TAp63γ and ΔNp63β promote osteoblastic differentiation of human mesenchymal stem cells: regulation by vitamin D3 Metabolites.
TAp63γ and ΔNp63β promote osteoblastic differentiation of human mesenchymal stem cells: regulation by vitamin D3 Metabolites.
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DOI：
10.1371/journal.pone.0123642
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Howard GA
中科院分区：
文献类型：
--
作者：
Curtis KM;Aenlle KK;Frisch RN;Howard GA
转录因子p63是骨骼形成所必需的，并且对人间充质干细胞（hMSC）中1α，25（OH）2D 3受体（VDR）的调节非常重要。在此，我们报道TAp 63 γ和Δ Np 63 β似乎是hMSC成骨分化的组成部分，并受到维生素D3代谢物1α，25（OH）2D 3和24 R，25（OH）2D 3的不同调节。我们比较了p63亚型（TA-和Δ Np 63）和剪接变体（p63α，-β，-γ）在幼稚hMSC和hMSC成骨分化过程中的内源性表达。TAp 63 α和-β是幼稚的、增殖的hMSC中的主要p63变体。相反，在成骨细胞分化条件下，p63的表达从TAp 63 α和-β变为TAp 63 γ和Δ Np 63 β变体。p63变体的瞬时过表达表明，TAp 63 β、Δ Np 63 β和Δ Np 63 γ增加碱性磷酸酶活性，Δ Np 63 α和-γ增加骨钙素和osterix的mRNA表达。我们的结果支持TAp 63 α和-β促进hMSC中幼稚状态的假设。此外，TAp 63 γ在早期成骨细胞分化过程中增加，并通过表达促成骨基因VDR、Osterix、Runx 2和骨桥蛋白促进早期成骨细胞分化。Δ Np 63 β似乎还通过增加碱性磷酸酶活性支持成骨成熟。用1α，25（OH）2D 3处理增加Δ Np 63的mRNA表达，而加入24 R，25（OH）2D 3增加TA-和Δ Np 63 γ变体的表达。这些新发现首次证明p63变体在幼稚hMSC中差异表达（TAp 63 α，β），在hMSC的成骨分化过程中重要（TAp 63 γ和Δ Np 63 β），并且受维生素D3代谢物1α，25（OH）2D 3和24 R，25（OH）2D 3的差异调节。这里提出的成骨细胞分化的分子细微差别和机制将有望提高我们对骨发育、骨修复并发症（骨不连和骨不连骨折）、骨质疏松症的理解，并可能导致新的治疗方式。
The transcription factor p63 is required for skeletal formation, and is important for the regulation of 1α,25(OH)2D3 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 D3 metabolites 1α,25(OH)2D3 and 24R,25(OH)2D3. 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)2D3 increased the expression of mRNA for ΔNp63, while addition of 24R,25(OH)2D3 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)2D3 and 24R,25(OH)2D3. 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.
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