title: Redundant miR-3077-5p and miR-705 mediate the shift of mesenchymal stem cell lineage commitment to adipocyte in osteoporosis bone marrow.
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.
authors.affiliation: Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, China.
authors.forename: L
authors.initials: L
authors.lastname: Liao
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.forename: X
authors.initials: X
authors.lastname: Su
authors.forename: C
authors.initials: C
authors.lastname: Hu
authors.forename: X
authors.initials: X
authors.lastname: Zhu
authors.forename: N
authors.initials: N
authors.lastname: Yang
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Shi
authors.forename: S
authors.initials: S
authors.lastname: Shi
authors.forename: Y
authors.initials: Y
authors.lastname: Jin
mesh_terms: D020413:3' Untranslated Regions; D017667:Adipocytes / Q000166:cytology*; D050156:Adipogenesis; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D019070:Cell Lineage; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D005260:Female; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010024:Osteoporosis / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D050659:Core Binding Factor Alpha 1 Subunit; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; C000613310:MIRN705 microRNA, mouse; D035683:MicroRNAs; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C092119:Hoxa10 protein, mouse