Defects in Mesenchymal Stem Cell Self-Renewal and Cell Fate Determination Lead to an Osteopenic Phenotype in Bmi-1 Null Mice
Defects in Mesenchymal Stem Cell Self-Renewal and Cell Fate Determination Lead to an Osteopenic Phenotype in Bmi-1 Null Mice
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间充质干细胞自我更新和细胞命运决定的缺陷导致 Bmi-1 无效小鼠出现骨质减少表型
DOI：
10.1359/jbmr.090812
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发表时间：
2010-03-01
影响因子：
6.2
通讯作者：
Miao, Dengshun
中科院分区：
文献类型：
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作者：
Zhang, Heng-Wei;Ding, Jiong;Miao, Dengshun
在甲状旁腺激素相关蛋白1-84[PTHrP(1-84)]敲击小鼠中，多梳蛋白Bmi-1的表达减少，并可能介导观察到的表型变化。因此，我们现在检测了体内BMI-1(-/-)小鼠的骨骼表型，并评估了体外培养的BMI-1(-/-)小鼠骨髓间充质干细胞(BM-MSCs)的功能。新生BMI-1-/-小鼠表现出骨骼生长迟缓，软骨细胞增殖减少，细胞凋亡增加。成骨细胞数、碱性磷酸酶、I型胶原、骨钙素基因表达、骨矿沉积率、骨小梁体积和骨密度均显著降低，而骨髓脂肪细胞数和PPAR-γ表达增加。这些变化与在PTHrP(1-84)敲击小鼠中观察到的骨骼表型一致。骨髓细胞集落形成单位成纤维细胞(CFU-F)形成率降低，碱性磷酸酶阳性CFU-F和Runx2表达百分率降低。相反，脂肪细胞的形成和PPAR-γ的表达增加，多连接蛋白sirtuin(Sirt1)的表达减少。BM-MSCs的增殖减少和凋亡增加与衰老相关的肿瘤抑制基因上调有关，包括p16、p19和p27。对小鼠骨骼表型的分析表明，Bmi-1(-/-)在PTHrP下游发挥作用。此外，我们的研究表明，Bmi-1通过抑制p27、p16和p19的表达来维持BM-MSCs的自我更新，并通过促进成骨细胞分化和至少部分通过刺激Sirt1表达来抑制脂肪细胞的分化来改变BM-MSCs的细胞命运。因此，Bmi-1在促进成骨方面起着关键作用。(C)2010年美国骨与矿物研究学会。
In parathyroid hormone-related protein 1-84 [PTHrP(1-84)] knockin mice, expression of the polycomb protein Bmi-1 is reduced and potentially can mediate the phenotypic alterations observed. We have therefore now examined the skeletal phenotype of Bmi-1(-/-) mice in vivo and also assessed the function of bone marrow mesenchymal stem cells (BM-MSCs) from Bmi-1(-/-) mice ex vivo in culture. Neonatal Bmi-1-/- mice exhibited skeletal growth retardation, with reduced chondrocyte proliferation and increased apoptosis. Osteoblast numbers; gene expression of alkaline phosphatase, type I collagen, and osteocalcin; the mineral apposition rate; trabecular bone volume; and bone mineral density all were reduced significantly; however, the number of bone marrow adipocytes and Ppar-gamma expression were increased. These changes were consistent with the skeletal phenotype observed in the PTHrP(1-84) knockin mouse. The efficiency of colony-forming unit fibroblast (CFU-F) formation in bone marrow cultures was decreased, and the percentage of alkaline phosphatase-positive CFU-F and Runx2 expression were reduced. In contrast, adipocyte formation and Ppar-gamma expression in cultures were increased, and expression of the polyconnb protein sirtuin (Sirt1) was reduced. Reduced proliferation and increased apoptosis of BM-MSCs were associated with upregulation of senescence-associated tumor-suppressor genes, including p16, p19, and p27. Analysis of the skeletal phenotype in mice suggests that Bmi-1(-/-) functions downstream of PTHrP. Furthermore, our studies indicate that Bmi-1 maintains self-renewal of BM-MSCs by inhibiting the expression of p27, p16, and p19 and alters the cell fate of BM-MSCs by enhancing osteoblast differentiation and inhibiting adipocyte differentiation at least in part by stimulating Sirt1 expression. Bmi-1 therefore plays a critical role in promoting osteogenesis. (C) 2010 American Society for Bone and Mineral Research.