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J Cell Mol Med. 2018 Apr;22(4):2162-2176. doi: 10.1111/jcmm.13490. Epub 2018 Jan 29.

MicroRNA-99a is a novel regulator of KDM6B-mediated osteogenic differentiation of BMSCs.

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Division of Oral Biology, Tufts University School of Dental Medicine, Boston, MA, USA.
State Key Laboratory of Oral Disease, West China School & Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
Department of Anatomy and Cell Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA.


Skeletal tissue originates from mesenchymal stem cells (MSCs) with differentiation potential into the osteoblast lineage regulated by essential transcriptional and post-transcriptional mechanisms. Recently, miRNAs and histone modifications have been identified as novel key regulators of osteogenic differentiation of MSCs. Here, we identified miR-99a and its target lysine (K)-specific demethylase 6B (KDM6B) gene as novel modulators of osteogenic differentiation of bone mesenchymal stem cells (BMSCs). Microarray profiling and further validation by quantitative real-time RT-PCR revealed that miR-99a was up-regulated during osteoblastic differentiation of BMSCs, and decreased in differentiated osteoblasts. Transfection of miR-99a mimics inhibited osteoblastic commitment and differentiation of BMSCs, whereas inhibition of miR-99a by inhibitors enhances these processes. KDM6B was determined as one of important targets of miR-99a, which was further confirmed by luciferase assay of 3'-UTR of KDM6B. Moreover, HOX gene level decreased after transfection of miR-99a mimics in BMSCs, which indicated that KDM6B is a bona fide target of miR-99a. Furthermore, in a model of in vivo bone regeneration, osteoblast-specific gain- and loss-of-function experiments performed using cranial bone defects revealed that miR-99a mimics-transfected BMSCs reduced bone formation, and conversely, miR-99a inhibitors-transfected BMSCs increased in vivo bone formation. Tissue-specific inhibition of miR-99a may be a potential novel therapeutic approach for enhancing BMSCs-based bone formation and regeneration.


BMSCs; KDM6B; miR-99a; osteogenic differentiation

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