title: Macrophage and osteoclast polarization in bisphosphonate associated necrosis and osteoradionecrosis.
abstract: OBJECTIVE
  Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a complication of antiresorptive therapy with nitrogen-containing bisphosphonates (BP). With various suggestions as to pathogenesis, the etiology of BRONJ is not sufficiently understood. Osteoclasts and their precursors, that is, macrophages, are the main target cells of BP. BP can repolarize regeneration- and healing-associated M2 macrophages towards the tissue destructive M1-type. The current study aims to elucidate differences in macrophage and osteoclast polarization in BRONJ, osteoradionecrosis (ORN) and healthy control specimens.
  
  
  METHODS
  A total of 39 jaw bone samples (18 BRONJ, 8 ORN and 13 healthy controls) were processed for immunohistochemistry to detect CD68-, CD11c- and CD163-positive cells. Macrophages and osteoclasts were distinguished on the basis of morphological differences. Samples were digitized, and the macrophage and osteoclast cell counts were quantitatively analyzed.
  
  
  RESULTS
  In jaw bone affected by BRONJ, a significantly increased macrophage infiltration and M1 polarization of macrophages can be seen. The density of CD68-expressing osteoclasts is significantly increased in BRONJ specimens compared to ORN and to healthy controls.
  
  
  CONCLUSIONS
  A bisphosphonate-derived shift of macrophage polarization towards M1-polarized macrophages might impair bone tissue homeostasis and thus contribute to the pathogenesis of BRONJ. The observed increase in osteoclast density might be caused by BP-induced prolonged osteoclast survival.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Wehrhan
authors.affiliation: Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Moebius
authors.affiliation: Institute of Pathology, Department of Nephropathology, Friedrich-Alexander University Erlangen-Nürnberg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.affiliation: Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Ries
authors.affiliation: Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Germany.
authors.forename: Raimund
authors.initials: R
authors.lastname: Preidl
authors.affiliation: Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Germany.
authors.forename: Friedrich W
authors.initials: FW
authors.lastname: Neukam
authors.affiliation: Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg, Germany. Electronic address: manuel.weber@uk-erlangen.de.
authors.forename: Manuel
authors.initials: M
authors.lastname: Weber
mesh_terms: D000368:Aged; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000473:pathology*; D002452:Cell Count; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007568:Jaw / Q000473:pathology; D008264:Macrophages / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010010:Osteoclasts / Q000473:pathology*; D010025:Osteoradionecrosis / Q000473:pathology*
keywords: BRONJ; Bisphosphonate associated osteonecrosis of the jaw; Macrophage polarization; ORN; Osteoclast polarization; Osteoradionecrosis