FOXO3 is targeted by miR-223-3p and promotes osteogenic differentiation of bone marrow mesenchymal stem cells by enhanci
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RESEARCH ARTICLE
FOXO3 is targeted by miR‑223‑3p and promotes osteogenic differentiation of bone marrow mesenchymal stem cells by enhancing autophagy Cheng Long1 · Shiqiang Cen1 · Zhou Zhong1 · Chang Zhou1 · Gang Zhong1 Received: 28 April 2020 / Accepted: 24 August 2020 © The Author(s) 2020
Abstract Mesenchymal stem cells (MSCs) are a promising regenerative medicine. The roles of miRNAs in osteogenic differentiation of bone marrow MSCs (BM-MSCs) remained less reported. Forkhead Box O3 (FOXO3) and alkaline phosphatase (ALP) levels in the BM-MSCs were measured on 3, 7, and 14 days after osteogenic differentiation. After transfection of FOXO3 overexpression plasmids or siFOXO3 into BM-MSCs, factors related to osteogenic differentiation or cell autophagy were determined. Besides, 3-methyladenine or rapamycin, as well as miR-223-3p mimic or inhibitor were applied to further determine the effect of FOXO3 in BM-MSCs. FOXO3 and ALP levels were increased in a time-dependent manner with osteogenic differentiation, supported by Alizarin Red Staining. Furthermore, up-regulated FOXO3 increased levels of ALP and factors related to osteogenic differentiation by increasing levels of autophagy-related factors. FOXO3, targeted by miR223-3p, reversed the effects of miR-223-3p on factors related to BM-MSC autophagy and osteogenic differentiation. Downregulated miR-223-3p expression promoted osteogenic differentiation of BM-MSCs by enhancing autophagy via targeting FOXO3, suggesting the potential of miR-223-3p as a therapeutic target for enhancing bone functions. Keywords Forkhead Box O3 · miR-223-3p · Bone marrow mesenchymal stem cells · Osteogenic differentiation · Autophagy
Introduction Mesenchymal stem cells (MSCs) could be isolated from human tissues such as bone marrow, adipose tissue, and birth-related tissues, for example, placenta, umbilical cord, cord blood, or amnion. Multifunctional MSCs have the abilities of self-renewal and differentiation into osteoblasts, chondrocytes, or adipocytes [1]. Bone marrow MSCs (BMMSCs), in particular, play a pivotal role during bone formation, and have attracted great attention for their ability to induce osteogenic differentiation and their secretion of growth factors and cytokines [2]. In clinical practice, osteogenic differentiation of BM-MSCs has been widely applied to the treatments such as large bone fracture and bone-related * Gang Zhong [email protected] 1
Department of Orthopedic, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Wuhou District, Chengdu 610041, Sichuan, China
tissue engineering [3]. However, abnormal osteogenic differentiation of BM-MSCs was related with the onset and progression of several diseases, such as osteoarthritis (OA) and ankylosing spondylitis (AS) [4, 5]. A deeper understanding of the molecular mechanisms underlying osteogenic differentiation of BM-MSCs has clinical significance for bone disease pathology and clinical treatment. The previous studies showed that Forkhead Box O3 (FOXO3) plays a critical role in osteogenic different
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