Opposing Roles of Insulin-Like Growth Factor Binding Protein 3 and Humanin in the Regulation of Testicular Germ Cell Apoptosis
Opposing Roles of Insulin-Like Growth Factor Binding Protein 3 and Humanin in the Regulation of Testicular Germ Cell Apoptosis
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DOI：
10.1210/en.2009-0577
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发表时间：
2010-01-01
期刊：
影响因子：
4.8
通讯作者：
Wang, Christina
中科院分区：
文献类型：
--
作者：
Lue, YanHe;Swerdloff, Ronald;Wang, Christina
调节生殖细胞的死亡和存活对男性不育和避孕具有重要的治疗潜力。我们以前已经表明，IGF结合蛋白3（IGFBP 3）基因表达上调时，在人类睾丸生殖细胞凋亡诱导睾丸内激素剥夺睾酮管理。Humanin（HN）是IGFBP 3的结合伴侣，两者都在大鼠睾丸中表达。因此，我们假设IGFBP 3，一个促凋亡因子，HN，一个抗凋亡因子，是男性生殖细胞凋亡的重要调节因子。而在睾丸中的基线凋亡是等效的Igfbp 3基因敲除和野生型小鼠，治疗与GnRH拮抗剂（GnRH-A）为2周诱导生殖细胞凋亡的野生型，这是显着减少Igfbp 3基因敲除小鼠。为了研究IGFBP 3和HN对生殖细胞凋亡的直接影响，在大鼠睾丸内给予IGFBP 3 5天，分别在生精上皮周期的第VII-VIII和XIV-I阶段诱导凋亡增加4.2倍和3.8倍。GnRH-A治疗5 d可增加细胞凋亡，主要发生在VII-VIII期。在第VII-VIII期，将IGFBP 3添加到GnRH-A治疗中使细胞凋亡增加到39.3倍，这高于单独的治疗。睾丸内注射HN显着降低GnRH-A诱导的细胞凋亡在第XIV-I期，但不是第VII-VIII期。我们的结论是IGFBP 3和HN在睾丸生殖细胞稳态的协调调节中发挥关键作用。这种相互作用的干扰在增强或预防生殖细胞死亡方面很重要，为未来的治疗提供了新的靶点。（内分泌学151：350-357，2010）
Modulating germ cell death and survival have significant therapeutic potential for male infertility and contraception. We have shown previously that IGF binding protein 3 (IGFBP3) gene expression is up-regulated in human testis when germ cell apoptosis is induced by intratesticular hormonal deprivation created by testosterone administration. Humanin (HN) is a binding partner of IGFBP3, and both are expressed in rat testes. We therefore hypothesized that IGFBP3, a proapoptotic factor, and HN, an antiapoptotic factor, are important regulators of male germ cell apoptosis. Whereas baseline apoptosis in the testis was equivalent between Igfbp3 knockout and wild-type mice, treatment with GnRH antagonist (GnRH-A) for 2wk induced germ cell apoptosis in wild type, which was dramatically reduced in Igfbp3 knockout mice. To investigate the direct effects of IGFBP3 and HN on germ cell apoptosis, intratesticular administration of IGFBP3 for 5 d in rats induced a 4.2- and 3.8-fold increase in apoptosis at stages VII-VIII and XIV-I of the seminiferous epithelium cycle, respectively. GnRH-A treatment for 5 d increased apoptosis, mainly at stages VII-VIII. Addition of IGFBP3 to GnRH-A treatment enhanced apoptosis to 39.3-fold at stages VII-VIII, which was higher than either treatment alone. Intratesticular injection of HN significantly decreased GnRH-A-induced apoptosis at stages XIV-I but not stages VII-VIII. We conclude that IGFBP3 and HN play key roles in the coordinated regulation of testicular germ cell homeostasis. Perturbation of this interaction is important in enhancing or preventing germ cell death, providing new targets for future therapies. (Endocrinology 151: 350-357, 2010)