Long noncoding RNA Bmncr regulates mesenchymal stem cell fate during skeletal aging
Chang-Jun Li, … , Yan Huang, Xiang-Hang Luo
Chang-Jun Li, … , Yan Huang, Xiang-Hang Luo
Published December 3, 2018; First published October 22, 2018
Citation Information: J Clin Invest. 2018;128(12):5251-5266. https://doi.org/10.1172/JCI99044.
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Research Article Endocrinology

Long noncoding RNA Bmncr regulates mesenchymal stem cell fate during skeletal aging

Abstract

Bone marrow mesenchymal stem cells (BMSCs) exhibit an age-related lineage switch between osteogenic and adipogenic fates, which contributes to bone loss and adiposity. Here we identified a long noncoding RNA, Bmncr, which regulated the fate of BMSCs during aging. Mice depleted of Bmncr (Bmncr-KO) showed decreased bone mass and increased bone marrow adiposity, whereas transgenic overexpression of Bmncr (Bmncr-Tg) alleviated bone loss and bone marrow fat accumulation. Bmncr regulated the osteogenic niche of BMSCs by maintaining extracellular matrix protein fibromodulin (FMOD) and activation of the BMP2 pathway. Bmncr affected local 3D chromatin structure and transcription of Fmod. The absence of Fmod modified the bone phenotype of Bmncr-Tg mice. Further analysis revealed that Bmncr would serve as a scaffold to facilitate the interaction of TAZ and ABL, and thus facilitate the assembly of the TAZ and RUNX2/PPARG transcriptional complex, promoting osteogenesis and inhibiting adipogenesis. Adeno-associated viral-mediated overexpression of Taz in osteoprogenitors alleviated bone loss and marrow fat accumulation in Bmncr-KO mice. Furthermore, restoring BMNCR levels in human BMSCs reversed the age-related switch between osteoblast and adipocyte differentiation. Our findings indicate that Bmncr is a key regulator of the age-related osteogenic niche alteration and cell fate switch of BMSCs.

Authors

Chang-Jun Li, Ye Xiao, Mi Yang, Tian Su, Xi Sun, Qi Guo, Yan Huang, Xiang-Hang Luo

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Figure 8

Bmncr served as a scaffold to assemble TAZ and ABL.

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Bmncr served as a scaffold to assemble TAZ and ABL. (A) TAZ and ABL pro...
(A) TAZ and ABL proteins interacting with Bmncr were identified by mass spectrum after RNA pull-down with biotinylated Bmncr in BMSCs. (B) Biotinylated Bmncr retrieves TAZ and ABL as detected by immunoblotting. (C) TAZ and ABL retrieves Bmncr RNA specifically as detected by qRT-PCR. n = 5 per group. Data are mean ± SD. *P < 0.05 (Student’s t test). (D) The diagram indicating the first 400 bp (blue boxes) of Bmncr is necessary and sufficient to bind TAZ; the last 647 bp (yellow boxes) is necessary and sufficient to bind ABL. The profiles were established by means of RNA pull-down assay. (E) Immunoprecipitation assays using antibody against ABL, the ABL-associated TAZ was detected by Western blotting with antibody against TAZ. (F) Immunoprecipitation assays using antibody against TAZ, the TAZ-associated RUNX2, and PPARG were detected by Western blotting with antibody against RUNX2 and PPARG. Data are representative of 3 independent experiments.