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）：不同材料的连接是一项重大挑战，因为在此类界面处会产生高水平的局部应力。一个有效的生物解决方案，这个问题的发展出生后在附着的肌腱骨。这种组织，肌腱“附着点”，在短距离内从肌腱过渡到纤维软骨，再过渡到矿化纤维软骨，再过渡到骨。肌腱-骨愈合过程中不会重新形成附着点。因此，这两种不同生物材料的手术再附着常常失败。更好地了解肌腱附着点的发展将使我们能够概括肌腱骨修复和附着点组织工程的发展。许多研究表明，机械生物学在胎儿关节发育和成人关节稳态中的作用。然而，很少有研究探讨的作用，机械负荷的联合发展，在出生后早期。出生后发育的机械生物学与肩部特别相关。新生儿臂丛神经麻痹，由于在分娩时受伤，可导致一些肩部的儿童病理。这些情况被认为是由于发育中的关节上的异常肩袖肌肉负荷造成的。关于驱动出生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来研究肌腱附着点发育的机械生物学。我们最近发表了一个小鼠模型，在出生时使用肉毒杆菌毒素注射使肩袖肌肉麻痹，并保持麻痹直到处死。我们证明了肌肉负荷是必要的出生后肌腱附着点的发展。在这项提议中，我们将使用正常和基因修饰的小鼠模型来研究影响肌腱与骨骼连接处独特组织发育的机械和分子因素。我们的第一组目标将检查三种分子的作用，这三种分子被认为对成骨细胞、纤维软骨细胞和肌腱成纤维细胞的分化和机械转导起重要作用（即，在接合处发现的三种主要细胞类型）。我们将分别研究连接蛋白43、印度刺猬蛋白和巩膜轴在附着点处对骨、纤维软骨和肌腱形成的作用。我们的第二组目标将检查在出生后发育期间挽救肌肉麻痹引起的缺陷的潜力。我们将尝试通过双膦酸盐抑制破骨细胞活性和PTH促进成骨细胞活性来挽救骨缺损。我们还将研究不同时间的麻痹和恢复的发展肌腱附着点的恢复潜力。公共卫生相关性：由于分娩时损伤引起的新生儿臂丛神经麻痹可导致儿童的许多肩部病变，包括肩关节脱位、肩关节后半脱位、肱骨头扁平和关节盂发育不良。虽然其中一些新生儿臂丛神经损伤自行解决，但许多需要手术干预。关于驱动出生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。