Promoting Healing of Tendinopathies Using Therapeutic Mechanobiologic Stimulation for Targeted Removal of Aggrecan-Rich Deposits

利用治疗性机械生物学刺激有针对性地去除富含聚集蛋白的沉积物，促进肌腱病的愈合

• 批准号: 9069423
• 负责人: VINCENT M WANG
• 金额: $ 25.87万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069423
• 关键词: Adopted; Age-Years; Appearance; Area; Becaplermin; Biochemical; Biological; Biomechanics; Cartilage; Cell Shape; Cells; Chronic; Clinical; Collagen; Collagen Fiber; Connexins; Deposition; Detection; Development; Disease; Elbow; Equus caballus; Excision; Exercise; Exhibits; Fibronectins; Future; Goals; Harvest; Healthcare; Heel; Histologic; Histopathology; Human; Human Pathology; Hyaluronan; In Vitro; Individual; Injection of therapeutic agent; Integrins; Knowledge; Mechanics; Mediating; Modeling; Morphology; Movement; Mus; Oligosaccharides; Operative Surgical Procedures; Outcome; Pain; Pathogenicity; Pathologic; Pathway interactions; Patients; Periodicity; Pharmaceutical Preparations; Physical therapy; Physiological; Platelet-Derived Growth Factor; Population; Prevention; Property; Proteoglycan; Recombinants; Recovery; Research; Role; Running; Series; Shoulder; Sports; System; Tendinopathy; Tendon Injuries; Tendon structure; Tennis Elbow; Testing; Therapeutic; Therapeutic Effect; Therapeutic Uses; Tissues; Translating; Trauma; Treatment Protocols; Wild Type Mouse; Work; achilles tendon; age group; aggrecan; chronic pain; clinical practice; experimental study; functional disability; gait examination; healing; improved mobility; in vivo; inhibitor/antagonist; mechanical load; mechanical properties; mouse model; mucoid; novel therapeutics; public health relevance; response; restoration; second harmonic generation imaging; treadmill; treatment strategy

DESCRIPTION (provided by applicant): Functional impairment in tendons, such as those which control movement in the heel, elbow and shoulder represents a major health care problem. It is now widely believed that tendon overuse, as seen in sports (tennis elbow) or work related (carpal tunnel) activities, is the initiating factor for development of tendinopathy. This appears to be true, at least for the expanding number of patients in the vulnerable 30-50 year age group. A pathogenic pathway, favored by most in the field, is that overuse results in persistent micro- injury of tendon collagen fibers and that this "wounding" precipitates a series o cellular responses which result in further loss of tissue material properties and chronic pain. Our long-term goal is to determine whether the aberrant cell responses which accompany tendinopathies, can be redirected from degeneration to healing by the application of tailored biologic and/or biomechanical therapies. We are optimistic about a successful outcome of our studies since we believe that we have uncovered a central pathogenic pathway to tendinopathy which we anticipate will be amenable to such therapeutic control. The pathogenic pathway involves the accumulation of deposits we term ARDs, or "aggrecan-rich deposits" in the tendon matrix. This pathway has emerged from studies on equine tendinopathy in a susceptible breed of horses. We are pursuing mechanistic studies in wild type and ADAMTS5-deficient mice which exhibit tendon changes (biomechanical and biochemical) that mimic the human pathology. The mechanistic pathway under study suggests that both mechanical loading (exercise) and ADAMTS5 pathway activation are required to eliminate the ARDs (pericellular aggrecan accumulation). We are working on therapeutic approaches to eliminate these deposits via different mechanical loading modes (eccentric versus concentric exercise) as well as by direct injection of aggrecanolytic agents. Furthermore, we will directly apply the knowledge gained from these murine studies in order to examine the efficacy of mechanobiologic strategies to treat human tendinopathic tissues.

描述（由申请人提供）：肌腱的功能性损伤，如控制足跟、肘部和肩部运动的肌腱，是一个主要的健康问题。现在人们普遍认为，肌腱过度使用，如在运动（网球肘）或工作相关（腕管）活动中所见，是肌腱病发展的起始因素。这似乎是正确的，至少对于30-50岁脆弱年龄组中不断增加的患者人数来说是如此。本领域大多数人所青睐的致病途径是过度使用导致肌腱胶原纤维的持续性微损伤，并且这种“创伤”沉淀了一系列细胞反应，其导致组织材料性质的进一步丧失和慢性疼痛。我们 长期目标是确定伴随腱病的异常细胞反应是否可以通过应用定制的生物学和/或生物力学疗法而从变性重定向到愈合。我们对我们研究的成功结果持乐观态度，因为我们相信我们已经发现了肌腱病的中心致病途径，我们预计这种治疗控制将是可行的。 致病途径涉及肌腱基质中沉积物的积累，我们称之为ARD，或“富含聚集蛋白聚糖的沉积物”。这一途径来自于对易感品种马的马肌腱病的研究。我们正在野生型和ADAMTS 5缺陷小鼠中进行机制研究，这些小鼠表现出模仿人类病理学的肌腱变化（生物力学和生物化学）。研究中的机制途径表明，机械负荷（运动）和ADAMTS 5途径激活都是消除ARDs（细胞周围聚集蛋白聚糖积累）所必需的。我们正在研究通过不同的机械负荷模式（离心与同心运动）以及直接注射聚集蛋白聚糖溶解剂来消除这些沉积物的治疗方法。此外，我们将直接应用从这些小鼠研究中获得的知识，以检查机械生物学策略治疗人类肌腱病变组织的疗效。