OSTEOCLAST DIFFERENTIATION BY MESENCHYMAL CELLS

描述(申请人提供)：破骨细胞分化增强是 导致大多数慢性骨骼疾病的主要机制 损失。因此，对这些疾病的发病机制有了更好的理解 病情需要对破骨细胞分化有详细的了解。 与间充质层接触刺激破骨细胞分化 支持细胞，这是成骨细胞谱系中相对不成熟的成员。 我们最近发现，与间充质细胞接触的影响 层反映了由间充质细胞产生的两种细胞外基质 和细胞表面分子。尽管其中一个分子RANKL具有 最近发现，其他细胞外基质/细胞表面的性质 参与这一过程的分子还不完全清楚。这 项目将测试特定细胞表面和/或 除RANKL外，细胞外基质分子由间充质细胞产生 支持破骨细胞分化的细胞。为此，我们将利用 噬菌体展示文库用于选择与 支持破骨细胞分化的间充质细胞决定了哪些 这些多肽调节破骨细胞分化，并识别 与这些多肽结合的细胞外基质/细胞表面分子。这 该项目将提供关于细胞外的重要新信息 间充质细胞产生的基质/细胞表面分子以支持 破骨细胞分化。该项目还将识别新的多肽， 特异性地抑制破骨细胞分化，因此，可能是 为模拟多肽药物发现计划提供有用的起点 慢性骨丢失的情况。

DESCRIPTION (provided by applicant): Increased osteoclast differentiation is the primary mechanism responsible for most conditions that cause chronic bone loss. Thus, improved understanding of the pathogenesis responsible for these conditions requires detailed knowledge of osteoclast differentiation. Osteoclast differentiation is stimulated by contact with a layer of mesenchymal support cells, which are relatively immature members of the osteoblast lineage. We have recently shown that the effect of contact with the mesenchymal cell layer reflects production by the mesenchymal cells of both extracellular matrix and cell surface molecules. Although one of these molecules, RANKL, has recently been identified, the nature of other extracellular matrix/cell surface molecules that are involved in this process is incompletely understood. This project will test the hypothesis that specific cell surface and/or extracellular matrix molecules in addition to RANKL are produced by mesenchymal cells to support osteoclast differentiation. For this purpose, we will utilize phage display libraries to select peptides that specifically bind to the mesenchymal cells that support osteoclast differentiation, determine which of the peptides regulate osteoclast differentiation, and identify the extracellular matrix/cell surface molecules that bind to these peptides. This project will provide significant new information on the extracellular matrix/cell surface molecules produced by mesenchymal cells in order to support osteoclast differentiation. This project will also identify novel peptides that specifically inhibit osteoclast differentiation and that,therefore, may be useful starting points for a peptidomimetic drug discovery program aimed at conditions of chronic bone loss.