MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation.
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.
Chang-Jun
CJ
Li
Peng
P
Cheng
Meng-Ke
MK
Liang
Yu-Si
YS
Chen
Qiong
Q
Lu
Jin-Yu
JY
Wang
Zhu-Ying
ZY
Xia
Hou-De
HD
Zhou
Xu
X
Cao
Hui
H
Xie
Er-Yuan
EY
Liao
Xiang-Hang
XH
Luo
D020413:3' Untranslated Regions / Q000235:genetics; D017667:Adipocytes / Q000166:cytology*; D000273:Adipose Tissue / Q000166:cytology; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D052157:Aptamers, Nucleotide / Q000494:pharmacology; D001483:Base Sequence; D015519:Bone Density / Q000235:genetics / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D016723:Bone Remodeling / Q000502:physiology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002454:Cell Differentiation / Q000235:genetics; D006655:Histone Deacetylases; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000166:cytology*; D015675:Osteocalcin / Q000032:analysis; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*; D010024:Osteoporosis / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000502:physiology
D020413:3' Untranslated Regions; D052157:Aptamers, Nucleotide; D002352:Carrier Proteins; C584093:MIRN188 microRNA, human; C000594549:MIRN188 microRNA, mouse; D035683:MicroRNAs; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D012097:Repressor Proteins; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; C525637:rictor protein, mouse; D015675:Osteocalcin; C486545:Hdac9 protein, mouse; D006655:Histone Deacetylases