Mechanobiology of Rotator Cuff Development

项目总结/摘要 不同材料的连接是一个主要的挑战，因为高水平的局部应力， 在这样的界面上开发。一个有效的生物解决方案，这个问题的发展，出生后在 腱与骨的连接。这种组织，肌腱“附着点”，从肌腱过渡到纤维软骨， 矿化的纤维软骨短距离地转移到骨头上。肌腱-骨移植过程中不会重建附着点 治愈因此，这两种不同生物材料的手术再附着常常失败。更好的 对肌腱附着点发育的理解将使我们能够概括肌腱-骨的发育 修复和附着点组织工程。 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的作用。 体内平衡然而，很少有研究探讨了机械负荷对关节发育的作用， 产后早期。出生后发育的机械生物学与以下方面特别相关： 肩膀新生儿臂丛神经麻痹由于在分娩时受伤，可导致一些肩 儿童的病理。这些情况被认为是由于不正常的肩袖肌肉负荷 穿过发育中的关节关于驱动出生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，在该模型中，在出生时使用注射 维持肉毒杆菌毒素和麻痹直到处死。我们证明了肌肉负荷是 出生后肌腱附着点发育所必需的。在本提案中，我们将使用正常和遗传 修改小鼠模型，以检查影响发育的机械和分子因素， 肌腱与骨骼连接处的独特组织。我们的第一组目标将检查三个角色 被认为对成骨细胞的分化和机械传导起重要作用的分子， 纤维软骨细胞和腱成纤维细胞（即，在接合处发现的三种主要细胞类型）。我们将 检查连接蛋白43、印度刺猬蛋白和巩膜轴在骨、纤维软骨和肌腱形成中的作用， 分别在端点处。我们的第二组目标将检查挽救所造成的缺陷的潜力 肌肉麻痹导致的我们将尝试通过抑制 二膦酸盐促进破骨细胞活性，PTH促进成骨细胞活性。我们亦会研究 发育中的肌腱附着点在不同的麻痹和恢复时间下的恢复潜力。

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.