UC2288-Mediated Increased Osteogenic Expression in Mesenchymal Stem Cells.

Abstract

p21 is a cell cycle regulator that has been implicated in regeneration of tissues and in development of certain tumors. p21 inhibition also enhances bone regeneration after injury in p21^-/- mice. To translate these findings to the clinic, we sought an FDA-approved p21 attenuator. UC2288, a derivative of sorafenib, selectively inhibits p21 independently of p53 and induces apoptosis in cancer cells. Given the central role of p21 in mesenchymal stem cell (MSC) proliferation and differentiation, its effects on MSCs merits investigation but remains unknown. Consequently, we hypothesized that UC2288 will improve the osteogenic potential of mesenchymal stem cells by suppressing p21. First, we examined the differential interaction of UC2288 with human bone marrow (BM) MSCs compared with breast cancer cells via viability assays. Increased cell death was observed in cancer cells, particularly at higher concentrations and with longer interaction times, whereas MSCs demonstrated lower cell death. Gene expression assay revealed upregulation of osteogenic genes, though the specific genes overexpressed varied depending on the culture medium. Interestingly, the culture medium also affected p21 expression, where p21 expression was upregulated in DMEM/F12 and downregulated in alpha-MEM as evidenced in gene and protein expression assays. Alizarin Red staining confirmed increased mineralization when UC2288 or UC2288+osteogenic factors were added. These findings indicate that UC2288 promotes osteogenesis in BM-MSCs in a concentration- and time-dependent manner. Further research is needed to optimize conditions for preclinical and clinical translation as an anabolic bone formation therapy.