Publication Date:
2014-07-22
Description:
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-beta-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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149606/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149606/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Krzeszinski, Jing Y -- Wei, Wei -- Huynh, HoangDinh -- Jin, Zixue -- Wang, Xunde -- Chang, Tsung-Cheng -- Xie, Xian-Jin -- He, Lin -- Mangala, Lingegowda S -- Lopez-Berestein, Gabriel -- Sood, Anil K -- Mendell, Joshua T -- Wan, Yihong -- 1P30 CA142543/CA/NCI NIH HHS/ -- 1S10RR02564801/RR/NCRR NIH HHS/ -- P01 CA134292/CA/NCI NIH HHS/ -- P30 CA142543/CA/NCI NIH HHS/ -- R01 CA120185/CA/NCI NIH HHS/ -- R01 CA139067/CA/NCI NIH HHS/ -- R01 DK089113/DK/NIDDK NIH HHS/ -- S10 RR024757/RR/NCRR NIH HHS/ -- S10 RR025648/RR/NCRR NIH HHS/ -- U54 CA151668/CA/NCI NIH HHS/ -- UH2 TR000943/TR/NCATS NIH HHS/ -- England -- Nature. 2014 Aug 28;512(7515):431-5. doi: 10.1038/nature13375. Epub 2014 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; 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. ; Division of Cellular and Developmental Biology, Molecular and Cell Biology Department, University of California at Berkeley, Berkeley, California 94705, USA. ; 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. ; 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. ; 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. ; 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. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043055" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Base Sequence
;
Bone Neoplasms/genetics/pathology/*prevention & control/*secondary
;
Bone Resorption/drug therapy/genetics
;
Cell Differentiation/drug effects/*genetics
;
Cell Line, Tumor
;
Disease Models, Animal
;
Female
;
Gene Deletion
;
Homeodomain Proteins/antagonists & inhibitors/genetics/metabolism
;
Humans
;
Male
;
Mammary Neoplasms, Animal/pathology
;
Mice
;
Mice, Transgenic
;
MicroRNAs/*genetics/pharmacology/therapeutic use
;
Neoplasm Transplantation
;
Organ Size/drug effects
;
Osteoclasts/drug effects/*pathology
;
Osteoporosis/genetics/pathology/*prevention & control
;
Ovariectomy
;
Repressor Proteins/antagonists & inhibitors/*deficiency/genetics/metabolism
;
Skin Neoplasms/pathology
;
Transgenes
;
Xenograft Model Antitumor Assays
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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