title: miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2.
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.
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Jing Y
authors.initials: JY
authors.lastname: Krzeszinski
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: HoangDinh
authors.initials: H
authors.lastname: Huynh
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Zixue
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Xunde
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Tsung-Cheng
authors.initials: TC
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Division of Cellular and Developmental Biology, Molecular and Cell Biology Department, University of California at Berkeley, Berkeley, California 94705, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.affiliation: 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.
authors.forename: Lingegowda S
authors.initials: LS
authors.lastname: Mangala
authors.affiliation: 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.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: 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.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: 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.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Mendell
authors.affiliation: 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.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Wan
mesh_terms: D000818:Animals; D001483:Base Sequence; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary*; D001862:Bone Resorption / Q000188:drug therapy / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000494:pharmacology / Q000627:therapeutic use; D009368:Neoplasm Transplantation; D009929:Organ Size / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology*; D010024:Osteoporosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D010052:Ovariectomy; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000473:pathology; D019076:Transgenes; D023041:Xenograft Model Antitumor Assays
chemical_list: D018398:Homeodomain Proteins; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D012097:Repressor Proteins; C505201:TG-interacting factor 2, mouse