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.
The proposal tests a novel hypothesis that COX-2 expressed in osteoclasts is an important regulator of bone fracture healing. Osteoclast culture models and mouse models of fracture repair will be used to test critical aspects of this hypothesis. Expected results will have significant implications on methods for managing fracture care and related fields.
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