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The transcription factor p63 is required for skeletal formation, and is important for the regulation of 1α,25(OH) 2 D 3  receptor (VDR) in human mesenchymal stem cells (hMSC). Herein we report that TAp63γ and ΔNp63β appear to be an integral part of the osteoblastic differentiation of hMSC and are differentially regulated by the vitamin D 3  metabolites 1α,25(OH) 2 D 3  and 24R,25(OH) 2 D 3 . We compared the endogenous expression of p63 isoforms (TA- and ΔNp63) and splice variants (p63α, -β, -γ), in naive hMSC and during osteoblastic differentiation of hMSC. TAp63α and -β were the predominant p63 variants in naive, proliferating hMSC. In contrast, under osteoblastic differentiation conditions, expression of p63 changed from the TAp63α and -β to the TAp63γ and ΔNp63β variants. Transient overexpression of the p63 variants demonstrated that TAp63β, ΔNp63β, and ΔNp63γ increased alkaline phosphatase activity and ΔNp63α and -γ increased the expression of mRNA for  osteocalcin  and  osterix . Our results support the hypothesis that TAp63α and -β promote a naive state in hMSC. Moreover, TAp63γ is increased during and promotes early osteoblastic differentiation through the expression of pro-osteogenic genes;  VDR ,  Osterix ,  Runx2  and  Osteopontin . ΔNp63β also appears to support osteogenic maturation through increased alkaline phosphatase activity. Treatment with 1α,25(OH) 2 D 3  increased the expression of mRNA for ΔNp63, while addition of 24R,25(OH) 2 D 3  increased the expression of TA- and ΔNp63γ variants. These novel findings demonstrate for the first time that p63 variants are differentially expressed in naive hMSC (TAp63α,β), are important during the osteoblastic differentiation of hMSC (TAp63γ and ΔNp63β), and are differentially regulated by the vitamin D3 metabolites, 1α,25(OH) 2 D 3  and 24R,25(OH) 2 D 3 . The molecular nuances and mechanisms of osteoblastic differentiation presented here will hopefully improve our understanding of bone development, complications in bone repair (mal- and non-union fractures), osteoporosis and possibly lead to new modalities of treatment.

TAp63γ and ΔNp63β Promote Osteoblastic Differentiation of Human Mesenchymal Stem Cells: Regulation by Vitamin D3 Metabolites