Abstract
Long noncoding RNAs (lncRNAs) play very important roles in cell differentiation. Our recent study has demonstrated that a novel lncRNA named lnc-OAD modulated 3T3-L1 adipocyte differentiation. In the present study, we examined the roles of lnc-OAD in bone morphogenetic protein 2- (BMP-2-) induced osteoblast differentiation. Lnc-OAD expression was increased during BMP-2-induced osteoblast differentiation in C3H10T1/2 mesenchymal stem cells and MC3T3-E1 preosteoblast cells. Knockdown of lnc-OAD expression by specific siRNA remarkably decreased early osteoblast differentiation. In addition, stable knockdown of lnc-OAD by lentivirus vector also significantly inhibited late osteoblast differentiation and matrix mineralization in vitro. Conversely, stably overexpressed lnc-OAD with lentiviral vector accelerated osteoblast differentiation. Mechanistically, knockdown of lnc-OAD reduced significantly the phosphorylation of AKT and the expression of Osterix induced by BMP-2, while overexpression of lnc-OAD enhanced the phosphorylation of AKT and the expression of Osterix. Taken together, our study suggests that lnc-OAD plays an important role in modulating BMP-2-induced osteoblast differentiation via, at least in part, regulating the AKT-Osterix signaling axis.
Highlights
Osteoblast commitment and differentiation from mesenchymal stem cells (MSCs) is a complex multistep process controlled by intricate signaling cascades and cellular molecules [1, 2]
Lnc-OAD was flanked by the Forkhead box Q1 (FOXQ1) and Forkhead box F2 (FOXF2) loci (Figure 1(a)). Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) results showed that lnc-OAD was highly expressed in MC3T3-E1 preosteoblast cells, but relatively low in 3T3-L1 preadipocyte cells and
Based on all current data, we proposed a model to explain the possible mechanism of lnc-OAD regulating bone morphogenetic protein 2- (BMP-2-)induced osteoblast differentiation as follows (Figure 7(e)): bone morphogenetic protein (BMP)-2 was able to upregulate the expression of long noncoding RNA lnc-OAD, which led to the increase of AKT phosphorylation level and activated the AKT pathway to upregulate the transcription factor Osterix
Summary
Osteoblast commitment and differentiation from mesenchymal stem cells (MSCs) is a complex multistep process controlled by intricate signaling cascades and cellular molecules [1, 2]. In the osteoblast commitment and differentiation process, bone morphogenetic protein (BMP) superfamily functions as a powerful and effective signal for osteoblast inducing [3]. Various BMPs, including BMP-2, BMP-4, BMP-7, and BMP-9, have been investigated extensively and proved to induce osteoblast differentiation [4, 5]. A number of signaling pathways such as PI3K-AKT, MAPK, BMP-Smad, and WNT; some key transcription factors; and noncoding RNAs have been identified to be involved in BMP-2-induced osteoblast differentiation [6,7,8,9]. Identification of additional novel factors may provide better insights into the precise regulation of osteoblast differentiation
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