Bisphosphonate-associated osteonecrosis of the jaw is linked to suppressed TGFβ1-signaling and increased Galectin-3 expression: A histological study on biopsies

Background: Bisphosphonate associated osteonecrosis of the jaw (BRONJ) implies an impairment in oral hard- and soft tissue repair. An understanding of the signal transduction alterations involved can inform therapeutic strategies. Transforming growth factor beta 1 (TGF beta 1) is a critical regulator of tissue repair; galectin-3 mediates tissue differentiation and specifically modulates periodontopathic bacterial infection. The aim of this study was to compare the expression of TGF beta 1-related signaling molecules and Galectin-3 in BRONJ-affected and healthy mucosal tissues. To discriminate between BRONJ-specific impairments in TGF beta 1 signaling and secondary inflammatory changes, the results were compared to the expression of TGF beta 1 and Galectin-3 in mucosal tissues with osteoradionecrosis. Methods: Oral mucosal tissue samples with histologically-confirmed BRONJ (n = 20), osteoradionecrosis (n = 20), and no lesions (normal, n = 20) were processed for immunohistochemistry. Automated staining with an alkaline phosphatase-anti-alkaline phosphatase kit was used to detect TGF beta 1, Smad-2/3, Smad-7, and Galectin-3. We semiquantitatively assessed the ratio of stained cells/total number of cells (labeling index, Bonferroni-adjustment). Results: TGF beta 1 and Smad-2/3 were significantly decreased (p < 0.032 and p(0.028, respectively) in the BRONJ samples and significantly increased (p < 0.04 and p < 0.043, respectively) in the osteoradionecrosis samples compared to normal tissue. Smad-7 was significantly increased (p < 0.031) in the BRONJ group and significantly decreased (p < 0.026) in the osteoradionecrosis group. Galectin-3 staining was significantly (p < 0.025) increased in both the BRONJ and the osteoradionecrosis (p < 0.038) groups compared to the normal tissue group. However, Galectin-3 expression was significantly higher in the BRONJ samples than in the osteoradionecrosis samples (p < 0.044). Conclusion: Our results showed that disrupted TGF beta 1 signaling was associated with delayed periodontal repair in BRONJ samples. The findings also indicated that impairments in TGF beta 1-signaling were different in BRONJ compared to osteoradionecrosis. BRONJ appeared to be associated with increased terminal osseous differentiation and decreased soft tissue proliferation. The increase in Galectin-3 reflected the increase in osseous differentiation of mucoperiosteal progenitors, and this might explain the inflammatory anergy observed in BRONJ-affected soft tissues. The results substantiated the clinical success of treating BRONJ with sequestrectomy, followed by strict mucosa closure. BRONJ can be further elucidated by investigating the specific intraoral osteoimmunologic status.