Mechanobiology of Rotator Cuff Development

肩袖发育的力学生物学

• 批准号: 8105191
• 负责人: Stavros Thomopoulos
• 金额: $ 29.25万
• 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/8105191
• 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; Health; Homeostasis; Hormones; Injection of therapeutic agent; Injury; Joints; Knockout Mice; Lead; Mechanics; Minerals; Modeling; Molecular; Muscle; Neonatal; Operative Surgical Procedures; Osteoblasts; Osteoclasts; Paralysed; Parathyroid gland; 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; improved; mineralization; mouse model; novel; 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）：不同材料的附着是一项重大挑战，因为在此类界面处会产生高水平的局部应力。针对这个问题的有效生物解决方案是在出生后在肌腱与骨骼的附着处形​​成的。这种组织，即肌腱“附着点”，在很短的距离内从肌腱过渡到纤维软骨，再到矿化纤维软骨，再到骨骼。在肌腱到骨头的愈合过程中不会重建附着点。因此，这两种不同的生物材料的手术重新附着常常失败。对肌腱附着点发育的更好理解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，很少有研究探讨机械负荷对产后早期关节发育的作用。产后发育的力学生物学与肩部尤其相关。分娩时受伤导致的新生儿臂丛神经麻痹可导致儿童出现多种肩部病变。这些情况被认为是由于发育中的关节肩袖肌肉负荷异常所致。人们对促进产后肩部发育的力学生物学知之甚少，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附着点发育的力学生物学。我们最近发表了一个小鼠模型，其中通过注射肉毒杆菌毒素在出生时使肩袖肌肉麻痹，并维持麻痹直至处死。我们证明肌肉负荷对于产后肌腱附着点发育是必要的。在本提案中，我们将使用正常和转基因小鼠模型来检查影响肌腱与骨骼附着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（即在附着点发现的三种主要细胞类型）的分化和机械转导发挥重要作用。我们将研究连接蛋白 43、印度刺猬和巩膜分别在附着点处的骨、纤维软骨和肌腱形成中的作用。我们的第二组目标将研究挽救产后发育过程中肌肉麻痹引起的缺陷的潜力。我们将尝试通过双磷酸盐抑制破骨细胞活性并使用 PTH 促进成骨细胞活性来挽救骨缺损。我们还将研究发育中的肌腱附着点在不同的麻痹和恢复持续时间下的恢复潜力。公众健康相关性：分娩时受伤导致的新生儿臂丛神经麻痹可导致儿童出现多种肩部病变，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可以自行痊愈，但许多需要手术干预。人们对促进产后肩部发育的力学生物学知之甚少，因此这些患者的临床选择有限。