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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

基本信息

批准号：
9212097
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
项目类别：
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/9212097
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 Factor 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 Pathogenicity Patients Pharmaceutical Preparations Phenotype Physicians Prevention strategy Process Prostaglandin Production Proteoglycan Quantitative Reverse Transcriptase PCR 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 mechanical load novel palliative patellar tendon progenitor protein expression public health relevance repaired response self-renewal stem stem cell differentiation treadmill treatment strategy

项目摘要

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.