IN VITRO CHONDROGENESIS OF BONE MARROW MESENCHYMAL CELLS

描述(来自申请者的逐字描述)：我们已经开发并确定了 一种促进兔成软骨细胞分化的体外培养体系 哺乳动物间充质祖细胞。我们现在建议使用该系统来 探索软骨形成的阶段，包括从凝结到进展 软骨细胞外基质分子的表达。最近的证据 提示MAP激酶通路在控制进展中发挥了作用。 此外，p38MAPK的作用与 WNT/β-连环蛋白在软骨形成中的信号转导。WNT通路可能连接到 MAP激酶，这些结合在一起来调节进程。WNTs是一个大家庭 分泌的蛋白质似乎在发育中起着重要作用。WNT 已经暗示与软骨形成有关，但尚不清楚哪些WNT是 很重要。Wnt结合蛋白Frzbs对Wnt作用的调节可能是 对软骨形成进程的另一种控制水平。总体假设 凝结相关的特定的、协调的和时间的调节 蛋白质是从凝聚到基质生成所必需的。 在软骨形成过程中。检验这一假设的具体目的是：(1) 进程中ERK 1/2和p38 MAPK信号的特征；(2) 描述在进程中运行的Wnt通路的特征；以及(3) 确定FRZB的作用，FRZB是Wnt结合蛋白在 软骨生成。这项工作将加深我们对成软骨细胞的认识 从祖细胞分化而来。这可能对设计新的 软骨相关问题的治疗策略。

DESCRIPTION (Verbatim from the Applicant): We have developed and characterized an in vitro culture system that facilitates the chondrogenic differentiation of mammalian mesenchymal progenitor cells. We now propose to use the system to explore the stage of chondrogenesis involving progression from condensation to expression of cartilage extracellular matrix molecules. Recent evidence suggests a role for the MAP kinase pathways in controlling progression. Furthermore, the effects of p38 MAPK are similar to those seen with Wnt/beta-catenin signaling during chondrogenesis. Wnt pathways may be linked to the MAP kinases, and these combine to regulate progression. Wnts are a family of secreted proteins that appear to have important roles in development. Wnt involvement in chondrogenesis has been implied but it is unclear which Wnts are important. Modulation of Wnt action by Frzbs, the Wnt binding proteins, may be another level of control for chondrogenic progression. The overall hypothesis is that a specific, coordinated and temporal regulation of condensation-related proteins is necessary for progression from condensation to matrix production during chondrogenesis. The Specific Aims to test this hypothesis are: (1) to characterize ERK 1/2 and p38 MAPK signaling during progression; (2) to characterize the Wnt pathways that operate during progression; and (3) to determine the role of Frzb, the Wnt binding protein expressed during chondrogenesis. This work will further our understanding of chondrogenic differentiation from progenitor cells. This may be of benefit for designing new therapeutic strategies for cartilage-related problems.