The role of host inflammation and the commensal microbiota in the pathogenesis of medication-related osteonecrosis of the jaw
Bisphosphonates (BPs) and denosumab (Dmab) are anti-resorptive drugs that are clinically used to treat bone disorders like osteoporosis and bone metastases. A detrimental side effect of these drugs that uniquely occurs in the oral cavity is BP- and Dmab-related osteonecrosis of the jaw (collectively called medication-related osteonecrosis of the jaw, or MRONJ), clinically defined as exposed necrotic bone with unclosed overlaying oral mucosa for at least 8 weeks. Although the first report of ONJ by BPs appeared in 2003, the exact pathophysiology of MRONJ is still largely unknown. Our laboratory has been working to examine and elucidate the pathophysiology of MRONJ. Previously, we established mouse models for MRONJ utilizing bisphosphonate and αRANKL antibody and identified that woven bone formation and inhibition of bone resorption are hallmarks of murine MRONJ lesions. We also utilized semi-unbiased gene profiling to identify and validate the importance of IL36 signaling in MRONJ pathogenesis.
MRONJ often occurs following a dental intervention such as a tooth extraction which is typically performed to eliminate localized periodontal or periapical inflammation. Periodontal disease is caused by polymicrobial infection and subsequent host immune response; thus, we hypothesize that local inflammation driven by host responses plays a critical role in MRONJ development. In this study, we found that 1) Long-term (10 weeks) ligature-induced periodontitis (L-LIP) exacerbates bone loss and local expression of Il17a; 2) Host response, not microbial community composition, drives bone loss in L-LIP; and 3) L-LIP combined with BP and extraction leads to significantly more necrotic bone formation than short-term (3 weeks) ligature-induced periodontitis. Additionally, we utilized a microbiota-depletion model to identify the role of the commensal microbiota in inflammation-induced osteonecrosis development and found that 1) MRONJ lesions have an increased number of infiltrating bacteria compared to vehicle controls; 2) The commensal microbiota partially protects against the development of osteonecrosis following extraction of periodontally diseased teeth, but not healthy teeth. Collectively, we show that the duration of periodontal disease is correlated with increased osteonecrosis and the oral microbiota plays a protective role in ligature-induced osteonecrosis development.