Horiuchi Keisuke, Kimura Tokuhiro, Miyamoto Takeshi, Miyamoto Kana, Akiyama Haruhiko, Takaishi Hironari, Morioka Hideo, Nakamura Takashi, Okada Yasunori, Blobel Carl P, Toyama Yoshiaki
Department of Anti-Aging Orthopedic Research, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan.
J Immunol. 2009 Feb 15;182(4):2093-101. doi: 10.4049/jimmunol.0802491.
The TNF-alpha converting enzyme (TACE/ADAM17) is involved in the proteolytic release of the ectodomain of diverse cell surface proteins with critical roles in development, immunity, and hematopoiesis. As the perinatal lethality of TACE-deficient mice has prevented an analysis of the roles of TACE in adult animals, we generated mice in which floxed Tace alleles were deleted by Cre recombinase driven by a Sox9 promoter. These mutant mice survived up to 9-10 mo, but exhibited severe growth retardation as well as skin defects and infertility. The analysis of the skeletal system revealed shorter long bones and prominent bone loss, characterized by an increase in osteoclast and osteoblast activity. In addition, these mice exhibited hypercellularity in the bone marrow and extramedullary hematopoiesis in the spleen and liver. Flow cytometric analysis of the bone marrow cells showed a sharp increase in granulopoiesis and in the population of c-Kit-1(+) Sca-1(+) lineage(-) cells, and a decrease in lymphopoiesis. Moreover, we found that serum levels of IL-17 and G-CSF were significantly elevated compared with control littermates. These findings indicate that TACE is associated with a regulation of IL-17 and G-CSF expression in vivo, and that the dysregulation in G-CSF production is causally related to both the osteoporosis-like phenotype and the defects in the hematopoietic system.
肿瘤坏死因子-α转换酶（TACE/ADAM17）参与多种细胞表面蛋白胞外域的蛋白水解性释放，这些蛋白在发育、免疫和造血过程中发挥关键作用。由于TACE缺陷小鼠的围产期致死性阻碍了对TACE在成年动物中作用的分析，我们构建了通过Sox9启动子驱动的Cre重组酶删除floxed Tace等位基因的小鼠。这些突变小鼠存活至9 - 10个月，但表现出严重的生长迟滞以及皮肤缺陷和不育。骨骼系统分析显示长骨较短且骨质明显流失，其特征是破骨细胞和成骨细胞活性增加。此外，这些小鼠骨髓细胞增多，脾脏和肝脏出现髓外造血。对骨髓细胞的流式细胞术分析显示粒细胞生成以及c-Kit-1(+) Sca-1(+)谱系(-)细胞群体急剧增加，淋巴细胞生成减少。而且，我们发现与对照同窝小鼠相比，血清白细胞介素-17和粒细胞集落刺激因子水平显著升高。这些发现表明TACE在体内与白细胞介素-17和粒细胞集落刺激因子的表达调节相关，并且粒细胞集落刺激因子产生的失调与骨质疏松样表型和造血系统缺陷均存在因果关系。
