Mycophenolic Acid Induces Osteogenesis in Tonsil-Derived Mesenchymal Stem Cells through Inhibition of IMPDH and HDAC3

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Abstract
BACKGROUND: Mycophenolic acid (MPA) is a well-known inhibitor of inosine monophosphate dehydrogenases (IMPDH), and our previous study also highlighted its inhibitory effects on histone deacetylases (HDACs). This study aims to evaluate MPA as a potential regulator of cell differentiation and to explore its mechanisms as an inhibitor of IMPDHs and HDACs using tonsil-derived mesenchymal stem cells (TMSCs). METHODS: TMSCs were treated with MPA at various concentrations for 48 h to evaluate its cytotoxic effects. The MPA treatment conditions were then optimized to induce differentiation of TMSCs. To investigate the underlying mechanisms, protein levels of IMPDH, HDAC3 and the histone acetyltransferase p300 (EP300) were assessed. RESULTS: MPA even at the highest concentration (160 μM) showed strong cytostatic effects on TMSCs without inducing cell death. Pre-treatment with 10 μM MPA for 48 h promoted osteogenic differentiation while inhibiting adipogenic differentiation. IMPDH inhibition via siRNA mimicked these effects, increasing calcium mineralization in the differentiated TMSCs. Co-treatment with guanosine reversed these effects, highlighting guanine depletion as a key mechanism of inducing osteogenesis. MPA also reduced the protein levels of HDAC3 and histone acetyltransferase p300 (EP300), which were also reversed by guanosine supplementation. The knockdown of HDAC3 or EP300 using siRNAs enhanced osteogenesis, with guanosine reversing these effects. HDAC3 overexpression reversed the effects of MPA, decreasing calcium mineralization. CONCLUSION: These findings suggest that MPA induces osteogenesis through guanine depletion, and that subsequent inhibition of HDAC3 and EP300 could be potential strategies for treating bone diseases.
Funding Information
  • National Research Foundation of Korea (2018R1D1A1A02085696)
  • Korean Fund for Regenerative Medicine (23B0101L1)

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