Ursolic Acid Attenuates Inflammatory and Severity of Osteonecrosis in Rats Treated with Zoledronic Acid.

Abstract

Bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) alters osteoclast function. Ursolic acid (UA) can inhibit the expression of interleukin-17 (IL-17). Evaluate the influence of UA treatment on the severity of BRONJ in zoledronic acid (ZA)-treated rats' jaws. Fifty male Wistar rats were used, divided into a negative control group (0.1 mL/kg sterile saline), a positive control group (ZA, 0.20 mg/kg), and three test groups treated with ZA and UA 10, 20 or 40 mg/kg by gavage every three days from the beginning of the protocol until euthanasia. After three consecutive weekly administrations of ZA intravenous (i.v.), exodontia of the 1st left lower molar was performed, administration of an additional dose of ZA, and euthanasia after 28 days from exodontia. Hemimandibles were removed for radiographical, histological, and immunohistochemical analysis and gum samples for Western blotting. The femur was removed for the three-point bending test. Analysis of variance (ANOVA)/Bonferroni was used. Radiographically, UA reduced the area suggestive of OM (7.2  ±  0.6 vs. 5.2 ±  0.4, P = .015) and the highest dose of UA reversed the number of nonviable osteocytes (80.3  ±  4.9 vs. 55.4 ±  4.6, P = .007), suggesting bone healing through IL-17 inhibition. UA reduced the number of polymorphonuclear cells (208 ± 17 vs. 30 ± 9, P < .001), mononuclear cells (207 ± 34 vs. 74 ± 20, P < 0.001) and apoptotic osteoclasts (87 ± 4 vs. 61 ± 3, P < .001), observing that these parameters are higher in groups treated only with ZA. The two highest doses of UA reduced the immunoexpression of IL-17 (429 ± 45 vs. 300 ± 42, P = .014) and increased the percentage of circulating lymphocytes (69 ± 2 vs. 82 ± 2, P < .001). AZ increased the expression of RORyT and the highest dose of UA (1.887  ±  0.114 vs. 0.869  ±  0.050, P < .001),) reduced this expression, suggesting that UA may be a specific antagonist of RORyT, which has the capacity to inhibit the expression of this protein. UA promise in reducing the severity of ZA-induced ONJ.