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通路，以增加 骨折成功愈合的比例，并减少愈合和疗养时间。尽管取得了进步 在复位和稳定骨折的方法中，仍有5-10%的骨折愈合延迟或受损。 骨折。此外，在遭受髋关节或其他严重疾病的老年患者中也会出现显著的死亡率。 骨折。死亡率通常与康复期不能动引起的继发性并发症有关， 比如肺炎。因此，临床上非常需要各种方法来改善骨折愈合结果。 并减少疗养时间。小鼠遗传学已经确定了几个调节骨骼的基因和途径 再生。我们的实验室致力于了解脂质介质在控制骨折中的作用。 治愈。脂质介质如前列腺素是通过环氧合酶活性(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显著损害骨折 在啮齿类动物身上可以治愈，在人类身上也发现了类似的效果。因为炎症是最早的 对于骨折的生理反应，人们认为抑制COX-2会损害炎症，导致 骨折愈合受阻。最近的数据表明，在骨折愈合高峰期，COX-2的表达并非如此 在炎症期后，COX-2在骨折骨痂中的表达发生在增殖的软骨细胞中 和破骨细胞。我们推测，骨痂破骨细胞提供与巨噬细胞相似的功能 伤口愈合。炎性巨噬细胞和再生巨噬细胞之间的极性转换是公认的 在伤口愈合过程中。因为破骨细胞和巨噬细胞可能来自相同的细胞前体细胞 破骨细胞也有多种极性，如吸收和再生破骨细胞。我们的初步数据 支持这一概念的是，单核细胞来源的细胞的枯竭会延迟骨折的愈合，而不是增加 骨痂骨量。此外，我们还表明，从单核细胞来源的细胞中删除COX-2也会损害 骨折愈合，表明COX-2的特定作用。在这里，我们进一步探索再生破骨细胞 通过测定破骨细胞中的COX-2活性，探讨COX-2在骨折愈合中的作用 正常骨折愈合所必需的(目标1)，如何控制破骨细胞中COX-2的表达(目标2)，以及 骨折时破骨细胞COX-2表达是否需要整合素受体或整合素配体 治疗(目标3)。这些实验的成功完成将证明COX-2依赖的调控 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.