Abstract
The lineage specification of mesenchymal stem/stromal cells (MSCs) is tightly regulated by a wide range of factors. Recently, the versatile functions of ZBP1 (also known as DAI or DLM-1) have been reported in the blood circulation and immune systems. However, the biological function of ZBP1 during the lineage specification of MSCs is still unknown. In the present study, we found that ZBP1 was upregulated during osteogenesis but downregulated during adipogenesis in mouse bone marrow-derived MSCs (mBMSCs). ZBP1 was highly expressed in osteoblasts but expressed at a relatively low level in marrow adipocytes. Knockdown of ZBP1 inhibited alkaline phosphataseactivity, extracellular matrix mineralization, and osteogenesis-related gene expression in vitro and reduced ectopic bone formation in vivo. Knockdown of ZBP1 also promoted adipogenesis in MSCs in vitro. Conversely, the overexpression of ZBP1 increased the osteogenesis but suppressed the adipogenesis of MSCs. When the expression of ZBP1 was rescued, the osteogenic capacity of ZBP1-depleted mBMSCs was restored at both the molecular and phenotypic levels. Furthermore, we demonstrated that ZBP1, a newly identified target of Wnt/β-catenin signaling, was required for β-catenin translocation into nuclei. Collectively, our results indicate that ZBP1 is a novel regulator of bone and fat transdifferentiation via Wnt/β-catenin signaling.
Highlights
The term Mesenchymal stem or stromal cell (MSC) refers to a group of heterogeneous multipotent stem cells that can selfrenew and further differentiate into several cell types, including osteoblasts, chondrocytes, and adipocytes.[1]
We found that Z-DNA binding protein 1 (ZBP1) was expressed in osteoblasts and was dramatically upregulated upon osteogenic stimulation in mBMSCs
The expression of ZBP1 in marrow adipocytes was relatively low compared with that in osteoblasts, and ZBP1 was downregulated during the adipogenic differentiation of mBMSCs
Summary
The term Mesenchymal stem or stromal cell (MSC) refers to a group of heterogeneous multipotent stem cells that can selfrenew and further differentiate into several cell types, including osteoblasts, chondrocytes, and adipocytes.[1]. Β-Catenin with T-cell factor/lymphoid enhancer factor promote the downstream gene expression.[11,12] In regard to osteogenesis, Wnts promote osteoblastic differentiation, proliferation, and mineralization activity.[10,13,14] Several osteogenesisrelated transcription factors are reported to be the direct targets of Wnt/β-catenin signaling, such as Runt-related transcription factor 2 (Runx2) and osterix ( known as transcription factor 7, Sp7).[15,16,17] On the other hand, activation of Wnt/β-catenin signaling represses the adipogenic and chondrogenic differentiation of MSCs.[18,19]. Tion and the expression levels of adipogenesis-related genes in mBMSCs, including CD36, CCAAT enhancer-binding protein alpha, lipoprotein lipase and peroxisome proliferator-activated receptor
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