Osteocyte Death in Osteonecrosis of the Jaw in Rice Rats: Role of Necroptosis and Temporal Relationship with Radiographic, Molecular and Histopathologic Findings

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PROJECT SUMMARY/ABSTRACT Osteonecrosis of the jaw (ONJ) is a potentially severe, debilitating condition affecting the mouth of patients with cancer or osteoporosis who have taken antiresorptive drugs, like zoledronic acid (ZOL) or denosumab, and concurrently have an oral risk factor such as tooth extraction, periodontitis, or periapical infection. Clinical ONJ (stages 1-3) is defined by the presence of exposed dead bone in the jaw for longer than 8wks in patients with no history of radiation therapy or metastatic cancer to the jaws. In contrast, early-stage ONJ (stage 0) lacks exposed bone, demonstrating intermittent pain and nonspecific radiographic findings. Whether the necrotic jaw bone with its dead osteocytes is present in the early stages, while the oral mucosa still covers the underlying tissues, or occurs only after it becomes exposed, remains to be determined. Further, the type(s) of cell death affecting osteocytes in ONJ is not completely elucidated. Understanding whether osteocyte death is a feature already present in stage 0 may represent a key first step to finding new therapies for ONJ. Indeed, early pharmacologic interventions that avert osteocyte death while oral risk factors are being removed could prevent ONJ. Gaps in knowledge limit the ability to identify ONJ in its earliest stages and intervene to stop its progression. The critical role of osteocyte apoptosis in the pathophysiology of various skeletal conditions has been substantiated. However, little attention has been paid to necroptosis, a specific “regulated” form of cell death triggered by inflammation, such as that associated with periodontitis and periapical infection. Unlike apoptosis, necroptosis enhances immune responses and inflammation. Notably, ZOL treated rats developing ONJ showed increased necroptosis, but not apoptosis, in osteocytes. Pharmacologic inhibitors targeting specific regulatory components of necroptosis have been developed. Some are now in clinical trials to treat inflammatory diseases. Thus, we hypothesize that: 1) osteocyte death occurs before bone exposure in ONJ; 2) osteocyte death occurs in temporal association with specific radiologic, cellular, and molecular features; and 3) necroptosis is the dominant type of cell death involved in ONJ. Our approach is to use rice rats with localized periodontitis that can be easily monitored by oral exams and start treating them with ZOL to determine: Aim 1: the timing and type(s) of cell death affecting osteocytes in the early stages of ONJ and the temporal relationship of osteocyte death to radiographic, cellular, and molecular findings; and Aim2: the contribution of necroptosis and apoptosis in the development of clinical ONJ in rice rats using pharmacologic inhibitors. The study outcomes will define temporally and mechanistically the prodrome of ONJ, potentially stage 0 in humans, supporting the development of targeted therapies to halt osteocyte death, and establish direct evidence for the role of necroptosis to ONJ and in vivo proof of concept for the therapeutic potential of inhibiting components of its signaling pathway from halting ONJ progression.