Previously, we showed that HDAC1 prevents vascular calcification (VC), whereas its E3 ligase, MDM2 exaggerates it by inducing the polyubiquitination of HDAC1. We further investigated the roles of MDM2 in VC. We observed that VSMC-specific conditional knockout of Mdm2 blunted VC. TgMDM2 WT mice elicited VC, while TgMDM2 Y489A or TgMDM2 ΔR failed to do so. By promoter mapping analysis, we found that Msx-binding element at -1331～1327 upstream of transcription start site of MDM2 promoter is Pi-responsive element for the induction of MDM2 transactivation. Chromatin immunoprecipitation as well as mutant promoter analysis further confirmed that both Msx1 and Msx2 bound to and activated MDM2 promoter. Pi potentiated the binding of Msx to its binding element of MDM2 promoter. Both Msx1 and Msx2 potentiated Pi-induced VC. Msx-induced potentiation of Pi-mediated VC was attenuated by MDM2 siRNA. As an alternative key epigenetic regulator, non-coding RNAs are under extensive investigation in association with VC. By RNA sequencing, we found some candidate circular and long non-coding RNAs that are expected to affect the VC. Taken together, the epigenetic regulation of both Msx/MDM2/HDAC1 axis and non-coding RNA participate in the development of VC, which will be novel therapeutic targets of the diseases.