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Nature. 2014 Aug 28;512(7515):431-5. doi: 10.1038/nature13375. Epub 2014 Jun 25.

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

Author information

1
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
2
Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
3
1] Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Clinical Sciences, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
4
Division of Cellular and Developmental Biology, Molecular and Cell Biology Department, University of California at Berkeley, Berkeley, California 94705, USA.
5
1] Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
6
1] Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
7
1] Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3] Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
8
1] Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
9
1] Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

Abstract

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.

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PMID:
25043055
PMCID:
PMC4149606
DOI:
10.1038/nature13375
[Indexed for MEDLINE]
Free PMC Article

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