferation in follicles from immature rats, revealed that short-lived isoforms were equally or even more efficient than their more acidic counterparts in maintaining granulosa cell proliferation when administered immediately after hypophysectomy. These results show that the naturally occuring human FSH isoforms may exhibit differential or even unique effects at the target cell level and that factors other than the metabolic clearance rate of the molecule (including receptor-binding affinity and capability of the ligand to activate its receptor and trigger intracellular signaling) also play an important role in determining the net in vivo effects of a particular FSH variant. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.