Mechanobiology of Rotator Cuff Development

肩袖发育的力学生物学

• 批准号: 7874571
• 负责人: Stavros Thomopoulos
• 金额: $ 30.47万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7874571
• 关键词: Adult; Affect; Biomechanics; Bioreactors; Birth; Bone Development; Bone Regeneration; Botulinum Toxins; Brachial plexus structure; Cartilage Matrix; Cell Communication; Cells; Child; Childbirth; Chondrocytes; Clinical; Collagen; Collagen Type I; Communication; Connexin 43; Connexins; Defect; Development; Dysplasia; Engineering; Erinaceidae; Failure; Fiber; Fibroblasts; Fibrocartilages; Head; Homeostasis; Injection of therapeutic agent; Injury; Joints; Knockout Mice; Lead; Mechanics; Minerals; Modeling; Molecular; Muscle; Neonatal; Operative Surgical Procedures; Osteoblasts; Osteoclasts; Paralysed; Parathyroid Hormones; Pathology; Patients; Pharmacological Treatment; Play; Publishing; Recovery; Reporting; Role; Rotator Cuff; Shoulder; Shoulder Dislocation; Signaling Molecule; Solutions; Stress; Tendon structure; Tissue Engineering; Tissues; Work; aggrecan; bisphosphonate; bone; bone healing; cell type; design; fetal; human PTH protein; improved; mineralization; mouse model; novel; public health relevance; repaired; scleraxis; soft tissue; transcription factor

DESCRIPTION (provided by applicant): The attachment of dissimilar materials is a major challenge because of the high levels of localized stress that develop at such interfaces. An effective biologic solution to this problem develops post-natally at the attachment of tendon to bone. This tissue, the tendon "enthesis", transitions from tendon to fibrocartilage to mineralized fibrocartilage to bone across a short distance. The enthesis is not recreated during tendon-to-bone healing. Surgical reattachment of these two dissimilar biologic materials therefore often fails. A better understanding of tendon enthesis development will allow us to recapitulate development for tendon-to-bone repair and enthesis tissue engineering. A number of studies have shown a role for mechanobiology in fetal joint development and in adult joint homeostasis. However, few studies have examined the role of mechanical loading on joint development in the early post-natal period. The mechanobiology of post-natal development is especially relevant with respect to the shoulder. Neonatal brachial plexus palsy due to injuries at childbirth can lead to a number of shoulder pathologies in children. These conditions are thought to be a result of abnormal rotator cuff muscle loading across the developing joint. Little is known about the mechanobiology that drives post-natal shoulder development, so clinical options for these patients is limited. We propose to study the mechanobiology of tendon enthesis development using mouse models. We recently published a mouse model in which rotator cuff muscles were paralyzed at birth using an injection of botulinum toxin and paralysis was maintained until sacrifice. We demonstrated that muscle loading is necessary for post-natal tendon enthesis development. In this proposal, we will use normal and genetically modified mouse models to examine the mechanical and molecular factors that influence the development of the unique tissue at the attachment of tendon to bone. Our first set of aims will examine the role of three molecules thought to play important roles for differentiation and mechanotransduction of osteoblasts, fibrochondrocytes, and tendon fibroblasts (i.e., the three main cell types found at the enthesis). We will examine the role of connexin43, Indian hedgehog, and scleraxis for bone, fibrocartilage, and tendon formation, respectively, at the enthesis. Our second set of aims will examine the potential for rescuing the defects caused by muscle paralysis during post-natal development. We will attempt to rescue the bony defects by suppressing osteoclasts activity with bisphosphonates and promoting osteoblast activity with PTH. We will also study the recovery potential of the developing tendon enthesis subjected to varying durations of paralysis and recovery. PUBLIC HEALTH RELEVANCE: Neonatal brachial plexus palsy due to injuries at childbirth can lead to a number of shoulder pathologies in children, including shoulder dislocation, posterior shoulder subluxation, humeral head flattening, and glenoid dysplasia. While some of these neonatal brachial plexus injuries resolve on their own, many require surgical intervention. Little is known about the mechanobiology that drives post-natal shoulder development, so clinical options for these patients is limited.

描述（由申请人提供）：由于在此类界面处出现了高水平的局部应力，因此相差材料的附着是一个主要的挑战。该问题的有效生物学解决方案是在肌腱附着在骨骼上的后产后发展的。该组织是肌腱“源性”，从肌腱到纤维球杆菌到矿化纤维球杆菌，再到短距离的骨骼。在肌腱到骨的愈合过程中未重新创建该分节。因此，这两种不同的生物学材料的手术重新处理常常失败。更好地了解肌腱的发育将使我们能够概括肌腱对肌腱修复和组织工程的发育。许多研究表明，机械生物学在胎儿关节发育和成人联合稳态中的作用。但是，很少有研究检查了在产后初期，机械载荷对关节发育的作用。产后发育的机械生物学与肩膀有关。由于分娩时受伤而导致的新生儿臂丛神经麻痹会导致儿童多种肩部病理。这些条件被认为是整个发育中的肩袖肌肉负荷异常的结果。关于驱动产后产后肩部发育的机械生物学知之甚少，因此这些患者的临床选择有限。我们建议使用小鼠模型研究肌腱衰减发育的机械生物学。我们最近发表了一个小鼠模型，其中肩袖肌肉在出生时使用肉毒杆菌毒素瘫痪，并保持瘫痪直到牺牲为止。我们证明，肌肉负荷对于产后肌腱发育是必要的。在此提案中，我们将使用正常和遗传修饰的小鼠模型来检查影响肌腱附着在骨骼附着时独特组织发展的机械和分子因子。我们的第一组目标将研究三个分子的作用，这些分子被认为在分化和机械传导的成骨细胞，纤维软骨细胞和肌腱成纤维细胞（即，在埃文中发现的三种主要细胞类型）起着重要作用。我们将分别研究connexin43，Indian Hedgehog和硬化性在骨骼，纤维球杆菌和肌腱形成的作用。我们的第二组目标将研究产后发育过程中肌肉麻痹引起的缺陷的潜力。我们将尝试通过抑制双膦酸盐的破骨细胞活性并用PTH促进成骨细胞活性来挽救骨缺陷。我们还将研究经受不同瘫痪和恢复持续时间的发展肌腱衰减的恢复潜力。公共卫生相关性：由于分娩时受伤而导致的新生儿臂丛神经麻痹会导致儿童多种肩部病理，包括肩膀脱位，后肩肩脱甲，肱骨头部平坦和腺体发育不全。尽管这些新生儿臂丛神经损伤自行解决，但许多损伤需要手术干预。关于驱动产后产后肩部发育的机械生物学知之甚少，因此这些患者的临床选择有限。