miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2
Authors: Lin He
Xunde Wang
Anil K Sood
Zixue Jin
Jing Y Krzeszinski
Lingegowda S Mangala
HoangDinh Huynh
Gabriel Lopez-Berestein
Joshua T Mendell
Xian-Jin Xie
Yihong Wan
Tsung-Cheng Chang
Wei Wei
Journal: Nature (2014)
Discipline: Multidisciplinary
Keywords: osteoclasts; osteoporosis; bone metastases; MicroRNAs; skeletal biology
Affiliations: 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.

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. 

Retracted: No

PubPeer comments:
 https: retractionwatch.com 2020 06 01 nature-retracts-study-touted-as-step-toward-treatments-for-bone-diseases Retraction to: Nature https: doi.org 10.1038 nature13375Published online 25 June 2014 Upon re-examination of the bone histomorphometry data in Extended Data Figs. 1i, 2d, 3h, 4h, 5n, 6e, 9g and 10f of this Letter, anomalies were found that call into question the integrity of these data. These concerns undermine the confidence in the study and the authors thus wish to retract the Letter in its entirety. The authors regret this situation and apologize to the scientific community. All authors agree with the Retraction, but author Xunde Wang did not respond. , 
 Federal Register, 28 December 2020: https: www.ncbi.nlm.nih.gov pmc articles PMC7769721  SUMMARY: *Findings of research misconduct have been made against Yihong Wan, Ph.D. (Respondent), Associate Professor, Department of Pharmacology, University of Texas Southwestern Medical Center (UTSMC). Respondent engaged in research misconduct in research supported by U.S. Public Health Service (PHS) funds, specifically National Institute of Diabetes and Digestive and Kidney (NIDDK), National Institutes of Health (NIH), grant R01 DK089113. The administrative actions, including supervision for a period of three (3) years, were implemented beginning on December 8, 2020, and are detailed below.* ,