Redundant miR-3077-5p and miR-705 mediate the shift of mesenchymal stem cell lineage commitment to adipocyte in osteoporosis bone marrow

L Liao,X Su,X Yang,X Chen,C Hu,S Shi,N Yang,Y Jin,X Zhu

doi:10.1038/cddis.2013.130

Abstract

During the process of aging, especially for postmenopausal females, the cell lineage commitment of mesenchymal stem cells (MSCs) shift to adipocyte in bone marrow, resulting in osteoporosis. However, the cell-intrinsic mechanism of this cell lineage commitment switch is poorly understood. As the post-transcription regulation by microRNAs (miRNAs) has a critical role in MSCs differentiation and bone homeostasis, we performed comprehensive miRNAs profiling and found miR-705 and miR-3077-5p were significantly enhanced in MSCs from osteoporosis bone marrow. Both miR-705 and miR-3077-5p acted as inhibitors of MSCs osteoblast differentiation and promoters of adipocyte differentiation, by targeting on the 3′untranslated region (3′UTR) of HOXA10 and RUNX2 mRNA separately. Combined inhibition of miR-705 and miR-3077-5p rescued the cell lineage commitment disorder of MSCs through restoring HOXA10 and RUNX2 protein level. Furthermore, we found excessive TNFα and reactive oxygen species caused by estrogen deficiency led to the upregulation of both miRNAs through NF-κB pathway. In conclusion, our findings showed that redundant miR-705 and miR-3077-5p synergistically mediated the shift of MSCs cell lineage commitment to adipocyte in osteoporosis bone marrow, providing new insight into the etiology of osteoporosis at the post-transcriptional level. Moreover, the rescue of MSCs lineage commitment disorder by regulating miRNAs expression suggested a novel potential therapeutic target for osteoporosis as well as stem cell-mediated regenerative medicine.

Highlights

The final cell fate decision of mesenchymal stem cells (MSCs) relies on the activation of lineage-specific transcription factors and repression of transcription factors promoting commitment to other lineages.[11,12,13,14] For example, osteoblastic differentiation of MSCs is controlled by Runx[2], Osterix and Dlx[5], whereas
The results showed that the trabecular bone structure was destroyed, and bone mass density (BMD) was significantly reduced in OVX femurs (Supplementary Figures S1A and B)
Based on computational miRNA target prediction analysis with several databases (DIANAMT, miRanda, miRwalk, PITA and RNA22), we found that HOXA10 was a predicted target of miR-705, and runt-related transcription factor 2 (RUNX2) was a target of miR-3077-5p

Summary

Introduction

The final cell fate decision of MSCs relies on the activation of lineage-specific transcription factors and repression of transcription factors promoting commitment to other lineages.[11,12,13,14] For example, osteoblastic differentiation of MSCs is controlled by Runx[2], Osterix and Dlx[5], whereas. PPARg and C/EBPa are the master transcription factors in adipocyte commitment.[15] in a transcription factor profiling, the mRNAs of the majority of the transcription factors that regulate MSCs differentiation were not altered in MSCs derived from aged bone.[7] Our preliminary gene expression profiling of MSCs derived from osteoporosis bone marrow showed a similar result, suggesting a limitation of investigating the cell-intrinsic mechanism of osteoporosis merely at the transcription level.

Methods

Results

Conclusion