Oct4 facilitates chondrogenic differentiation of mesenchymal stem cells by mediating CIP2A expression

Bone development and cartilage formation require strict modulation of gene expression for mesenchymal stem cells (MSCs) to progress through their differentiation stages. Octamer-binding transcription factor 4 (Oct4) expression is generally restricted to developing embryonic pluripotent cells, but its role in chondrogenic differentiation (CD) of MSCs remains unclear. We therefore investigated the role of Oct4 in CD using a microarray, quantitative real-time polymerase chain reaction, and western blotting. The expression of Oct4 was elevated when the CD of cultured MSCs was induced. Silencing Oct4 damaged MSC growth and proliferation and decreased CD, indicated by decreased cartilage matrix formation and the expression of Col2a1, Col10a1, Acan, and Sox9. We found a positive correlation between the expression of CIP2A, a natural inhibitor of protein phosphatase 2A (PP2A) and that of Oct4. Cellular inhibitor of PP2A (CIP2A) expression gradually increased after CD. Overexpression of CIP2A in MSCs with Oct4 depletion promoted cartilage matrix deposition as well as Col2a1, Col10a1, Acan, and Sox9 expression. The chondrogenic induction triggered c-Myc, Akt, ERK, and MEK phosphorylation and upregulated c-Myc and mTOR expression, which was downregulated upon Oct4 knockdown and restored by CIP2A overexpression. These findings indicated that Oct4 functions as an essential chondrogenesis regulator, partly via the CIP2A/PP2A pathway.