The Role of Macrophages in PTH Directed Osseous Wound Healing

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

? DESCRIPTION (provided by applicant): Ineffective oral osseous wound healing post tooth extraction, periodontal therapy or implant placement can cause severe discomfort and decreased function. Better understanding of normal wound healing as well as the mechanisms of compromised wound healing will aid in the development of therapeutic strategies to prevent complications in healthy and systemically challenged patients. Parathyroid hormone (PTH 1-34) is an anabolic agent that also increases healing of extraction sockets when administered intermittently in animal models and facilitates oral bone healing in humans. Several mechanisms have been proposed for the anabolic actions in bone, yet little is known regarding its ability to facilitate osseous wound healing. PTH increases apoptosis of mature osteoblasts which are then engulfed by phagocytic cells, a process termed efferocytosis. It is hypothesized that these phagocytic cells are predominantly alternatively activated (M2) macrophages and are further upregulated by PTH. M2 macrophages are implicated in the removal of apoptotic cells at the site of injury which then triggers the release of factors (TGFß and IL10) to promote the resolution of inflammation. TGFß has been further shown to stimulate osteoblastogenesis through stem cell recruitment. It is hypothesized that efferocytosis via M2 macrophages enhances PTH-driven osseous wound healing. Two aims are proposed: 1) to identify the role of M2 macrophages and efferocytosis during oral osseous wound healing, and 2) to determine the role of a bridging protein termed milk fat globule E8 (MFG-E8) in mediating efferocytosis in PTH-enhanced oral osseous wound healing. To accomplish these aims, M2 macrophages will be either ablated (via anti-CD206 peptide) or enhanced (via IL-4 administration) to determine the dependence on M2 macrophages for osseous wound healing in a well characterized tooth extraction model. Micro-CT and histological analyses of extraction sockets will be evaluated for hard and soft tissue healing. Macrophage populations will be characterized using immunohistochemical and flow cytometric analyses. To assess the role of efferocytosis in socket healing, mice lacking MFG-E8 (KO) will be evaluated for wound healing. In addition, PTH will be administered to MFG-E8KO and WT mice to investigate the effect of diminished efferocytosis on PTH directed healing of extraction sockets. Given the strong therapeutic potential of PTH to enhance oral osseous wounds, delineating the cellular mechanisms involved in normal and PTH-directed oral osseous wound healing will aid in the effective treatment of inadequate healing states.