MECHANISMS OF CHONDROCYTE RESPONSE TO MECHANICAL STIMULI

最近的数据表明，有多种调节途径， 软骨细胞感知并响应机械刺激，包括上游 信号通路和机制，可能导致直接变化， 转录、翻译和翻译后水平 修饰和细胞介导的细胞外组装和降解 矩阵。相应地，可能存在多种途径， 物理刺激不仅可以改变基质产生的速率， 新合成的蛋白聚糖的质量和功能， 胶原蛋白和其他分子。 以这种方式，特定的机械 加载制度可能会提高或损害的极限 软骨的生物力学功能 我们建议（1）量化静态，动态和有害的影响 压缩细胞内细胞器的形态 软骨外植体的软骨细胞;（2）定量静态， 动态的，有害的压力对细胞内的变化， 软骨素6-0-磺基转移酶（C6 ST）的定位和活性 转染到原代牛软骨细胞中， 藻酸盐凝胶盘进行压缩;（3）确定影响 损伤应变和应变率对细胞活力的影响; 对聚集蛋白聚糖、I型、IIA型、IIB型胶原和选择的 基质金属蛋白酶;细胞内形态学改变 细胞器;和基质周转的细胞水平空间分布，以及 (4)量化人类软骨对静电的生物合成反应， 使用股骨远端的组织， 胫骨平台和距小腿关节面，并确定生物合成 以及组织和细胞水平的降解反应 组织的年龄、位置和位置。

Recent data suggest that there are multiple regulatory pathways by which chondrocytes sense and respond to mechanical stimuli, including upstream signaling pathways and mechanisms that may lead to direct changes at the level of transcription, translation and post-translational modifications, and cell-mediated extracellular assembly and degradation of matrix. Correspondingly, there may be multiple pathways by which physical stimuli can alter not only the rate of matrix production, but the quality and functionality of newly synthesized proteoglycans, collagens, and other molecules. In this manner, specific mechanical loading regimes may either enhance or compromise the ultimate biomechanical function of cartilage. We propose to (1) Quantify the effects of static, dynamic, and injurious compression on the morphology of intracellular organelles within chondrocytes of cartilage explants; (2) Quantify the effects of static, dynamic, and injurious compression on changes in the intracellular localization and activity of chondroitin 6-0-sulfotransferase (C6ST) transfected into primary bovine chondrocytes that are seeded into alginate gel disks subjected to compression; (3) Determine the effects of graded levels of injurious strain and strain rate on cell viability; on mRNA levels for aggrecan, collagen types I, IIA, IIB, and selected matrix metalloproteinases; on changes in morphology of intracellular organelles; and on cell-level spatial profiles of matrix turnover, and (4) Quantify the biosynthetic response of human cartilages to static, dynamic and injurious compression, using tissue from the distal femur, tibial plateau, and talocrural joint surfaces, and identify biosynthetic and degradative responses at the tissue and cell levels as a function of tissue age, location, and position.