Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect
Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect
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DOI：
10.1073/pnas.192460799
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发表时间：
2002-10-01
影响因子：
11.1
通讯作者：
Young, SG
中科院分区：
文献类型：
--
作者：
Bergo, MO;Gavino, B;Young, SG
Zmpste 24是内质网的整合膜金属蛋白酶。来自Zmpste 24缺陷型小鼠（Zmpste 24（-/-））的组织的生化研究已经表明Zmpste 24在CAAX型异戊二烯化蛋白质的加工中的作用。在这里，我们报告的病理后果Zmpste 24缺陷的小鼠。Zmpste 24（-/-）小鼠体重增加缓慢，出现营养不良，并表现出进行性脱发。最引人注目的病理表型是多发性自发性骨肿瘤-类似于发生在小鼠模型中的骨生成瘤。在Zmpste 24（-/-）小鼠中，皮质骨和松质骨体积显著减少。Zmpste 24（-/-）小鼠也表现出下肢和上肢的肌肉无力，类似于缺乏法尼基化CAAX蛋白前层蛋白A的小鼠。前体蛋白A的加工在缺乏Zmpste 24的成纤维细胞和缺乏CAAX羧甲基转移酶Icmt的成纤维细胞中都有缺陷，但在缺乏CAAX内切蛋白酶Rce 1的成纤维细胞中是正常的。Zmpste 24（-/-）小鼠的肌无力可以合理地归因于前层蛋白A的加工缺陷，但脆骨表型表明Zmpste 24在哺乳动物生物学中具有更广泛的作用。
Zmpste24 is an integral membrane metalloproteinase of the endoplasmic reticulum. Biochemical studies of tissues from Zmpste24-deficient mice (Zmpste24(-/-)) have indicated a role for Zmpste24 in the processing of CAAX-type prenylated proteins. Here, we report the pathologic consequences of Zmpste24 deficiency in mice. Zmpste24(-/-) mice gain weight slowly, appear malnourished, and exhibit progressive hair loss. The most striking pathologic phenotype is multiple spontaneous bone fractures-akin to those occurring in mouse models of osteogenesis imperfecta. Cortical and trabecular bone volumes are significantly reduced in Zmpste24(-/-) mice. Zmpste24(-/-) mice also manifested muscle weakness in the lower and upper extremities, resembling mice lacking the farnesylated CAAX protein prelamin A. Prelamin A processing was defective both in fibroblasts lacking Zmpste24 and in fibroblasts lacking the CAAX carboxyl methyltransferase Icmt but was normal in fibroblasts lacking the CAAX endoprotease Rce1. Muscle weakness in Zmpste24(-/-) mice can be reasonably ascribed to defective processing of prelamin A, but the brittle bone phenotype suggests a broader role for Zmpste24 in mammalian biology.