Impaired differentiation of macrophage lineage cells attenuates bone remodeling and inflammatory angiogenesis in Ndrg1 deficient mice.
Impaired differentiation of macrophage lineage cells attenuates bone remodeling and inflammatory angiogenesis in Ndrg1 deficient mice.
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DOI：
10.1038/srep19470
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发表时间：
2016-01-18
影响因子：
4.6
通讯作者：
Ono M
中科院分区：
文献类型：
--
作者：
Watari K;Shibata T;Nabeshima H;Shinoda A;Fukunaga Y;Kawahara A;Karasuyama K;Fukushi J;Iwamoto Y;Kuwano M;Ono M
N-myc下游调节基因1(NDRG1)是遗传性运动和感觉神经病-LOM(Charcot-Marie-Tooth病4D)的致病基因。这是第一个旨在评估NDRG1在巨噬细胞系细胞分化中的作用的研究，巨噬细胞系细胞对骨重建和炎性血管生成具有重要意义。Ndrg1基因敲除(KO)小鼠表现出脊柱弯曲异常，骨小梁质量增加，破骨细胞数量减少。我们观察到KO小鼠血清巨噬细胞集落刺激因子(M-CSF)和巨噬细胞相关细胞因子水平明显降低。骨髓(BM)细胞向破骨细胞、M1/M2型巨噬细胞和树突状细胞的分化均受到抑制。此外，KO小鼠还表现出肿瘤生长和癌细胞血管生成减少，并伴有肿瘤相关巨噬细胞浸润减少。将来自KO小鼠的BM来源的巨噬细胞转移到BM根除的野生型(WT)小鼠中，诱导的肿瘤血管生成比在WT小鼠中观察到的要少得多。角膜对炎症刺激的血管生成也受到抑制，巨噬细胞的渗透减少。综上所述，这些结果表明，NDRG1缺陷减弱了巨噬细胞系细胞的分化，抑制了骨重建和炎性血管生成。这项研究有力地表明了NDRG1在巨噬细胞分化过程中的关键作用。
N-myc downstream regulated gene 1 (NDRG1) is a responsible gene for a hereditary motor and sensory neuropathy-Lom (Charcot–Marie–Tooth disease type 4D). This is the first study aiming to assess the contribution of NDRG1 to differentiation of macrophage lineage cells, which has important implications for bone remodeling and inflammatory angiogenesis. Ndrg1 knockout (KO) mice exhibited abnormal curvature of the spine, high trabecular bone mass, and reduced number of osteoclasts. We observed that serum levels of macrophage colony-stimulating factor (M-CSF) and macrophage-related cytokines were markedly decreased in KO mice. Differentiation of bone marrow (BM) cells into osteoclasts, M1/M2-type macrophages and dendritic cells was all impaired. Furthermore, KO mice also showed reduced tumor growth and angiogenesis by cancer cells, accompanied by decreased infiltration of tumor-associated macrophages. The transfer of BM-derived macrophages from KO mice into BM-eradicated wild type (WT) mice induced much less tumor angiogenesis than observed in WT mice. Angiogenesis in corneas in response to inflammatory stimuli was also suppressed with decreased infiltration of macrophages. Taken together, these results indicate that NDRG1 deficiency attenuates the differentiation of macrophage lineage cells, suppressing bone remodeling and inflammatory angiogenesis. This study strongly suggests the crucial role of NDRG1 in differentiation process for macrophages.