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

摘要 : Bone marrow mesenchymal stem cells (BMSCs) exhibit an age-dependent reduction in osteogenesis that is accompanied by an increased propensity toward adipocyte differentiation.

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.


Figure 8. MiR-188 directly targets HDAC9 and RICTOR.

(A) western blot analysis of the relative levels of HDAC9, RICTOR, PTEN, ZNF281, GLIS3, and EFNB2 protein expression in BMSCs transfected with agomiR-188 and antagomiR-188. β-Actin was used as loading control. Data are representative of 3 independent experiments.

(B) Schematic of miR-188 putative target sites in mouse Hdac9 and Rictor 3′-UTR. CDS, coding sequence.

(C–E) BMSCs were transfected with luciferase reporter carrying WT or MUT 3′-UTR of the HDAC9 GENE (WT–HDAC9–3′-UTR and MUT–HDAC9-3′–UTR) (C) WT1–Rictor–3′-UTR and MUT1–Rictor–3′-UTR (D), WT2–Rictor–3′-UTR and MUT2–Rictor–3′-UTR (E), respectively, and cotransfected with agomiR-188 or agomiR-NC. Effects of miR-188 on the reporter constructs were determined at 48 hours after transfection. Firefly luciferase values, normalized for renilla luciferase, are presented. n = 3 per group.

(F) Western blot analysis of HDAC9 and RICTOR protein expression in BMSCs from different mice as indicated. Data are representative of 3 independent experiments. Data shown as mean ± SD. *P < 0.01 vs. MUT-pGL3-HDAC9 or -RICTOR (Student’s t test).

原文链接：http://www.jci.org/articles/view/77716

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