Mechanobiology of Rotator Cuff Development

项目摘要/摘要 不同材料的附着是一个重大挑战，因为局部应力水平很高， 在这样的界面上发展。对于这个问题的有效的生物解决方案是在出生后在 肌腱与骨的连接。这种组织，即肌腱“末端”，从肌腱过渡到纤维软骨，然后 矿化的纤维软骨与骨骼之间的距离很短。在肌腱到骨的过程中不能重建末端。 治愈。因此，手术重新附着这两种不同的生物材料常常失败。更好的 对肌腱连接发育的了解将使我们能够概括肌腱到骨的发育过程。 修复和植入组织工程学。 许多研究表明，机械生物学在胎儿关节发育和成人关节发育中起作用。 动态平衡。然而，很少有研究考察机械负荷在关节发育中的作用。 产后早期。出生后发育的机制生物学与以下方面尤其相关 肩膀。新生儿因分娩时受伤而导致的臂丛神经麻痹可导致多个肩膀 儿童的病理学。这些情况被认为是肩袖肌肉负荷异常的结果。 穿过发展中的关节。人们对驱动产后肩部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端部发育的力学生物学。我们 最近发表了一种小鼠模型，在该模型中，肩袖肌肉在出生时通过注射 肉毒杆菌毒素和瘫痪一直维持到牺牲。我们证明了肌肉负荷是 对于产后肌腱吻合的发育来说是必要的。在这个提案中，我们将使用正常和基因 用改良的小鼠模型研究影响血管紧张素转换酶发展的力学和分子因素 肌腱与骨骼连接处的独特组织。我们的第一套目标将考察三个方面的作用 被认为对成骨细胞分化和机械转导起重要作用的分子， 纤维软骨细胞和肌腱成纤维细胞(即在末端发现的三种主要细胞类型)。我们会 研究连接蛋白43、印度刺猬和硬化症在骨、纤维软骨和肌腱形成中的作用， 分别在雌蕊处。我们的第二组目标将检查修复造成的缺陷的可能性 在出生后发育过程中肌肉瘫痪。我们将试图通过抑制的方式来挽救骨骼缺陷 用双膦酸类药物激活破骨细胞，用甲状旁腺素促进成骨细胞活性。我们亦会研究 在不同的瘫痪和恢复时间下，肌腱末端发育的恢复潜力。

PROJECT SUMMARY / ABSTRACT 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.