COX-2 Functions in Bone Fracture Healing

摘要 我们的目标是操纵控制骨折愈合的分子途径，以增加骨折愈合的可能性。 成功愈合的骨折比例，并减少愈合和恢复时间。尽管取得了进展 在减少和稳定骨折的方法中， 骨折此外，在患有髋关节或其他严重疾病的老年患者中， 骨折通常死亡与恢复期间不动引起的继发性并发症有关， 例如肺炎。因此，对于改善骨折愈合结果的方法存在显著的临床需求 并减少恢复时间。小鼠遗传学已经确定了几个基因和途径，调节骨 再生本实验室致力于了解脂质介质在控制骨折中的作用 治愈脂质介质如洋地黄素通过环氧合酶活性（考克斯-1或考克斯-2）合成 并且以促进炎症而闻名。我们发现，抑制考克斯-2显着损害骨折 啮齿动物的愈合和人类的类似效果也已被发现。因为炎症是最早的 对于骨折的生理反应，假定考克斯-2的抑制损害炎症，导致 骨折愈合受损。最近的数据表明，骨折愈合期间考克斯-2的表达达到高峰， 在炎症阶段之后，骨折骨痂中增殖的软骨细胞中出现考克斯-2表达 和破骨细胞。我们的理论是，愈伤组织破骨细胞提供类似的功能，巨噬细胞做， 伤口愈合炎症性和再生性巨噬细胞之间的极性转换已得到很好的建立 在伤口愈合过程中。由于破骨细胞与巨噬细胞来源于相同的细胞祖细胞， 破骨细胞也具有多个极性，例如再吸收和再生破骨细胞。我们的初步数据 支持这一概念，因为单核细胞衍生细胞的耗竭延迟骨折愈合，而不是增加 骨痂骨体积。此外，我们发现单核细胞来源的细胞中考克斯-2的缺失也损害了 骨折愈合，表明考克斯-2的特定作用。在这里，我们进一步探讨再生破骨细胞 通过确定破骨细胞中考克斯-2活性是否与骨折愈合相关， 正常骨折愈合所需的（目标1），破骨细胞中考克斯-2表达的控制方式（目标2），以及 骨折时破骨细胞表达考克斯-2是否需要整合素受体或整合素配体 治愈（目标3）。这些实验的成功完成将证明考克斯-2依赖性调节性细胞凋亡。 破骨细胞在控制骨折愈合中的作用。

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.