1. MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation.
- Author
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Li CJ, Cheng P, Liang MK, Chen YS, Lu Q, Wang JY, Xia ZY, Zhou HD, Cao X, Xie H, Liao EY, and Luo XH
- Subjects
- 3' Untranslated Regions genetics, Adipose Tissue cytology, Aging metabolism, Animals, Aptamers, Nucleotide pharmacology, Base Sequence, Bone Density genetics, Bone Density physiology, Bone Marrow Cells metabolism, Bone Remodeling physiology, Carrier Proteins antagonists & inhibitors, Cell Differentiation genetics, Histone Deacetylases, Humans, Mice, Mice, Knockout, Mice, Transgenic, MicroRNAs analysis, MicroRNAs genetics, Molecular Sequence Data, Osteocalcin analysis, Osteogenesis genetics, Osteoporosis genetics, Osteoporosis physiopathology, Rapamycin-Insensitive Companion of mTOR Protein, Repressor Proteins antagonists & inhibitors, Sp7 Transcription Factor, Transcription Factors physiology, Adipocytes cytology, Aging genetics, Bone Marrow Cells cytology, MicroRNAs physiology, Osteoblasts cytology, Osteogenesis physiology, Osteoporosis prevention & control
- Abstract
Bone marrow mesenchymal stem cells (BMSCs) exhibit an age-dependent reduction in osteogenesis that is accompanied by an increased propensity toward adipocyte differentiation. This switch increases adipocyte numbers and decreases the number of osteoblasts, contributing to age-related bone loss. Here, we found that the level of microRNA-188 (miR-188) is markedly higher in BMSCs from aged compared with young mice and humans. Compared with control mice, animals lacking miR-188 showed a substantial reduction of age-associated bone loss and fat accumulation in bone marrow. Conversely, mice with transgenic overexpression of miR-188 in osterix+ osteoprogenitors had greater age-associated bone loss and fat accumulation in bone marrow relative to WT mice. Moreover, using an aptamer delivery system, we found that BMSC-specific overexpression of miR-188 in mice reduced bone formation and increased bone marrow fat accumulation. We identified histone deacetylase 9 (HDAC9) and RPTOR-independent companion of MTOR complex 2 (RICTOR) as the direct targets of miR-188. Notably, BMSC-specific inhibition of miR-188 by intra-bone marrow injection of aptamer-antagomiR-188 increased bone formation and decreased bone marrow fat accumulation in aged mice. Together, our results indicate that miR-188 is a key regulator of the age-related switch between osteogenesis and adipogenesis of BMSCs and may represent a potential therapeutic target for age-related bone loss.
- Published
- 2015
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