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首页> 外文学位 >Coordination of cell cycle and cell differentiation by receptor activator of NF-kappa-B ligand during osteoclast differentiation.
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Coordination of cell cycle and cell differentiation by receptor activator of NF-kappa-B ligand during osteoclast differentiation.

机译：在破骨细胞分化过程中通过NF-κB配体的受体激活剂协调细胞周期和细胞分化。

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摘要

Osteoclasts are bone resorbing multinuclear cells formed by the fusion of hematopoietic mononuclear precursor cells. Microphthalmia transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor important for the differentiation osteoclasts. MITF regulates the expression of osteoclast-differentiation marker genes, Tartrate-resistant acid phosphatase (TRAP) and cathepsin K. Deletion in arginine 215 in the basic domain of MITF results in severe osteopetrosis in Mitfmi/mi mice. A substitution of arginine 216, in the basic domain, with lysine results in age resolving osteopetrosis in Mitfor/or mice. Mitfwh/wh mice with a substitution of isoleucine to asparagine in the basic domain of Mitf do not exhibit any osteopetrosis. We identified several novel genes regulated by Mitf with potential roles in osteoclast differentiation via microarray analysis of cDNA from WT and Mitfmi/mi osteoclasts. In particular, Eos, HOX11L2, Hematopoietic cell phosphatase (HCP) and p9 were confirmed to be expressed in lower levels in Mitfmi/mi osteoclasts. We also observed that while TRAP mRNA levels were unregulated in Mitfor/or, similar to the levels in WT, Cathepsin K levels were lower in both Mitfmi/mi and Mitfor/or osteoclasts.; Osteoclast progenitors quit proliferating prior to fusion to become multinuclear osteoclasts. We observed that the cytokine, receptor activator of NF-kB ligand (RANKL), induces wild type (WT) osteoclast progenitors to withdraw from cell cycle within 24 hours of its application. This event coincides with elevation in p27KIP1 and p21CIP1 and with decreased CDK2 activity. Also, p27KIP1 is required by osteoclast progenitors to exit from the cell cycle in response to RANKL and p27KIP1 −/− osteoclasts express lower levels of TRAP mRNA. Osteoclast progenitors from p27KIP1−/− p21CIP1−/− double knockout mice do not withdraw from cell cycle in response to RANKL and express significantly lower levels of TRAP and cathepsin K mRNA. p27KIP1−/−p21 CIP1−/− mice exhibit age resolving osteopetrosis. Also, precursors from the double mutant mice form fewer multinuclear functional osteoclasts in vitro. These data suggest that both p21 CIP1 and p27KIP1 might have redundant roles during osteoclast differentiation.
机译：破骨细胞是由造血单核前体细胞融合形成的骨吸收性多核细胞。小眼症转录因子（MITF）是基本的螺旋-环-螺旋亮氨酸拉链转录因子，对分化破骨细胞很重要。 MITF调节破骨细胞分化标志物基因，抗酒石酸酸性磷酸酶（TRAP）和组织蛋白酶K的表达。在MITF基本域中精氨酸215的缺失会导致 Mitf mi / mi严重骨化。 super> 小鼠。在基本域中，用赖氨酸替代精氨酸216可导致 Mitf 或/或 小鼠的年龄骨化。在Mitf基本域中用异亮氨酸替代天冬酰胺的 Mitf wh / wh 小鼠未显示任何骨质疏松症。通过WT和 Mitf mi / mi 破骨细胞的cDNA的微阵列分析，我们鉴定了由Mitf调控的在破骨细胞分化中具有潜在作用的几个新基因。特别是，证实了Eos，HOX11L2，造血细胞磷酸酶（HCP）和p9在 Mitf mi / mi 破骨细胞中以较低的水平表达。我们还观察到，虽然 Mitf 或/或 中的TRAP mRNA水平不受调节，但与WT中的水平相似，两个 Mitf mi / mi 和 Mitf 或/或 破骨细胞。破骨细胞祖细胞在融合之前就停止增殖，成为多核破骨细胞。我们观察到细胞因子，NF-kB配体的受体激活剂（RANKL），诱导野生型（WT）破骨细胞祖细胞在应用后24小时内退出细胞周期。该事件与p27 KIP1 和p21 CIP1 升高以及CDK2活性降低同时发生。此外，破骨细胞祖细胞需要p27 KIP1 来响应RANKL而退出细胞周期，而p27 KIP1 -/-破骨细胞表达的水平较低TRAP mRNA的表达。来自p27 KIP1 -/- p21 CIP1 -/-双敲除小鼠的破骨细胞祖细胞不会退出细胞周期响应RANKL并表达显着较低的TRAP和组织蛋白酶K mRNA水平。 p27 KIP1 − / − p21 CIP1 − / − 小鼠表现出年龄分辨性骨质疏松症。同样，双重突变小鼠的前体在体外形成的多核功能破骨细胞更少。这些数据表明p21 CIP1 和p27 KIP1 在破骨细胞分化过程中可能具有冗余作用。

著录项

  • 作者

    Sankar, Uma.;

  • 作者单位

    The Ohio State University.;

  • 授予单位 The Ohio State University.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 309 p.
  • 总页数 309
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;
  • 关键词

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