The role of TSCs in the degenerative tendinopathy induced by mechanical loading

TSCs 在机械负荷引起的退行性肌腱病中的作用

• 批准号: 9014514
• 负责人: JAMES H-C. WANG
• 金额: $ 33.88万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014514
• 关键词: Adipocytes; Adipose tissue; Affect; American; Anti-Inflammatory Agents; Anti-inflammatory; Athletic; Atomic Force Microscopy; Biochemical; Biological Models; Calcified; Cartilage; Cell Count; Cell Lineage; Cell Proliferation; Cells; Chondrocytes; Chronic; Clinic; Clinical Treatment; Data; Deposition; Development; Dinoprostone; Disease; Enzymes; Exhibits; Gene Expression; Genes; Growth; Health; Healthcare; Histocytochemistry; Human; Immunohistochemistry; In Situ; In Vitro; Inflammation; Inflammation Mediators; Injection of therapeutic agent; Insulin-Like Growth Factor I; Interstitial Collagenase; Lead; Light; Lipids; Location; Measures; Mechanics; Methods; Modeling; Mus; Occupational; Orthopedics; Osteocytes; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Prevention strategy; Process; Production; Proteoglycan; RNA Splicing; Rattus; Regimen; Research; Role; Running; Specimen; Sports Medicine; Stem cells; Stromelysin 1; Surgeon; Tendinopathy; Tendon Injuries; Tendon structure; Testing; Tissue Inhibitor of Metalloproteinase-1; Tissues; Traction; Training; Treatment Protocols; United States; Variant; Western Blotting; base; calcification; cell type; collagenase 3; cost; disability; effective therapy; immunocytochemistry; implantation; in vitro Model; in vivo; inhibitor/antagonist; innovation; irradiation; novel; palliative; progenitor; protein expression; repaired; response; self-renewal; stem; stem cell differentiation; treadmill; treatment strategy

 DESCRIPTION (provided by applicant): Degenerative tendinopathy is characterized by the formation of non-tendinous tissues in the tendon matrix. This tendon disease is a leading cause of chronic disability and affects millions of Americans. Intensive research has been conducted in the past decades, but the pathogenesis of degenerative tendinopathy remains unclear and, as a result, current treatments of the tendon disease are largely palliative. Recently, we and others identified tendon/progenitor stem cells (TSCs), which exhibit multi-differentiation potential and can differentiate into adipocytes, chondrocytes, and osteocytes both in vitro and in vivo. The diverse cell types formed by TSCs correspond well with three non-tendinous tissues observed in human tendinopathic tendons: fatty tissue, cartilage-like tissue, and bony tissue. Moreover, we discovered that excessive mechanical loading alone is sufficient to induce differentiation of TSCs into non-tenocyte lineages. In light of these exciting findings, we hypothesize that TSCs are the primary contributors to the development of degenerative tendinopathy, which is a result of their aberrant differentiation into non-tenocyte lineages of cells in response to excessive mechanical loading placed on tendons. To test this innovative hypothesis, we propose two major aims in this project: (1) To define the effect of mechanical loading on TSCs by using a novel in vitro model system to analyze cell proliferation, self-renewal, and differentiation; and () to determine the effects of excessive mechanical loading conditions on mouse tendons in vivo using a well-established mouse treadmill running model. The second aim includes two sub-aims, which are to determine the effects of both "over-use" and "over-loading" on mouse tendons. The key innovation of our proposed studies is that they will uncover the mechanobiological responses of tendons by clarifying and analyzing the role of TSCs at the cellular, tissue, and functional levels under well-controlled mechanical loading conditions, which are of direct relevance to an important disease process. This study represents the initial efforts to determine the pathogenic role of TSCs in the development of degenerative tendinopathy. The successful completion of this study will reveal the stem-cell based mechanism of degenerative tendinopathy. This will lead to new prevention and treatment strategies such as targeting TSCs by blocking their differentiation into non-tenocytes and altering training regimens for athletes and laymen alike that will be more effective than current tendinopathy treatment methods, which mostly rely on the use of anti- inflammatory drugs.

 描述（由申请人提供）：退行性肌腱病的特征是在肌腱基质中形成非肌腱组织。这种肌腱疾病是慢性残疾的主要原因，影响着数百万美国人。在过去的几十年里，人们进行了深入的研究，但退行性肌腱病的发病机制仍不清楚，因此，目前对肌腱病的治疗大多是姑息性的。最近，我们和其他人鉴定了肌腱/祖干细胞（TSC），其表现出多分化潜力，并且可以在体外和体内分化为脂肪细胞、软骨细胞和骨细胞。 TSC 形成的多种细胞类型与在人类肌腱病肌腱中观察到的三种非肌腱组织很好地对应：脂肪组织、软骨样组织和骨组织。此外，我们发现仅过度的机械负荷就足以诱导 TSC 分化为非肌腱细胞谱系。鉴于这些令人兴奋的发现，我们假设 TSC 是退行性肌腱病发生的主要原因，这是由于肌腱承受过度机械负荷而异常分化为非肌腱细胞谱系的结果。为了检验这一创新假设，我们提出了本项目的两个主要目标：（1）通过使用新型体外模型系统来分析细胞增殖、自我更新和分化，定义机械负荷对 TSC 的影响； () 使用完善的小鼠跑步机跑步模型确定过度机械负荷条件对体内小鼠肌腱的影响。第二个目标包括两个子目标，即确定“过度使用”和“超负荷”对小鼠肌腱的影响。我们提出的研究的关键创新在于，他们将通过澄清和分析 TSC 在良好控制的机械负荷条件下在细胞、组织和功能水平上的作用来揭示肌腱的机械生物学反应，这与重要的疾病过程直接相关。这项研究代表了确定 TSC 在退行性肌腱病发展中致病作用的初步努力。这项研究的成功完成将揭示退行性肌腱病的干细胞机制。这将带来新的预防和治疗策略，例如通过阻止 TSC 分化为非肌腱细胞来靶向 TSC，并改变运动员和外行人的训练方案，这将比目前主要依赖使用抗炎药物的肌腱病治疗方法更有效。