TY - JOUR TI - Mechanism of bisphosphonate-related osteonecrosis of the jaw (BRONJ) revealed by targeted removal of legacy bisphosphonate from jawbone using competing inert hydroxymethylene diphosphonate AU - Okawa, Hiroko AU - Kondo, Takeru AU - Hokugo, Akishige AU - Cherian, Philip AU - Campagna, Jesus J AU - Lentini, Nicholas A AU - Sung, Eric C AU - Chiang, Samantha AU - Lin, Yi-Ling AU - Ebetino, Frank H AU - John, Varghese AU - Sun, Shuting AU - McKenna, Charles E AU - Nishimura, Ichiro A2 - Rubin, Mishaela R A2 - Zaidi, Mone VL - 11 PY - 2022 DA - 2022/08/26 SP - e76207 C1 - eLife 2022;11:e76207 DO - 10.7554/eLife.76207 UR - https://doi.org/10.7554/eLife.76207 AB - Bisphosphonate-related osteonecrosis of the jaw (BRONJ) presents as a morbid jawbone lesion in patients exposed to a nitrogen-containing bisphosphonate (N-BP). Although it is rare, BRONJ has caused apprehension among patients and healthcare providers and decreased acceptance of this antiresorptive drug class to treat osteoporosis and metastatic osteolysis. We report here a novel method to elucidate the pathological mechanism of BRONJ by the selective removal of legacy N-BP from the jawbone using an intra-oral application of hydroxymethylene diphosphonate (HMDP) formulated in liposome-based deformable nanoscale vesicles (DNV). After maxillary tooth extraction, zoledronate-treated mice developed delayed gingival wound closure, delayed tooth extraction socket healing and increased jawbone osteonecrosis consistent with human BRONJ lesions. Single cell RNA sequencing of mouse gingival cells revealed oral barrier immune dysregulation and unresolved proinflammatory reaction. HMDP-DNV topical applications to nascent mouse BRONJ lesions resulted in accelerated gingival wound closure and bone socket healing as well as attenuation of osteonecrosis development. The gingival single cell RNA sequencing demonstrated resolution of chronic inflammation by increased anti-inflammatory signature gene expression of lymphocytes and myeloid-derived suppressor cells. This study suggests that BRONJ pathology is related to N-BP levels in jawbones and demonstrates the potential of HMDP-DNV as an effective BRONJ therapy. KW - bisphosphonate KW - osteonecrosis of the jaw KW - oral barrier inflammation KW - therapeutic JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -