COX-2 Functions in Bone Fracture Healing

COX-2 在骨折愈合中的作用

• 批准号: 9766814
• 负责人: J Patrick O'Connor
• 金额: $ 42.54万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766814
• 关键词: Affect; Alleles; Arachidonic Acids; Bone Regeneration; Bone callus; Caring; Cartilage; Cells; Chondrocytes; Clinical; Data; Disease; Drug Targeting; Environment; Enzymes; Epiphysial cartilage; Failure; Fracture; Fracture Healing; Genes; Genetic; Goals; Hip region structure; Human; Hypertrophy; Immunohistochemistry; Impaired wound healing; Impairment; In Situ Hybridization; In Vitro; Inflammation; Inflammatory; Integrin alphaVbeta3; Integrins; Knockout Mice; Laboratories; Ligands; LoxP-flanked allele; Measures; Mediating; Messenger RNA; Metabolism; Methods; Modeling; Molecular; Mus; Osteoblasts; Osteoclasts; Osteogenesis; Outcome; PTGS2 gene; Pathway interactions; Pharmacologic Substance; Phase; Physiologic Ossification; Physiological; Pneumonia; Proliferating; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Rattus; Reporting; Resolution; Rodent; Role; Signal Transduction; Testing; Time; Transgenes; Wound Healing; aggrecan; cartilaginous; celecoxib; cyclooxygenase 1; cyclooxygenase 2; experimental study; healing; improved; in vivo; inhibitor/antagonist; lipid mediator; macrophage; monocyte; mortality; mouse model; novel; older patient; progenitor; receptor; regenerative; repaired; response; synthetic enzyme; therapeutic target; therapy development

ABSTRACT Our goal is to manipulate the molecular pathways controlling fracture healing in order to increase the proportion of fractures that successfully heal and to reduce healing and recuperation times. Despite advances in methods to reduce and stabilize bone fractures, delayed and impaired healing still occurs in 5-10% of all bone fractures. In addition, significant mortality occurs in older patients that have suffered hip or other severe fractures. Often mortality is associated with secondary complications caused by immobility during recuperation, such as pneumonia. Thus there is a significant clinical need for methods to improve fracture healing outcomes and reduce recuperation times. Mouse genetics has identified several genes and pathways that regulate bone regeneration. Our laboratory has focused on understanding the role of lipid mediators in controlling fracture healing. Lipid mediators such as prostaglandins are synthesized by cyclooxygenase activity (COX-1 or COX-2) and are well-known for promoting inflammation. We found that inhibiting COX-2 significantly impairs fracture healing in rodents and similar effects have been noted in humans. As inflammation is one of the first physiological responses to fracture, it was assumed that inhibition of COX-2 impaired inflammation leading to impaired fracture healing. Recent data indicate otherwise as COX-2 expression during fracture healing peaks after the inflammatory phase and COX-2 expression in the fracture callus occurs in proliferating chondrocytes and osteoclasts. We theorize that callus osteoclasts provide similar functions as macrophages do during wound healing. Polarity switching between inflammatory and regenerative macrophages is well established during wound healing. As osteoclasts derive from the same cellular progenitors as macrophages, perhaps osteoclasts also have multiple polarities such as resorbtive and regenerative osteoclasts. Our preliminary data supports this concept in that depletion of monocyte-derived cells delays fracture healing rather than increases callus bone volume. In addition, we show that deletion of COX-2 from monocyte-derived cells also impairs fracture healing, indicating a specific role for COX-2. Here we further explore the regenerative osteoclast concept and the function of COX-2 in fracture healing by determining whether COX-2 activity in osteoclasts is required for normal fracture healing (Aim 1), how COX-2 expression is controlled in osteoclasts (Aim 2), and whether integrin receptors or integrin ligands are necessary for osteoclast COX-2 expression during fracture healing (Aim 3). Successful completion of these experiments will demonstrate a COX-2-dependent regulatory role for osteoclasts in controlling fracture healing.

抽象的 我们的目标是操纵控制断裂愈合的分子途径，以增加 成功愈合并减少愈合时间的骨折比例。尽管进步 在减少和稳定骨折的方法中，延迟和受损的愈合仍然发生在5-10％中 骨断裂。此外，患有髋关节或其他严重的老年患者发生了显着的死亡率 断裂。死亡率通常与恢复过程中固定性引起的继发并发症有关， 例如肺炎。因此，对改善断裂愈合结果的方法有很大的临床需求 并减少恢复时间。小鼠遗传学已经确定了调节骨骼的几种基因和途径 再生。我们的实验室专注于了解脂质介质在控制骨折中的作用 康复。脂质介质（例如前列腺素）是通过环氧酶活性（COX-1或COX-2）合成的 并以促进炎症而闻名。我们发现抑制COX-2显着损害断裂 人类已经注意到啮齿动物的愈合和类似的作用。因为炎症是第一个 对骨折的生理反应，假定抑制COX-2损害炎症导致 骨折治愈受损。最近的数据表明否则是裂缝愈合峰期间的COX-2表达 炎症阶段和骨折愈伤组织中的COX-2表达发生在增殖的软骨细胞中 和破骨细胞。我们认为愈伤组织破骨细胞提供了与巨噬细胞一样的类似功能 伤口愈合。炎症和再生巨噬细胞之间的极性切换已建立 在伤口愈合期间。由于破骨细胞从与巨噬细胞相同的细胞祖细胞衍生而来，也许 破骨细胞也具有多种极性，例如吸收性和再生破骨细胞。我们的初步数据 在单核细胞衍生的细胞的耗尽中支持这一概念，延迟了骨折的愈合，而不是增加 愈伤组织骨体积。此外，我们表明单核细胞衍生细胞的cox-2删除也会损害 断裂愈合，表明COX-2具有特定作用。在这里，我们进一步探索再生破骨细胞 通过确定破骨细胞中的Cox-2活性是否为，COX-2在断裂愈合中的功能 正常骨折愈合所需（AIM 1），如何在破骨细胞中控制Cox-2的表达（AIM 2），而 整联蛋白受体或整联蛋白配体是否对于骨折期间破骨细胞COX-2表达是必需的 康复（目标3）。这些实验的成功完成将证明COX-2依赖性调节 破骨细胞在控制断裂愈合中的作用。