The Role of Matrix Metalloproteinases in Tendon Growth

基质金属蛋白酶在肌腱生长中的作用

• 批准号: 8900112
• 负责人: Kristoffer Bradley Sugg
• 金额: $ 7.12万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900112
• 关键词: Adult; Appearance; Architecture; Area; Attenuated; Binding; Biology; Cell Survival; Cell membrane; Cell physiology; Cells; Collagen; Collagen Fibril; Collagen Type I; Data; Development; Disease; Elements; Environment; Enzymes; Epithelial; Event; Extracellular Matrix; Family; Fibroblasts; Future; Gene Expression; Growth; Growth Factor; Health; Histocompatibility Testing; Human; In Vitro; Infiltration; Injury; LacZ Genes; Lead; Locomotion; MMP-20; Maintenance; Matrix Metalloproteinases; Measurement; Mechanics; Membrane; Mission; Modeling; Molecular; Molecular Biology; Molecular Profiling; Morphology; Movement; Mus; Muscle; Musculoskeletal; Musculoskeletal System; Pain; Patients; Pattern; Peptide Hydrolases; Play; Population; Process; Productivity; Property; Proteins; Public Health; Quality of life; Reporter; Role; Signaling Molecule; Stem cells; Stimulus; Stress; Subgroup; Tamoxifen; Tendon Injuries; Tendon structure; Testing; Tissues; Translating; Treatment Cost; Work; Zinc; base; bone; cell motility; crosslink; disability; effective therapy; human MMP14 protein; in vivo; insight; interdisciplinary approach; membrane-type matrix metalloproteinase; migration; novel; overexpression; prevent; promoter; proteinase In; repaired; research study; response; restoration; scleraxis; tendon development; translational study; transmission process

DESCRIPTION (provided by applicant): Tendon is a dynamic tissue that connects muscle to bone and allows for force transmission during locomotion. Despite the importance of tendon in the overall function of the musculoskeletal system, relatively little is known about the cellular and molecular mechanisms that control its growth, maintenance and repair. Clinically, tendon injuries and diseases are among the most frequent and debilitating musculoskeletal conditions, resulting in billions of dollars in treatment costs and lost productivity. Tendon is primarily composed of a dense network of type I collagen fibrils that provides structural support to the tendon, binds and releases growth factors that regulate multiple cellular functions, and acts as a natural barrier to the infiltration of cells. The predominant cells in tendon are fibroblasts, and central feature to nearly all tendon disorders is abnormal fibroblast morphology and grossly disrupted appearance of the tendon extracellular matrix (ECM). Thus, understanding the interaction between tendon fibroblasts and their ECM environment will likely provide an important basis for the development of novel and effective therapies for these painful conditions. During periods of tendon growth, fibroblasts express matrix metalloproteinases (MMPs), a family of zinc-dependent enzymes that collectively degrade multiple ECM components, including type I collagen. While more than 20 MMPs have been described, previous studies in other tissues have identified the subgroup of membrane-type MMPs (MT-MMPs) as the proteinases that allow fibroblasts to migrate through their ECM. Within the MT-MMP subgroup, MT1- and MT2-MMP are the MMPs that appear most important for cellular movement, as cells that are deficient in either MT1- or MT2-MMP lose their ability to migrate. Both MT1- and MT2-MMP are expressed in tendon, but the role of these proteinases in tendon fibroblast migration is unknown, as is their overall importance in tendon growth. Using an informative tendon overload model that recapitulates the key elements of tendon growth, changes in MT1-MMP expression correlate with pivotal events in the growth response. Furthermore, MT1-MMP expression appears to be restricted to areas of newly formed tendon tissue. While MT2-MMP is also expressed in tendon, it has been less extensively studied as MT1-MMP, and both its pattern of expression and function is presently unclear. We posit that MT1-MMP, working alone or in concert with MT2- MMP, is a key regulator of tendon fibroblast function in response to mechanical loading of tendons. My central hypothesis is that MT1- and MT2-MMP are both required for tendon growth and function cooperatively to allow tendon fibroblast migration through the tendon ECM. This hypothesis will be rigorously tested in two Specific Aims using a multidisciplinary approach involving a combination of molecular biology and tissue mechanics experiments in a tendon overload model. Findings from this proposal will provide important insights into basic tendon fibroblast biology and potentially lead to future translational studies focused on MT-MMPs in the treatment of tendon injuries and diseases.

描述（由申请人提供）：肌腱是一种动态组织，将肌肉连接到骨骼并允许在运动过程中传递力。尽管肌腱在肌肉骨骼系统的整体功能中很重要，但人们对控制其生长、维持和修复的细胞和分子机制知之甚少。在临床上，肌腱损伤和疾病是最常见和最使人衰弱的肌肉骨骼疾病之一，导致数十亿美元的治疗费用和生产力损失。肌腱主要由密集的 I 型胶原纤维网络组成，为肌腱提供结构支撑，结合和释放调节多种细胞功能的生长因子，并充当细胞浸润的天然屏障。肌腱中的主要细胞是成纤维细胞，几乎所有肌腱疾病的核心特征是成纤维细胞形态异常和肌腱细胞外基质 (ECM) 外观严重破坏。因此，了解肌腱成纤维细胞与其 ECM 环境之间的相互作用可能为开发针对这些疼痛病症的新型有效疗法提供重要基础。在肌腱生长期间，成纤维细胞表达基质金属蛋白酶 (MMP)，这是一种锌依赖性酶家族，可共同降解多种 ECM 成分，包括 I 型胶原蛋白。虽然已经描述了 20 多种 MMP，但之前在其他组织中的研究已经确定膜型 MMP (MT-MMP) 亚组是允许成纤维细胞通过其 ECM 迁移的蛋白酶。在 MT-MMP 亚组中，MT1-和 MT2-MMP 是对细胞运动最重要的 MMP，因为缺乏 MT1-或 MT2-MMP 的细胞会失去迁移能力。 MT1-和MT2-MMP均在肌腱中表达，但这些蛋白酶在肌腱成纤维细胞迁移中的作用以及它们在肌腱生长中的总体重要性尚不清楚。使用信息丰富的肌腱过载模型概括肌腱生长的关键要素，MT1-MMP 表达的变化与生长反应中的关键事件相关。此外，MT1-MMP 表达似乎仅限于新形成的肌腱组织区域。虽然 MT2-MMP 也在肌腱中表达，但与 MT1-MMP 相比，其研究较少，并且其表达模式和功能目前尚不清楚。我们认为，单独或与 MT2-MMP 协同作用的 MT1-MMP 是响应肌腱机械负荷的肌腱成纤维细胞功能的关键调节剂。我的中心假设是 MT1- 和 MT2-MMP 都是肌腱生长和协同功能所必需的，以允许肌腱成纤维细胞通过肌腱 ECM 迁移。该假设将在两个具体目标中使用多学科方法进行严格测试，该方法涉及肌腱超载模型中的分子生物学和组织力学实验的结合。该提案的研究结果将为基本肌腱成纤维细胞生物学提供重要见解，并可能导致未来重点关注 MT-MMP 在肌腱损伤和疾病治疗中的转化研究。