MiRNA-10b Reciprocally Stimulates Osteogenesis and Inhibits Adipogenesis Partly through the TGF-β/SMAD2 Signaling Pathway
Authors: Robert Chunhua Zhao
Luchan Deng
Xisheng Weng
Tao Li
Shihua Wang
Haoying Xu
Tangping Li
Linyuan Fan
Junfen Fan
Yanlei Yang
Hongling Li
Jing Li
Journal: Aging and Disease (2018)
Discipline: CLINICAL MEDICINE
Keywords: SMAD2; adipogenesis; mesenchymal stem cells; miR-10b; osteogenesis.
Affiliations: 1Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing Key Laboratory (No. BZO381), Beijing 100005, China., 2Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing 100730, China., 3Current address: Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, China.

Abstract:  As the population ages, the medical and socioeconomic impact of age-related bone disorders will further increase. An imbalance between osteogenesis and adipogenesis of mesenchymal stem cells (MSCs) can lead to various bone and metabolic diseases such as osteoporosis. Thus, understanding the molecular mechanisms underlying MSC osteogenic and adipogenic differentiation is important for the discovery of novel therapeutic paradigms for these diseases. miR-10b has been widely reported in tumorigenesis, cancer invasion and metastasis. However, the effects and potential mechanisms of miR-10b in the regulation of MSC adipogenic and osteogenic differentiation have not been explored. In this study, we found that the expression of miR-10b was positively correlated with bone formation marker genes ALP, RUNX2 and OPN, and negatively correlated with adipogenic markers CEBPα, PPARγ and AP2 in clinical osteoporosis samples. Overexpression of miR-10b enhanced osteogenic differentiation and inhibited adipogenic differentiation of human adipose-derived mesenchymal stem cells (hADSCs) in vitro, whereas downregulation of miR-10b reversed these effects. Furthermore, miR-10b promoted ectopic bone formation in vivo. Target prediction and dual luciferase reporter assays identified SMAD2 as a potential target of miR-10b. Silencing endogenous SMAD2 expression in hADSCs enhanced osteogenesis but repressed adipogenesis. Pathway analysis indicated that miR-10b promotes osteogenic differentiation and bone formation via the TGF-β signaling pathway, while suppressing adipogenic differentiation may be primarily mediated by other pathways. Taken together, our findings imply that miR-10b acts as a critical regulator for balancing osteogenic and adipogenic differentiation of hADSCs by repressing SMAD2 and partly through the TGF-β pathway. Our study suggests that miR-10b is a novel target for controlling bone and metabolic diseases. 

Retracted: No

PubPeer comments:
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 2020 retraction. https: journals.plos.org plosone article?id=10.1371 journal.pone.0230279 Following the publication of this article [1], concerns have been raised regarding panels presented in Figs 3, 4, 5 and 6: In Fig 3C there appear to be horizontal and vertical edges around the bands presented in lanes 3 and 4. In addition, the bands in lane 3 and lane 5 appear similar. In Fig 3C, the top bands in lane 4 and lane 6 appear similar. In addition, the bottom band in lane 4 appears similar to the top band in lane 4, when rotated 180u00b0. In Fig 4B, the bands in lane 1 and 2 representing WT-EPOR in the Con and MutEPOR samples (7 days) appear similar. In Fig 4D, the bands in lane 2 and 3 representing MutEPOR in the MutEPOR LnLL + andu2013cells appear similar. Lanes 3 and 4 in Fig 4B representing 10 day WT-EPOR and MutEPOR look similar to lanes 1 and 2 in Fig 5B representing EPOR and MutEPOR. Lanes 1 and 2 in Fig 5D representing STAT5 look similar to lanes 2 and 3 in Fig 4B representing GlyA when rotated 180u00b0. There appear to be horizontal edges surrounding the pErk1 and pErk2 bands in Fig 6A, and the background granularity surrounding the bands appears dissimilar to the background of the rest of the panel. There appear to be horizontal and vertical edges surrounding the Erk1 and Erk2 bands in Fig 6A, and the background granularity surrounding the bands appears dissimilar to the background of the rest of the panel There is a rectangular grey area located between the control actin band and the Mutated EpoR actin band in Fig 6D which does not match the overall background of the panel. The underlying data for the western blots and PCR results of concern are not available. The authors provided replicate data and data from new experiments in support of Figs 3, 4, 5, and 6, but these did not resolve the concerns about the published figures. In light of the concerns affecting multiple figure panels that question the integrity of these data, the PLOS ONE Editors retract this article. SP, LR, FR, AB, MDC, ARM, IMP, FB, DY, and FDR agree with retraction. DR did not agree with the retraction. JTP did not confirm agreement or disagreement with the retraction decision. VC, MF, AT, ACS, BN, AO, GA, and PM did not respond directly or could not be reached. SP, LR, FR, AB, MDC, ARM, IMP, FB, DR and FDR stand by the conclusions reported in the paper. References 1.Perrotta S, Cucciolla V, Ferraro M, Ronzoni L, Tramontano A, Rossi F, et al. (2010) EPO Receptor Gain-of-Function Causes Hereditary Polycythemia, Alters CD34+ Cell Differentiation and Increases Circulating Endothelial Precursors. PLoS ONE 5(8): e12015. https: doi.org 10.1371 journal.pone.0012015 pmid:20700488 ,