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

作     者：Jing Y Krzeszinski Wei Wei HoangDinh Huynh Zixue Jin Xunde Wang Tsung-Cheng Chang Xian-Jin Xie Lin He Lingegowda S Mangala Gabriel Lopez-Berestein Anil K Sood Joshua T Mendell Yihong Wan 

作者机构：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. 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. Center for RNA Interference and Non-coding 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 Cancer Biology The University of Texas MD Anderson Cancer Center Houston Texas 77030 USA. Simmons Cancer Center 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. 

出 版 物：《Nature》 

年 卷 期：2014年第512卷第7515期

页      面：431-5页

学科分类：07[理学] 08[工学] 

摘      要：Bone-resorbing osteoclasts significantly contribute to osteoporosis and bone metastases of cancer. MicroRNAs play important roles in physiology and disease, and present tremendous therapeutic potential. 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.