TY - JOUR
T1 - MiR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2
AU - Krzeszinski, Jing Y.
AU - Wei, Wei
AU - Huynh, Hoangdinh
AU - Jin, Zixue
AU - Wang, Xunde
AU - Chang, Tsung Cheng
AU - Xie, Xian Jin
AU - He, Lin
AU - Mangala, Lingegowda S.
AU - Lopez-Berestein, Gabriel
AU - Sood, Anil K.
AU - Mendell, Joshua T.
AU - Wan, Yihong
N1 - Funding Information:
Acknowledgements We thank University of Texas Southwestern transgenic core and small animal imaging core for their assistance in our studies; P. Dechow, J. Feng and C. Qin for assistance with micro-computed tomography, histomorphometry and X-ray analysis; A. Ventura for miR-34abc triple knockout mice; D. Wotton for Tgif2-KO mice; H. Kronenberg for Osx-CreER mice; Y. Mishina for CAG-Z-EGFP vector. Y. Wan is a Virginia Murchison Linthicum Scholar in Medical Research. This work was in part supported by CPRIT (RP130145, Y.W.; R1008, J.M.), DOD (BC122877, Y.W.), National Institutes of Health (R01 DK089113, Y.W.; R01 CA120185 and P01 CA134292, J.M.; U54 CA151668 and UH2 TR000943, A.S.; R01 CA139067, L.H.), The Welch Foundation (I-1751, Y.W.) and a University of Texas Southwestern Endowed Scholar Startup Fund (Y.W.). The University of Texas Southwestern Small Animal Imaging Resourceis supported in part by the Harold C. Simmons Cancer Center through an NCI Cancer Center Support Grant (1P30 CA142543) and The Department of Radiology. The VisualSonics Vevo 770 was purchased with National Institutes of Health American Recovery and Reinvestment Act stimulus funds 1S10RR02564801.
PY - 2014/8/28
Y1 - 2014/8/28
N2 - 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-Î 2-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.
AB - 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-Î 2-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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U2 - 10.1038/nature13375
DO - 10.1038/nature13375
M3 - Article
C2 - 25043055
AN - SCOPUS:84907406375
SN - 0028-0836
VL - 512
SP - 431
EP - 435
JO - Nature
JF - Nature
IS - 7515
ER -