title: Bisphosphonate-associated osteonecrosis of the jaw is linked to suppressed TGFβ1-signaling and increased Galectin-3 expression: a histological study on biopsies.
abstract: 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 β1 (TGFβ1) 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 TGFβ1-related signaling molecules and Galectin-3 in BRONJ-affected and healthy mucosal tissues. To discriminate between BRONJ-specific impairments in TGFβ1 signaling and secondary inflammatory changes, the results were compared to the expression of TGFβ1 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 TGFβ1, 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
  TGFβ1 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).
  
  
  CONCLUSIONS
  Our results showed that disrupted TGFβ1 signaling was associated with delayed periodontal repair in BRONJ samples. The findings also indicated that impairments in TGFβ1-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.
authors: Department of Oral and Maxillofacial Surgery University of Erlangen-Nuremberg, Germany. Falk.Wehrhan@uk-erlangen.de
authors: Falk
authors: F
authors: Wehrhan
authors: Peter
authors: P
authors: Hyckel
authors: Arndt
authors: A
authors: Guentsch
authors: Emeka
authors: E
authors: Nkenke
authors: Phillip
authors: P
authors: Stockmann
authors: Karl A
authors: KA
authors: Schlegel
authors: Friedrich W
authors: FW
authors: Neukam
authors: Kerstin
authors: K
authors: Amann
mesh_terms: D001706:Biopsy; D004164:Diphosphonates / Q000009:adverse effects*; D037502:Galectin 3 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007568:Jaw / Q000473:pathology*; D007571:Jaw Diseases / Q000139:chemically induced* / Q000473:pathology; D010020:Osteonecrosis / Q000139:chemically induced* / Q000473:pathology; D010521:Periosteum / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D004164:Diphosphonates; D037502:Galectin 3; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1