MiR-1292 Targets FZD4 to Regulate Senescence and Osteogenic Differentiation of Stem Cells in TE/SJ/Mesenchymal Tissue System via the Wnt/β-catenin Pathway
Authors: Robert Chunhua Zhao
Xingyan An
Luchan Deng
Xisheng Weng
Tao Li
Haoying Xu
Linyuan Fan
Junfen Fan
Yanlei Yang
Jianmin Zhang
Journal: Aging and Disease (2018)
Discipline: CLINICAL MEDICINE
Keywords: FZD4; TE/SJ/mesenchymal tissue system; hADSCs; miR-1292; 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, China., 2Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China., 3Department of Immunology, Research Center on Pediatric Development and Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences and School of Basic Medicine Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing, China.

Abstract:  With the expansion of the elderly population, age-related osteoporosis and the resulting bone loss have become a significant health and socioeconomic issue. In Triple Energizer (TE)/San Jiao (SJ)/mesenchymal tissue system, mesenchymal stem cell (MSC) senescence, and impaired osteogenesis are thought to contribute to age-related diseases such as osteoporosis. Therefore, comprehending the molecular mechanisms underlying MSC senescence and osteogenesis is essential to improve the treatment of bone metabolic diseases. With the increasing role of miRNAs in MSC aging and osteogenic differentiation, we need to understand further how miRNAs participate in relevant mechanisms. In this study, we observed that the expression of miR-1292 was augmented during cellular senescence and lessened with osteogenesis in human adipose-derived mesenchymal stem cells (hADSCs). miR-1292 expression was positively correlated with senescence markers and negatively associated with bone formation markers in clinical bone samples. Overexpression of miR-1292 notably accelerated hADSC senescence and restrained osteogenesis, whereas its knockdown decreased senescence and enhanced osteogenic differentiation. Furthermore, miR-1292 upregulation inhibited ectopic bone formation in vivo. Mechanistically, FZD4 was identified as a potential target of miR-1292. Downregulation of FZD4 phenocopied the effect of miR-1292 overexpression on hADSC senescence and osteogenic differentiation. Moreover, the impact of miR-1292 suppression on senescence and osteogenesis were reversed by the FZD4 knockdown. Pathway analysis revealed that miR-1292 regulates hADSC senescence and osteogenesis through the Wnt/β-catenin signaling pathway. Thus, TE/SJ/mesenchymal tissue system is the largest organ composed of various functional cells derived from mesoderm, responsible for maintaining homeostasis and regulating cell senescence. miR-1292 might serve as a novel therapeutic target for the prevention and treatment of osteoporosis or other diseases related to bone metabolism and aging. 

Retracted: No

PubPeer comments:
 The statistical tests applied in this paper seem to have been selected without regard to the experimental design. These are simple errors one might hope that CalTech authors and eLife editors referees would be alert to. In Fig. 1, panels A-E are all clearly two-way designs in which the interaction between murine (ASO) and bacterial (u0394csgBAC) genotypes is the point of interest. Instead of using two-way ANOVA, the data are analysed with a one-way ANOVA. Decorative stars are awarded to some of the groups. The assumption of normality might not hold for the data in panel D, while generally the small samples allow no recourse to the central limit theorem nor to tests for normality (not that any attempt to validate such test prerequisites is made). Multiple behaviours are tested, but there is no correction for this multiplicity of tests. ![image] In Fig. 1A-supplement 1, the authors apply one-way ANOVA and post-hoc tests without concerning themselves with the requirement for equal variances. This will be a problem for most of the panels (A-D, H) and cause an overestimation of significance. Furthermore, as for the main Fig. 1, the one-way analyses are incompatible with the two-way designs. ![image] Exactly the same concerns of incompatible analysis (one-way ANOVA) and design (two-way), and occasional violation of equal variances pertain in Fig. 1-supplement 2A-C,Q. ![image] In Fig. 2A-E, G the authors DO apply a two-way ANOVA. But they shouldn t, because these are all repeated measures. The authors are violating the prerequisite of independence in the two-way ANOVA. The significance will have been overestimated. There is no correction for the multiple behavioural assays. ![image] Similar misapplication of a two-way ANOVA in the presence of repeated measures occurs in Fig. 3-supplement 3 A-E, G. Should the differences between striatal and mid-brain u03b1Syn fibrils be compared? They are not. ![image] Repeated measures are analysed with a two-way ANOVA in Fig. 4-supplement 1 D-H. ![image] ,