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miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2

机译:miR-34a通过抑制破骨细胞生成和Tgif2来阻止骨质疏松和骨转移

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摘要

破骨细胞参与骨再吸收, 因此在骨质疏松和骨转移中起一定作用。Yihong Wan及同事识别出一种微RNA, 即miR-34a, 其表达调控破骨细胞生成。miR-34a的上调或转基因表达与骨再吸收程度较低有关, 因此也与骨质增加有关。miR-34a与这一过程有关的一个目标是Tgif2, 后者是促进破骨细胞生成的转录调控因子, 其删除会以独立于miR-34a的方式恢复骨质。这项工作表明, miR-34a(在癌症中被普遍删除)对于骨架保护以及改善癌症骨转移的策略有潜在的治疗好处。%Bone-resorbing osteoclasts significantly contribute to osteoporosis and bone metastases of cancer. MicroRNAs play important roles in physiology and disease, and present tremendous therapeutic potentialo. Nonetheless, how microRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is downregulated during osteoclast differentiation. Osteoclastic miR-34a-overexpressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify transforming growth factor-β-induced factor 2 (Tgif2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers.
机译:破骨细胞参与骨再吸收, 因此在骨质疏松和骨转移中起一定作用。Yihong Wan及同事识别出一种微RNA, 即miR-34a, 其表达调控破骨细胞生成。miR-34a的上调或转基因表达与骨再吸收程度较低有关, 因此也与骨质增加有关。miR-34a与这一过程有关的一个目标是Tgif2, 后者是促进破骨细胞生成的转录调控因子, 其删除会以独立于miR-34a的方式恢复骨质。这项工作表明, miR-34a(在癌症中被普遍删除)对于骨架保护以及改善癌症骨转移的策略有潜在的治疗好处。%Bone-resorbing osteoclasts significantly contribute to osteoporosis and bone metastases of cancer. MicroRNAs play important roles in physiology and disease, and present tremendous therapeutic potentialo. Nonetheless, how microRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is downregulated during osteoclast differentiation. Osteoclastic miR-34a-overexpressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify transforming growth factor-β-induced factor 2 (Tgif2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers.

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  • 来源
    《Nature》 |2014年第7515期|431-435337|共6页
  • 作者单位

    Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;

    Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;

    Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;

    Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;

    Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;

    Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;

    Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA, Department of Clinical Sciences, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;

    Division of Cellular and Developmental Biology, Molecular and Cell Biology Department, University of California at Berkeley, Berkeley, California 94705, USA;

    Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA, Center for RNA Interference and Noncoding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;

    Center for RNA Interference and Noncoding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;

    Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA, Center for RNA Interference and Noncoding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;

    Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA, Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;

    Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA, Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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