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首页> 外文学位 >Molecular biology of anabolic and catabolic activities in rabbit knee joint connective tissues.
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Molecular biology of anabolic and catabolic activities in rabbit knee joint connective tissues.

机译：兔膝关节结缔组织中合成代谢和分解代谢活动的分子生物学。

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摘要

The knee joint of animals and humans represents a complex system involving both biological and biomechanical homeostatic mechanisms. Tissue responsiveness to microenvironmental changes, external loads, trauma and injury is controlled by structural and cellular elements within the tissue. The principle objective of this study was to understand the molecular biology of knee joint connective tissues, with particular emphasis on the expression of mRNA levels for various molecules involved in the maintenance of structural and functional integrity, and homeostasis.;The data presented will be discussed in terms of the various physiological states on expression and regulation of a critical subset of mRNAs in knee joint connective tissues that include the medial collateral ligament, anterior cruciate ligament, synovium, articular cartilage, and meniscus. The physiological models analyzed in this study consist of: (i) medial collateral scar/wound healing, (ii) medial collateral ligament and anterior cruciate ligament maturation and the influence of load deprivation, (iii) anterior cruciate ligament transection/osteoarthritic development, and (iv) ovariohysterectomy and the influence of sex steroid hormones in knee joint connective tissue homeostasis.;In the first series of experiments, using a medial collateral ligament wound healing model, a subset of growth factors and growth factor receptors were found to be differentially expressed during the healing phases of the medial collateral ligament compared to controls. The second set of experiments was designed to assess the effects of biomechanical deprivation (i.e immobilization) on ligament maturation. Based on the analysis of molecules involved in matrix synthesis, degradation and remodeling, as well as potential regulatory molecules (eg. growth factors), immobilization of the MCL and ACL appeared to shift the balance in favor of a catabolic environment within the tissue. This altered cellular balance in activity is the likely mechanism for the observed failure of immobilized ligaments to mature. A specific matrix remodeling enzyme, matrix metalloproteinase-13, was demonstrated to be significantly elevated in immobilized ligaments compared to controls. The third series of experiments analysed expression of matrix metalloproteinase-13 at both the mRNA and protein level in normal and healing medial collateral ligament as well as articular cartilage and meniscus using a rabbit anterior cruciate ligament transection (ie. Osteoarthritis) model. Results of these studies demonstrated tissue specific elevations in matrix metalloproteinase-13 levels. A final series of experiments were designed based on observations that an inverse correlation existed between expression of matrix metalloproteinase-13 and the steroid receptor, estrogen receptor alpha, at the mRNA level. Preliminary experiments demonstrated the presence of estrogen receptor alpha at the mRNA level in rabbit knee joint connective tissues. Cotransfection experiments using a luciferase promoter construct containing the proximal 667 base pairs of the rabbit matrix metalloproteinase-13 promoter and the human estrogen receptor alpha expression vector demonstrated that estrogen receptor alpha may regulate matrix metalloproteinase-13 expression at the promoter level. The data presented in this dissertation demonstrates that knee joint connective tissue homeostasis is complex and involves contributions from a diverse family of genes in a tissue specific manner.
机译：动物和人类的膝关节代表了一个复杂的系统，涉及生物和生物力学的稳态机制。组织对微环境变化，外部负荷，创伤和损伤的反应能力由组织内的结构和细胞成分控制。这项研究的主要目的是了解膝关节结缔组织的分子生物学，特别着重于参与维持结构和功能完整性以及体内平衡的各种分子的mRNA水平的表达。在膝关节结缔组织中，包括内侧副韧带，前十字韧带，滑膜，关节软骨和半月板的各种关键mRNA的表达和调控方面的各种生理状态方面。在这项研究中分析的生理模型包括：（i）内侧副疤痕/伤口愈合，（ii）内侧副韧带和前十字韧带的成熟以及负荷剥夺的影响，（iii）前十字韧带横断/骨关节炎的发展，以及（iv）卵巢子宫切除术和性类固醇激素对膝关节结缔组织动态平衡的影响；在第一个系列实验中，使用内侧副韧带伤口愈合模型，发现生长因子和生长因子受体的一个子集被差异表达与对照相比，在内侧副韧带的愈合阶段。设计第二组实验以评估生物机械剥夺（即固定化）对韧带成熟的影响。基于对参与基质合成，降解和重塑的分子以及潜在的调节分子（例如生长因子）的分析，MCL和ACL的固定化似乎改变了平衡，有利于组织内的分解代谢环境。这种活动性细胞平衡的改变是观察到固定韧带无法成熟的可能机制。与对照相比，在固定的韧带中，一种特定的基质重塑酶基质金属蛋白酶-13被证明显着升高。第三系列实验使用兔前交叉韧带横断（即骨关节炎）模型分析了正常和愈合中的内侧副韧带以及关节软骨和半月板中mRNA和蛋白水平上基质金属蛋白酶13的表达。这些研究结果表明基质金属蛋白酶13水平的组织特异性升高。根据观察结果，设计了最后一系列实验，即在mRNA水平上，基质金属蛋白酶-13的表达与类固醇受体雌激素受体α呈负相关。初步实验表明，兔膝关节结缔组织中存在mRNA水平的雌激素受体α。使用包含兔基质金属蛋白酶-13启动子的近667个碱基对和人雌激素受体α表达载体的荧光素酶启动子构建体进行的共转染实验表明，雌激素受体α可以在启动子水平上调节基质金属蛋白酶-13的表达。本论文提供的数据表明，膝关节结缔组织的体内稳态是复杂的，并且涉及以组织特异性方式来自多种基因家族的贡献。

著录项

  • 作者

    Sciore, Paul John Anthony.;

  • 作者单位

    University of Calgary (Canada).;

  • 授予单位 University of Calgary (Canada).;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2001
  • 页码 221 p.
  • 总页数 221
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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