MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation
Chang-Jun Li, … , Er-Yuan Liao, Xiang-Hang Luo
Chang-Jun Li, … , Er-Yuan Liao, Xiang-Hang Luo
Published March 9, 2015
Citation Information: J Clin Invest. 2015;125(4):1509-1522. https://doi.org/10.1172/JCI77716.
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Research Article Bone biology Article has an altmetric score of 21

MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation

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.

Authors

Chang-Jun Li, Peng Cheng, Meng-Ke Liang, Yu-Si Chen, Qiong Lu, Jin-Yu Wang, Zhu-Ying Xia, Hou-De Zhou, Xu Cao, Hui Xie, Er-Yuan Liao, Xiang-Hang Luo

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Figure 4

Mice with transgenic overexpression of miR-188 in osterix+ osteoprogenitors exhibit accelerated bone marrow fat accumulation and bone loss.

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Mice with transgenic overexpression of miR-188 in osterix+ osteoprogenit...
(A) Representative μCT images with quantitative μCT analysis of trabecular and cortical bone microarchitecture (B–H) in femora from 6- and 12-month-old WT and miR-188 transgenic (Tg) mice. n = 6 per group. (I) Quantitative μCT analysis of the ratio of bone volume to tissue volume of L4 vertebrae (Vt. BV/TV). (J and K) Three-point bending measurement of tibia stiffness (J) and maximum load (K). n = 5 per group. (L–N) Calcein double labeling–based quantification of bone formation rate per bone surface (BFR/BS) in femora. n = 5 per group. (O–R) Representative images of toluidine blue staining (O, top) and osteocalcin immunohistochemical staining (O, bottom) and quantification of number and area of adipocytes (P and Q) and number of osteoblasts (R) in distal femora. n = 8 per group. Data shown as mean ± SD. *P < 0.05, **P < 0.01 (Student’s t test). Scale bar: 100 μm.