Inhibition of HMGB1/RAGE Signaling Reduces the Incidence of Medication-Related Osteonecrosis of the Jaw (MRONJ) in Mice

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of antiresorptive or antiangiogenic medications, used in the treatment of bone malignancy or osteoporosis. Bone necrosis, mainly represented by osteocytic death, is always present in MRONJ sites; however, the role of osteocyte death in MRONJ pathogenesis is unknown. High mobility group box 1 (HMGB1) is a non-histone nucleoprotein that in its acetylated form accumulates in the cytoplasm, whereas non-acetylated HMGB1 localizes in the nucleus. SIRT1 deacetylase regulates cellular localization of HMGB1. Interestingly, HMGB1 is released during cell necrosis and promotes inflammation through signaling cascades, including activation of the RAGE receptor. Here, we utilized a well-established mouse MRONJ model that utilizes ligature-induced experimental periodontitis (EP) and treatment with either vehicle or zolendronic acid (ZA). Initially, we evaluated HMGB1-SIRT1 expression in osteocytes at 1, 2, and 4 weeks of treatment. Significantly increased cytoplasmic and perilacunar HMGB1 expression was observed at EP sites of ZA versus vehicle (Veh) animals at all time points. SIRT1 colocalized with cytoplasmic HMGB1 and presented a statistically significant increased expression at the EP sites of ZA animals for all time points. RAGE expression was significantly higher in the submucosal tissues EP sites of ZA animals compared with those in vehicle group. To explore the significance of increased cytoplasmic and extracellular HMGB1 and increased RAGE expression in MRONJ pathogenesis, we used pharmacologic inhibitors of these molecules. Combined HMGB1/RAGE inhibition resulted in lower MRONJ incidence with statistically significant decrease in osteonecrotic areas and bone exposure versus non-inhibitor treated ZA animals. Together, our data point to the role of HMGB1 as a central alarmin, overexpressed at early phase of MRONJ pathogenesis during osteocytic death. Moreover, HMGB1-RAGE pathway may represent a new promising therapeutic target in patients at high risk of MRONJ.

Pathophysiology of Medication‐Related Osteonecrosis of the Jaw—A Minireview

“…Osteocytic death during MRONJ likely involves multiple mechanisms, including apoptosis and cell necrosis, and is observed at early stages of disease setting. ( 97 , 98 , 99 ) Dying osteocytes release cellular signals that enhance the degree and severity of periodontal tissue inflammation. The presence of necrotic bone that cannot be removed further inhibits healing of periodontal tissues.…”

Local E-rhBMP-2/β-TCP Application Rescues Osteocyte Dendritic Integrity and Reduces Microstructural Damage in Alveolar Bone Post-Extraction in MRONJ-like Mouse Model

“…It has been demonstrated that this lacunar–canalicular network acts as a mechano-sensing system [ 10 , 11 , 12 ] that regulates bone remodeling not only by controlling osteoblast and osteoclast function but also by modulating the gradient of ionic substitutions in bone mineralization [ 13 , 14 , 15 ]. Importantly, previous studies have indicated the association of osteocyte death and empty osteocyte lacunae with impaired bone remodeling and jawbone necrosis in MRONJ [ 16 , 17 , 18 ]. However, the exact conditions and roles of osteocytes in MRONJ remain unclear.…”