Chondroprogenitor cells in mature cartilage

描述（由申请人提供）：骨关节炎（OA）是最常见的 老年人常见的肌肉骨骼疾病。 严重老化- 软骨细胞和软骨细胞外基质的相关变化 是OA发病机制中的主要因素。 尽管被称为 退行性关节疾病，OA是一种主动的软骨重塑过程。 OA软骨中的细胞被激活，不仅产生基质降解， 酶，还有新的细胞外基质。 重塑过程最终 由于基质合成和降解之间的不平衡而失败， 由于新形成的软骨是非透明修复组织，而基质是 经常异常钙化。 我们的初步研究表明成年人 关节软骨含有软骨祖细胞。 所提出的实验基于以下假设：1）间充质干细胞 祖细胞存在于成人软骨中，并且它们可以被分离， 扩增并诱导分化为多个成熟的间充质细胞 表型 2)频率、定位、激活和反应模式 间充质祖细胞的数量在衰老和骨关节炎中改变。 3)间充质细胞从祖细胞分化的遗传基础 成熟软骨细胞的离散子集可以建立与DNA 微阵列来定义这个过程的标记和调节器。 以下具体目标将测试这些假设：1）确定 正常人关节软骨中祖细胞的分布 软骨使用免疫组织化学，细胞分离，流式细胞术和 多能分化的功能评估。 通过这些研究， 我们将开发用于鉴定祖细胞的标记物和用于 孤立和扩张。 2)分析衰老中祖细胞的存在 和骨关节炎的人软骨。 确定是否存在老化- 相关的祖细胞数量减少，无论细胞是否具有 对生长因子的反应性受损，以及祖细胞是否 与增殖的软骨细胞簇和 钙化的软骨。 3)用DNA微阵列来确定 对于正常人关节软骨细胞亚群的不同区域， 软骨 建立骨髓源性和 软骨来源的祖细胞和分化的软骨细胞， 他们 成体软骨祖细胞的发现为软骨细胞的研究开辟了新的前景。 利用这些细胞修复软骨，并提高了衰老的可能性- 其频率或功能的相关变化决定了关节老化， 它们会导致异常的软骨重塑过程， 关节炎

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is one of the most common musculoskeletal disorders in older individuals. Profound aging- associated changes in chondrocytes and cartilage extracellular matrix represent a major factor in OA pathogenesis. Although referred to as a degenerative joint disease, OA is an active cartilage remodeling process. Cells in OA cartilage are activated and not only produce matrix degrading enzymes, but also new extracellular matrix. The remodeling process ultimately fails because of an imbalance between matrix synthesis and degradation, because the newly formed cartilage is non-hyaline repair tissue and matrix is often abnormally calcified. Our preliminary studies suggest that adult human articular cartilage contains chondroprogenitor cells. The proposed experiments are based on the following hypotheses: 1) Mesenchymal progenitor cells are present in adult cartilage, and they can be isolated, expanded and induced to differentiate to multiple mature mesenchymal phenotypes. 2) The frequency, localization, activation and response patterns of mesenchymal progenitor cells are altered in aging and osteoarthritis. 3) The genetic basis of mesenchymal cell differentiation from the progenitor to the discrete subsets of mature chondrocytes can be established with DNA microarrays to define markers and regulators of this process. The following specific aims will test these hypotheses: 1) Determine the frequency and localization of progenitor cells in normal human articular cartilage using immunohistochemistry, cell isolation, flow cytometry and functional assessment of pluripotential differentiation. With these studies, we will develop markers for identification of progenitor cells and methods for isolation and expansion. 2) Analyze the presence of progenitor cells in aging and osteoarthritic human cartilage. Determine whether there is an aging- associated reduction in the number of progenitor cells, whether the cells have an impaired responsiveness to growth factors and whether progenitor cells are associated with the clusters of proliferating chondrocytes and areas of calcified cartilage. 3) With the DNA microarrays, define the genetic basis for the chondrocyte subsets in the various zones of normal human articular cartilage. Establish the relationship between bone marrow derived and cartilage derived progenitors and differentiated chondrocytes generated from them. The discovery of progenitor cells in adult cartilage opens new perspectives to harness these cells in cartilage repair and raises the possibility that aging- associated changes in their frequency or function determine joint aging and that they contribute to the aberrant cartilage remodeling process in arthritis.