Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.
Institute of Veterinary Pathology at the Center for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
J Neuroendocrinol. 2024 Jul;36(7):e13277. doi: 10.1111/jne.13277. Epub 2023 May 9.
Growth hormone receptor deficiency (GHRD) results in low serum insulin-like growth factor 1 (IGF1) and high, but non-functional serum growth hormone (GH) levels in human Laron syndrome (LS) patients and animal models. This study investigated the quantitative histomorphological and molecular alterations associated with GHRD. Pituitary glands from 6 months old growth hormone receptor deficient (GHR-KO) and control pigs were analyzed using a quantitative histomorphological approach in paraffin (9 GHR-KO [5 males, 4 females] vs. 11 controls [5 males, 6 females]), ultrathin sections tissue sections (3 male GHR-KO vs. 3 male controls) and label-free proteomics (4 GHR-KO vs. 4 control pigs [2 per sex]). GHR-KO pigs displayed reduced body weights (60% reduction in comparison to controls; p < .0001) and decreased pituitary volumes (54% reduction in comparison to controls; p < .0001). The volume proportion of the adenohypophysis did not differ in GHR-KO and control pituitaries (65% vs. 71%; p = .0506) and GHR-KO adenohypophyses displayed a reduced absolute volume but an unaltered volume density of somatotrophs in comparison to controls (21% vs. 18%; p = .3164). In GHR-KO pigs, somatotroph cells displayed a significantly reduced volume density of granules (23.5%) as compared to controls (67.7%; p < .0001). Holistic proteome analysis of adenohypophysis samples identified 4660 proteins, of which 592 were differentially abundant between the GHR-KO and control groups. In GHR-KO samples, the abundance of somatotropin precursor was decreased, whereas increased abundances of proteins involved in protein production, transport and endoplasmic reticulum (ER) stress were revealed. Increased protein production and secretion as well as significantly reduced proportion of GH-storing granules in somatotroph cells of the adenohypophysis without an increase in volume density of somatotroph cells in the adenohypophysis could explain elevated serum GH levels in GHR-KO pigs.
生长激素受体缺乏症（GHRD）导致人类拉隆综合征（LS）患者和动物模型的血清胰岛素样生长因子 1（IGF1）水平降低，而血清生长激素（GH）水平升高但无功能。本研究探讨了与 GHRD 相关的定量组织形态学和分子变化。使用定量组织形态学法（9 只 GHR-KO [5 只雄性，4 只雌性]与 11 只对照[5 只雄性，6 只雌性]）、超薄切片组织切片（3 只雄性 GHR-KO 与 3 只雄性对照）和无标记蛋白质组学（4 只 GHR-KO 与 4 只对照猪[每性别 2 只]）分析了 6 个月大的生长激素受体缺陷（GHR-KO）和对照猪的垂体。GHR-KO 猪的体重明显减轻（与对照组相比减少 60%；p<0.0001），垂体体积减少（与对照组相比减少 54%；p<0.0001）。GHR-KO 和对照组的垂体前叶体积比例无差异（65%比 71%；p=0.0506），与对照组相比，GHR-KO 腺垂体的生长激素细胞的绝对体积减少，但体积密度不变（21%比 18%；p=0.3164）。在 GHR-KO 猪中，生长激素细胞的颗粒体积密度明显降低（23.5%比 67.7%；p<0.0001）。对腺垂体样本的整体蛋白质组分析鉴定出 4660 种蛋白质，其中 592 种在 GHR-KO 和对照组之间差异丰富。在 GHR-KO 样本中，生长激素前体的丰度降低，而与蛋白质产生、运输和内质网（ER）应激相关的蛋白质的丰度增加。生长激素细胞中 GH 储存颗粒的比例显著降低，而生长激素细胞的体积密度没有增加，这可能解释了 GHR-KO 猪血清 GH 水平升高的原因。
