Cbfb enhances the osteogenic differentiation of both human and mouse mesenchymal stem cells induced by cbfa-1 via reducing its ubiquitination-mediated degradation
Cbfb enhances the osteogenic differentiation of both human and mouse mesenchymal stem cells induced by cbfa-1 via reducing its ubiquitination-mediated degradation
复制标题
DOI：
10.1634/stemcells.2006-0391
复制
发表时间：
2007-06-01
期刊：
影响因子：
5.2
通讯作者：
Su, Yeu
中科院分区：
文献类型：
--
作者：
Lien, Chun-Yang;Lee, Oscar K.;Su, Yeu
核心结合因子是异源二聚体转录因子的一个小家族，在发育过程中起着关键作用。Cbfa-1是该家族的三个α亚基之一，是成骨所必需的，而Cbfb是唯一的SS亚基，它与不同的Cbfas形成异二聚体，通过诱导构象变化来增加它们与DNA的结合亲和力。虽然在CBFA-1和Cbfb基因敲除动物中都发现了缺陷的骨形成，但后者在成骨过程中的确切作用仍不清楚。为探讨Cbfb在骨髓间充质干细胞成骨分化中的作用，构建了携带Cbfb和CBFA-1的重组腺病毒AdHACbfb和AdCbfa-1，分别感染小鼠C3H10T1/2细胞和人骨髓间充质干细胞。Cbfb单独作用虽不能诱导MSCs成骨，但能显著增强CBFA-1高表达细胞的碱性磷酸酶基因表达和酶活性以及骨钙素活性。Cbfb增强CBFA-1的成骨诱导分化作用是由于Cbfb抑制泛素化介导的蛋白酶体降解，从而提高了CBFA-1的稳定性。综上所述，除了明确Cbfb在MSCs成骨分化中的作用外，我们的研究结果还表明，共表达CBFA-1和Cbfb的MSCs可能是一种合适的骨修复和再生治疗策略。
Core-binding factors are a small family of heterodimeric transcription factors that play critical roles in development. Whereas Cbfa-1, one of the three a subunits in the family, is essential for osteogenesis, Cbfb, the only ss subunit, forms heterodimers with different Cbfas to increase their DNA binding affinity by inducing conformational changes. Although defective bone formation was found in both Cbfa-1 and Cbfb knockout animals, the precise role of the latter in osteogenesis remains unclear. To dissect the contribution of Cbfb in osteogenic differentiation of mesenchymal stem cells (MSCs), recombinant adenoviruses carrying Cbfb (AdHACbfb) and Cbfa-1 (AdCbfa-1) were generated and used to infect both the mouse C3H10T1/2 cells and human bone marrow-derived MSCs. Although Cbfb alone failed to trigger osteogenesis of MSCs, it markedly enhanced the gene expression and enzyme activity of alkaline phosphatase as well as osteocalcin activation in those cells overexpressing Cbfa-1. Enhancement of the osteogenic differentiation-inducing effect of Cbfa-1 by Cbfb resulted from an increase in stability of the former due to the suppression of ubiquitination-mediated proteasomal degradation by the latter. Taken together, in addition to defining the role of Cbfb in osteogenic differentiation of MSCs, our,results also suggest that the Cbfa-1 and Cbfb coexpressing MSCs might be an appropriate strategy for bone repairing and regeneration therapies.