Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
J Exp Med. 2014 Jan 13;211(1):153-63. doi: 10.1084/jem.20130538. Epub 2013 Dec 23.
Signal transducer and activator of transcription 5 (Stat5) is essential for cytokine-regulated processes such as proliferation, differentiation, and survival in hematopoietic cells. To investigate the role of Stat5 in osteoclasts, we generated mice with an osteoclast-specific conditional deletion of Stat5 (Stat5 conditional knockout [cKO] mice) and analyzed their bone phenotype. Stat5 cKO mice exhibited osteoporosis caused by an increased bone-resorbing activity of osteoclasts. The activity of mitogen-activated protein kinases (MAPKs), in particular extracellular signal-related kinase, was increased in Stat5 cKO osteoclasts, whereas the expression of the MAPK phosphatases dual specificity phosphatase 1 (Dusp1) and Dusp2 was significantly decreased. Interleukin-3 (IL-3) stimulated the phosphorylation and nuclear translocation of Stat5 in osteoclasts, and Stat5 expression was up-regulated in response to receptor activator of nuclear factor κB ligand (RANKL). The results suggest that Stat5 negatively regulates the bone-resorbing function of osteoclasts by promoting Dusp1 and Dusp2 expression, and IL-3 promotes Stat5 activation in osteoclasts.
信号转导子和转录激活子 5（Stat5）对于细胞因子调节的过程是必需的，如造血细胞的增殖、分化和存活。为了研究 Stat5 在破骨细胞中的作用，我们生成了破骨细胞特异性条件性敲除 Stat5 的小鼠（Stat5 条件性敲除 [cKO] 小鼠），并分析了它们的骨骼表型。Stat5 cKO 小鼠表现出骨质疏松症，这是由于破骨细胞的骨吸收活性增加所致。Stat5 cKO 破骨细胞中丝裂原活化蛋白激酶（MAPKs）的活性，特别是细胞外信号相关激酶，增加，而 MAPK 磷酸酶双特异性磷酸酶 1（Dusp1）和 Dusp2 的表达显著降低。白细胞介素 3（IL-3）刺激破骨细胞中 Stat5 的磷酸化和核易位，并且受体激活核因子 κB 配体（RANKL）响应上调 Stat5 的表达。结果表明，Stat5 通过促进 Dusp1 和 Dusp2 的表达来负调控破骨细胞的骨吸收功能，IL-3 促进破骨细胞中 Stat5 的激活。
