Long noncoding RNA ZBTB40-IT1 regulates bone mass by directing the differentiation of human bone marrow mesenchymal stromal cells via the microRNA-514a-3p/FOXO4 axis

This study intended to clarify the mechanism of long noncoding RNA ZBTB40-IT1 in directing human bone marrow-derived mesenchymal stromal cell (hBMSC) differentiation. hBMSCs underwent osteogenic and adipogenic induction, and an osteoporosis mouse model was established via ovariectomy (OVX). Gain- an...

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Published in:	Human cell : official journal of Human Cell Research Society 2022-09, Vol.35 (5), p.1408-1423
Main Authors:	Shi, Zhe, Zhong, Qiang, Chen, Yuhang, Luo, Xin
Format:	Article
Language:	eng
Subjects:	Adipogenesis Biomedical and Life Sciences Bone marrow Bone mass Cbfa-1 protein Cell Biology Cell differentiation Femur Forkhead protein FOXO4 protein Gynecology Life Sciences Mesenchymal stem cells Mesenchyme MicroRNAs miRNA Oncology Osteogenesis Osteoporosis Ovariectomy Peroxisome proliferator-activated receptors Reproductive Medicine Research Article Ribonucleic acid RNA Stem Cells Stromal cells Surgery
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Summary:	This study intended to clarify the mechanism of long noncoding RNA ZBTB40-IT1 in directing human bone marrow-derived mesenchymal stromal cell (hBMSC) differentiation. hBMSCs underwent osteogenic and adipogenic induction, and an osteoporosis mouse model was established via ovariectomy (OVX). Gain- and loss-of-function approaches were utilized in hBMSCs and mice to investigate the function of ZBTB40-IT1, microRNA (miR)-514a-3p, and forkhead box O4 (FOXO4). Dual-luciferase reporter and RNA pulldown assays were applied to evaluate the binding of miR-514a-3p to ZBTB40-IT1 or FOXO4. The femur of the OVX mice had upregulated ZBTB40-IT1 and FOXO4 expression and downregulated miR-514a-3p expression. The bone mass was increased in OVX mice through ZBTB40-IT1 or FOXO4 knockdown. ZBTB40-IT1 and FOXO4 were downregulated, whereas miR-514a-3p was upregulated in osteogenesis-induced hBMSCs, which was the opposite in adipogenesis-induced hBMSCs. ZBTB40-IT1 or FOXO4 knockdown or miR-514a-3p overexpression increased ARS/ALP absorbance and RUNX2 and OCN levels but decreased fat density and PPARγ and FABP4 levels in hBMSCs. Mechanistically, ZBTB40-IT1 elevated FOXO4 expression by binding to miR-514a-3p. miR-514a-3p inhibition annulled the effects of ZBTB40-IT1 downregulation on hBMSC osteogenesis and adipogenesis, and FOXO4 overexpression abolished the impacts of miR-514a-3p upregulation on hBMSC osteogenesis and adipogenesis. Conclusively, ZBTB40-IT1 inhibition promotes the osteogenic differentiation of hBMSCs via the miR-514a-3p/FOXO4 axis, thereby increasing bone mass.
ISSN:	1749-0774 0914-7470 1749-0774