CHONDROCYTE SUBPOPULATIONS IN AGING AND OSTEOARTHRITIS

衰老和骨关节炎中的软骨细胞亚群

• 批准号: 7609256
• 负责人: Martin K Lotz
• 金额: $ 54.39万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609256
• 关键词: Abnormal Cell; Address; Affect; Age; Aging; Apoptotic; Biology; Cartilage; Cell Death; Cell Differentiation process; Cell physiology; Cell surface; Cells; Cellularity; Chondrocytes; Chondrogenesis; Data; Degenerative polyarthritis; Development; Differentiation Antigens; Disruption; Epiphysial cartilage; Exhibits; Extracellular Matrix; Failure; Frequencies; Functional disorder; Funding; Gene Deletion; Gene Expression; Growth Factor; Histopathology; In Situ; In Vitro; Inflammatory; Joints; Lubricants; MAP Kinase Activation Pathway; Measurement; Mediating; Mesenchymal Stem Cells; Mitogen-Activated Protein Kinases; Modification; Pathology; Production; Regulation; Research Personnel; Risk Factors; Role; Signal Transduction; Stem cells; Surface; TGFB1 gene; Tissues; Wound Healing; adult stem cell; age related; arthropathies; articular cartilage; base; cartilage cell; cytokine; early onset; normal aging; programs; repaired; response

Aging-related changes in cartilage extracellular matrix, cellularity and cell function that may predispose to issue failure and inadequate repair responses have been documented. The OA paradox is that despite the aging-related deficiencies in cartilage cell function, OA cartilage pathology is the consequence of cell activation which does not result in successful tissue repair but in destruction and abnormal modification of existing matrix and production of matrix components that are not part of normal articular cartilage, indicative of an abnormal cell differentiation. We propose the hypothesis that cartilage aging is associated with loss, abnormal differentiation and dysfunction that differentially affects cartilage cell subpopulations. Mature chondrocytes are reduced through apoptotic mechanisms and compromised in function. Adult stem cells are present in aging cartilage but chondrocytic differentiation is compromised by aging-associated changes in signaling mechanisms and the nflammatory milieu of OA. AIM 1: Chondrocyte aging: an analysis of cartilage zones and cell subpopulations. artilage cell subpopulations (differentiated chondrocytes and progenitor cells) in specific zones of normal aging and OA cartilage will be identified using cell surface and differentiation markers. Aging-associated changes in frequency will be correlated with OA histopathology, and markers of abnormal chondrocyte differentiation. In vitro analysis of cell functions will be performed by stimulation of cartilage explants and in situ measurement of activation and differentiation markers. AIM 2: Sox9 expression and activation. Sox9 is a key regulator of chondrocyte differentiation and cartilage specific gene expression but its role in articular chondrocyte differentiation and in activation of differentiated chondrocytes remains to be established. Preliminary studies suggest changes in Sox9 expression in aging and OA chondrocytes. The proposed studies will address details of Sox9 expression and activation in aging and OAchondrocytes. AIM 3: TGFG activation of Sox9: role in chondrocyte activation and differentiation and changes in aging. TGFG regulates chondrogenesis in mesenchymal stem cells and this is in part mediated via Smad3 dependent Sox9 activation and by MAP kinase pathways.TGFC. also activates differentiated articular chondrocytes but these responses are compromised with aging. This aim will address the role of Smad and MAP kinase signaling and Sox9 in TGFB-mediated activation of normal and aging chondrocytes. The results from the proposed studies will add important new information on chondrocyte biology, cartilage aging and osteoarthritis pathophysiology.

软骨细胞外基质、细胞结构和细胞功能的衰老相关变化可能导致 问题故障和不充分的维修响应已被记录。 OA 悖论是，尽管 与衰老相关的软骨细胞功能缺陷，OA 软骨病理学是细胞功能缺陷的结果 激活不会导致成功的组织修复，而是导致组织的破坏和异常修饰 现有基质和不属于正常关节软骨一部分的基质成分的产生，指示性 细胞分化异常。 我们提出这样的假设：软骨老化与损失、异常分化和 对软骨细胞亚群产生不同影响的功能障碍。成熟软骨细胞的减少是通过 凋亡机制和功能受损。成体干细胞存在于老化的软骨中，但 软骨细胞的分化受到与衰老相关的信号机制和 OA 的炎症环境。 目标 1：软骨细胞老化：软骨区和细胞亚群的分析。 正常特定区域的软骨细胞亚群（分化的软骨细胞和祖细胞） 将使用细胞表面和分化标记物来识别衰老和骨关节炎软骨。与衰老相关的 频率的变化与 OA 组织病理学和异常软骨细胞标志物相关 差异化。细胞功能的体外分析将通过刺激软骨外植体和在 激活和分化标记的原位测量。 目标 2：Sox9 表达和激活。 Sox9 是软骨细胞分化和软骨特异性基因表达的关键调节因子，但其作用 关节软骨细胞的分化和分化软骨细胞的激活仍有待研究 已确立的。初步研究表明衰老和 OA 软骨细胞中 Sox9 表达发生变化。这 拟议的研究将解决衰老和软骨细胞中 Sox9 表达和激活的细节。 目标 3：TGFG 激活 Sox9：在软骨细胞激活和分化以及衰老变化中的作用。 TGFG 调节间充质干细胞中的软骨形成，这部分是通过 Smad3 介导的 依赖的 Sox9 激活和 MAP 激酶途径。TGFC。还激活分化的关节 软骨细胞，但这些反应会随着衰老而受到损害。这一目标将解决 Smad 和 TGFB 介导的正常和老化软骨细胞激活中的 MAP 激酶信号传导和 Sox9。 拟议研究的结果将增加有关软骨细胞生物学、软骨的重要新信息 衰老和骨关节炎病理生理学。