Altered macrophagic THP-1 cell phagocytosis and migration in bisphosphonate-related osteonecrosis of the jaw (BRONJ).
OBJECTIVE
Local immune dysfunction via macrophages is a proposed aetiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ). This study aimed to clarify the effects of various bisphosphonates on macrophage function using a THP-1 monocytic model to examine migration, phagocytosis, and fibrin structure.


METHODS
THP-1 cell migration was measured in the presence and absence of zoledronate, ibandronate, risedronate, alendronate, pamidronate (0.5, 5 and 50 μM) and clodronate (125, 250 and 500 μM) using the real-time xCELLigence system. Phagocytosis and actin fibre assays were performed after 72 h with zoledronate, ibandronate, alendronate and clodronate.


RESULTS
Time to maximum migration for THP-1 cells was significantly reduced (p < 0.05) for high dosages of zoledronate, ibandronate and alendronate compared to controls. All dosages of clodronate and a low dose of zoledronate exhibited prolonged migrations. Phagocytic capacity was significantly reduced in high dosages of all bisphosphonates and for 5 μM zoledronate and ibandronate (p < 0.05). Low bisphosphonate exposure was accompanied by overcharged phagosoms. Altered appearance in F-actin fibrin structure was observed in bisphosphonate-exposed cells.


CONCLUSIONS
All bisphosphonates altered the migration of THP-1 cells dose-dependently. Low doses also prolonged migration and altered cell morphology. These findings support the idea of a disturbed local immune function of macrophages even in jaw bone exposed to low concentrations of bisphosphonate.


CONCLUSIONS
These are the first real-time results for disrupted migration and function of macrophagic THP-1 cells in high doses. Low dosages also demonstrated altered macrophage phagocytosis and cell morphology, suggesting a disturbed local immune function in BRONJ pathogenesis.
Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany. sebastian.hoefert@med.uni-tuebingen.de.
Sebastian
S
Hoefert
Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany.
Claudia
C
Sade Hoefert
Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany.
Adelheid
A
Munz
Institute for Clinical and Experimental Transfusion Medicine, University Hospital Tuebingen, Otfried-Mueller Strasse 4/1, 72076, Tuebingen, Germany.
Hinnak
H
Northoff
Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany.
Anna
A
Yuan
Department of Conservative Dentistry and Periodontology, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany.
Kathrin
K
Reichenmiller
Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany.
Siegmar
S
Reinert
Department of Oral and Maxillofacial Surgery, University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany.
Martin
M
Grimm
D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000276:immunology*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D057899:Cytophagocytosis / Q000187:drug effects*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology*
D050071:Bone Density Conservation Agents
Bisphosphonate-related osteonecrosis of the jaw (BRONJ); F-actin fibres; Local immunosuppression; Macrophages; Migration; Monocytes; Phagocytosis; THP-1 cells