Anti-VEGF neutralizing antibody delays osteomucosal healing by reducing collagen formation in mice

Abstract

Abstract Medication-related osteonecrosis of the jaw (MRONJ) is a detrimental side effect in patients undergoing treatment with antiresorptive agents. The anti-angiogenic agent, bevacizumab (anti-VEGF antibody (Ab)), has also been reported to be associated with MRONJ. However, the role of anti-VEGF Ab in MRONJ development, especially under conditions of pre-existing inflammation, remains elusive. This study examined anti-VEGF Ab effects on bone necrosis and osteomucosal healing, with or without pre-inflammation. Forty mice received biweekly i.p. injections of anti-VEGF Ab (10 mg/kg) or saline (Veh). For the tooth extraction (TE) model ( n = 10), maxillary first molars were extracted. For the ligature-induced periodontitis and tooth extraction (LIP-TE) model ( n = 10), maxillary second molars were ligated with 5−0 silk for 8 weeks before extraction. Mice were euthanized after 3 weeks of post-extraction healing. In both TE and LIP-TE models, anti-VEGF Ab-treated mice showed delayed osteomucosal healing with diminished bone formation, lower CD31 and collagen III expression, and increased osteoclast numbers than Veh-treated mice. There was no significant difference in necrotic bone areas. IL-23- or IL-17-producing cell numbers remained unchanged in both Veh- and anti-VEGF Ab-treated mice. Anti-VEGF Ab delayed osteomucosal healing by reducing collagen production in the presence or absence of pre-inflammatory conditions, without causing bone necrosis. Our data suggest anti-VEGF Ab delays osteomucosal wound healing but does not cause bone necrosis alone.