泛素水解酶USP22被认为是肿瘤干细胞的标记基因。而我们发现USP22在骨髓间充质干细胞(MSC)的成骨分化早期出现显著上调，抑制其表达可致成骨分化受阻；差异蛋白质组学显示成骨特异性转录因子Osterix的蛋白表达受控于USP22变化，而mRNA水平不受影响。据此推测：USP22去泛素化修饰Osterix调控MSC的成骨分化。本项目以诱导MSC成骨分化模型为研究对象，采用基因克隆、定点突变、siRNA、免疫共沉淀等方法，在细胞与分子水平证实：(1) USP22与Osterix在细胞内存在直接的相互作用；(2) USP22直接调控Osterix泛素化水平，影响Osterix半衰期；(3) USP22通过Osterix调节成骨分化过程。研究结果将拓展USP22作用的新机制，获得USP22调控Osterix的直接证据，为确立USP22作为骨质疏松症治疗的新靶点提供充分的科学依据。

USP22 plays an important role in cancer initiation and progression and is proposed to be a "cancer stem cell" marker in a number of cancers. Interestingly, our recent study discovered that USP22 was highly induced during early osteogenic differentiation in human mesenchymal stem cells (hMSCs). Furthermore, know-down of USP22 in hMSCs resulted in a significant blockage of osteogenic differentiation. In the following proteomic screen, we identified the osteopath-specific transcription factor Osterix as one of the most down-regulated proteins upon USP22 knock-down. Notably, Osterix mRNA was not affected by the USP22 knock-down. Based on these interesting findings, we hypothesize that USP22 regulates osteogenic differentiation of hMSCs by deubiquitinating Osterix protein. To validate this hypothesis, we will focus on MSC osteogenic differentiation at cellular and molecular levels to address three questions. (1) Dose USP22 interact directly with Osterix? (2) Dose USP22 deubiquitinate Osterix directly during osteogenic differentiation? (3) Dose USP22 regulate of hMSCs osteogenic differentiation via modifying Osterix? This research will explore the novel physiological function of USP22 in osteogenesis, which will provide sufficient experimental evidence to support USP22 being a potential novel target for osteoporosis therapy.