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.

间充质干细胞/基质细胞（MSC）的谱系规范受到多种因素的严格调控。最近，ZBP1（也称为 DAI 或 DLM-1）在血液循环和免疫系统中的多功能功能已被报道。然而，ZBP1在MSC谱系分化过程中的生物学功能仍不清楚。在本研究中，我们发现在小鼠骨髓源性间充质干细胞（mBMSCs）中，ZBP1在成骨过程中上调，但在脂肪形成过程中下调。ZBP1在成骨细胞中高表达，但在骨髓脂肪细胞中表达水平相对较低。ZBP1 的敲低可在体外抑制碱性磷酸酶活性、细胞外基质矿化和成骨相关基因表达，并减少体内异位骨形成。ZBP1 的敲低也促进体外 MSC 的脂肪形成。相反，ZBP1 的过度表达增加了 MSC 的成骨作用，但抑制了脂肪形成。当ZBP1的表达得到恢复时，ZBP1耗尽的mBMSC的成骨能力在分子和表型水平上都得到恢复。此外，我们证明了 ZBP1（一种新发现的 Wnt/β-连环蛋白信号传导靶标）是 β-连环蛋白易位到细胞核中所必需的。总的来说，我们的结果表明 ZBP1 是通过 Wnt/β-catenin 信号传导调节骨和脂肪转分化的新型调节剂。