Activin signaling through activin receptor type II causes the cachexia-like symptoms in inhibin-deficient mice
Activin signaling through activin receptor type II causes the cachexia-like symptoms in inhibin-deficient mice
复制标题
DOI：
10.1210/me.10.5.534
复制
发表时间：
1996-05-01
影响因子：
--
通讯作者：
Matzuk, MM
中科院分区：
文献类型：
--
作者：
Coerver, KA;Woodruff, TK;Matzuk, MM
活化素和β-转化生长因子超家族的成员，参与多种生理和发育过程。我们以前已经证明，缺乏α-glucose的小鼠在早期发展性腺性索间质肿瘤。肿瘤发展后迅速出现消瘦综合征，包括严重的体重减轻、中央静脉周围的肝细胞坏死和腺胃壁细胞耗竭。重组激活素A缺乏小鼠的肝脏组织学与大鼠和小鼠短期治疗的病理学效应相似。与这些发现相一致，我们已经表明，性腺肿瘤中的白细胞介素缺陷小鼠分泌高水平的激活素。此外，北方印迹分析已将激活素受体II型（ActRII）定位于肝脏。基于这些研究，我们假设肿瘤产生的激活素通过ActRII作用，导致白细胞介素缺乏小鼠的消耗综合征。为了检验这一假设并确定体内通过ActRII的激活素信号传导水平升高的意义，我们产生了α-腺苷酸和ActRII两者都缺乏的复合纯合突变小鼠。尽管性腺性索间质肿瘤持续发展，血清激活素A和B水平升高，但复合纯合突变小鼠没有出现异常体重减轻，大多数小鼠的胃和肝脏组织学正常。这些结果表明，在肝细胞和腺胃中通过ActRII的激活素信号传导水平的增加导致肝细胞坏死和腺胃中壁细胞的消耗以及体内严重的体重减轻。
Activins and inhibins, members of the transforming growth factor-beta superfamily, are involved in diverse physiological and developmental processes. We have previously shown that mice deficient in alpha-inhibin develop gonadal sex cord-stromal tumors at an early age. The tumor development is rapidly followed by a wasting syndrome that includes severe weight loss, hepatocellular necrosis around the central vein, and depletion of the parietal cells in the glandular stomach. The liver histology in inhibin-deficient mice is similar to the pathological effects of short-term treatment of rats and mice with recombinant activin A. Consistent with these findings, we have shown that the gonadal tumors in the inhibin-deficient mice secrete high levels of activins. In addition, Northern blot analysis has localized activin receptor type II (ActRII) to the liver. Based on these studies, we postulated that tumor-produced activins act through ActRII to cause the wasting syndrome in inhibin-deficient mice. To test this hypothesis and determine the significance of elevated levels of activin signaling through ActRII in vivo, we generated compound homozygous mutant mice deficient in both alpha-inhibin and ActRII. Despite the continued development of gonadal sex cord-stromal tumors and elevated serum levels of activin A and B, the compound homozygous mutant mice suffered no unusual weight loss, and the stomachs and livers of the majority of the mice were histologically normal. These results demonstrate that increased levels of activin signaling through ActRII in hepatocytes and the glandular stomach causes the hepatocellular necrosis and depletion of parietal cells in the glandular stomach as well as the severe weight loss in vivo.