Adenomatous polyposis coli-mediated control of β-catenin is essential for both chondrogenic and osteogenic differentiation of skeletal precursors
Adenomatous polyposis coli-mediated control of β-catenin is essential for both chondrogenic and osteogenic differentiation of skeletal precursors
复制标题
DOI：
10.1186/1471-213x-9-26
复制
发表时间：
2009-04-08
影响因子：
--
通讯作者：
Robanus-Maandag, Els C.
中科院分区：
文献类型：
--
作者：
Miclea, Razvan L.;Karperien, Marcel;Robanus-Maandag, Els C.
背景资料：在骨骼发生过程中，经典Wnt信号通路中β-连环蛋白的蛋白水平决定了骨骼前体细胞向成骨细胞和软骨细胞的谱系定型。结肠腺瘤性息肉病（Apc）通过下调细胞内β-连环蛋白水平，是β-连环蛋白转换的关键控制者。结果：为了研究Apc是否参与骨骼前体细胞的谱系定型，我们产生了在Col 2a 1表达细胞中缺乏功能性Apc的条件性敲除小鼠。与使用β-连环蛋白的致癌变体的其他模型相反，我们的方法由于Apc的功能丧失而导致野生型β-连环蛋白的积累。条件性纯合子Apc突变小鼠围产期死亡，显示骨骼发育严重受损。所有软骨内骨均畸形，缺乏结构完整性。缺乏功能性Apc导致多效性骨骼细胞表型。大多数缺乏Apc的前体细胞不能分化为软骨细胞或成骨细胞。然而，在近端肋骨的骨骼前体细胞能够逃脱的APC的功能丧失，导致形成高活性的成骨细胞的有害影响。失活的APC在软骨细胞与去分化的这些cells.Conclusion：我们的数据表明，一个紧密的APC介导的β-连环蛋白水平的控制是必不可少的骨骼前体细胞的分化，以及为维护软骨细胞表型的时空调节的方式。
Background: During skeletogenesis, protein levels of beta-catenin in the canonical Wnt signaling pathway determine lineage commitment of skeletal precursor cells to osteoblasts and chondrocytes. Adenomatous polyposis coli (Apc) is a key controller of beta-catenin turnover by down-regulating intracellular levels of beta-catenin.Results: To investigate whether Apc is involved in lineage commitment of skeletal precursor cells, we generated conditional knockout mice lacking functional Apc in Col2a1-expressing cells. In contrast to other models in which an oncogenic variant of beta-catenin was used, our approach resulted in the accumulation of wild type beta-catenin protein due to functional loss of Apc. Conditional homozygous Apc mutant mice died perinatally showing greatly impaired skeletogenesis. All endochondral bones were misshaped and lacked structural integrity. Lack of functional Apc resulted in a pleiotropic skeletal cell phenotype. The majority of the precursor cells lacking Apc failed to differentiate into chondrocytes or osteoblasts. However, skeletal precursor cells in the proximal ribs were able to escape the noxious effect of functional loss of Apc resulting in formation of highly active osteoblasts. Inactivation of Apc in chondrocytes was associated with dedifferentiation of these cells.Conclusion: Our data indicate that a tight Apc-mediated control of beta-catenin levels is essential for differentiation of skeletal precursors as well as for the maintenance of a chondrocytic phenotype in a spatio-temporal regulated manner.