Our goal is to manipulate the molecular pathways controlling fracture healing in order to increase theproportion of fractures that successfully heal and to reduce healing and recuperation times. Despite advancesin methods to reduce and stabilize bone fractures, delayed and impaired healing still occurs in 5-10% of allbone fractures. In addition, significant mortality occurs in older patients that have suffered hip or other severefractures. 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 outcomesand reduce recuperation times. Mouse genetics has identified several genes and pathways that regulate boneregeneration. Our laboratory has focused on understanding the role of lipid mediators in controlling fracturehealing. 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 fracturehealing in rodents and similar effects have been noted in humans. As inflammation is one of the firstphysiological responses to fracture, it was assumed that inhibition of COX-2 impaired inflammation leading toimpaired fracture healing. Recent data indicate otherwise as COX-2 expression during fracture healing peaksafter the inflammatory phase and COX-2 expression in the fracture callus occurs in proliferating chondrocytesand osteoclasts. We theorize that callus osteoclasts provide similar functions as macrophages do duringwound healing. Polarity switching between inflammatory and regenerative macrophages is well establishedduring wound healing. As osteoclasts derive from the same cellular progenitors as macrophages, perhapsosteoclasts also have multiple polarities such as resorbtive and regenerative osteoclasts. Our preliminary datasupports this concept in that depletion of monocyte-derived cells delays fracture healing rather than increasescallus bone volume. In addition, we show that deletion of COX-2 from monocyte-derived cells also impairsfracture healing, indicating a specific role for COX-2. Here we further explore the regenerative osteoclastconcept and the function of COX-2 in fracture healing by determining whether COX-2 activity in osteoclasts isrequired for normal fracture healing (Aim 1), how COX-2 expression is controlled in osteoclasts (Aim 2), andwhether integrin receptors or integrin ligands are necessary for osteoclast COX-2 expression during fracturehealing (Aim 3). Successful completion of these experiments will demonstrate a COX-2-dependent regulatoryrole for osteoclasts in controlling fracture healing.
|Effective start/end date||9/1/16 → 8/31/21|
- National Institutes of Health (NIH)