Manuel Weber1, Andi Homm1, Stefan Müller1, Silke Frey2, Kerstin Amann3, Jutta Ries1, Carol Geppert4, Raimund Preidl1, Tobias Möst1, Peer W Kämmerer5, Marco Kesting1, Falk Wehrhan1. 1. Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany. 2. Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany. 3. Institute of Pathology, Department of Nephropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany. 4. Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany. 5. Department of Oral and Maxillofacial Surgery, University of Mainz, 55122 Mainz, Germany.
Abstract
BACKGROUND: Immunomodulatory properties of bisphosphonates (BP) are suggested to contribute to the development of medication-associated osteonecrosis of the jaw (MRONJ). Furthermore, bisphosphonate-derived immune modulation might contribute to the anti-metastatic effect observed in breast cancer patients. Macrophages are potential candidates for the mediation of immunomodulatory effects of bisphosphonates. The study aimed to investigate the influence of bisphosphonates alone and in combination with surgical trauma on systemic macrophage polarization (M1 vs. M2) using an in vivo rat model. METHODS: A total of 120 animals were divided into four groups. Groups 2 and 4 were treated with 8 × 40 μg/kg body weight of the BP Zoledronate i.p. (week 0-7). Groups 3 and 4 were exposed to surgical trauma (week 8, tooth extraction + tibia fracture), whereas in Group 1 neither medication nor surgical trauma was applied. After 8, 10, 12 and 16 weeks, skin, lung and spleen were immunohistochemically examined for macrophage polarization via expression analysis of CD68, CD163 and iNOS using a tissue microarray (TMA). RESULTS: A significant shift of macrophage polarization towards M1 was observed in skin, spleen and lung tissue of animals, with and without surgical trauma, treated with BP when compared to those without BP application. Surgical trauma did not cause a significant increase towards M1 polarization. CONCLUSIONS: BP application leads to a systemic pro-inflammatory situation in vivo, independent of surgical trauma, as evidenced by the shift in macrophage polarization towards M1 in various somatic tissues. This provides a possible explanation for the clinically observed anti-tumor effect of bisphosphonates and might also contribute to pathogenesis of MRONJ.
BACKGROUND: Immunomodulatory properties of bisphosphonates (BP) are suggested to contribute to the development of medication-associated osteonecrosis of the jaw (MRONJ). Furthermore, bisphosphonate-derived immune modulation might contribute to the anti-metastatic effect observed in breast cancerpatients. Macrophages are potential candidates for the mediation of immunomodulatory effects of bisphosphonates. The study aimed to investigate the influence of bisphosphonates alone and in combination with surgical trauma on systemic macrophage polarization (M1 vs. M2) using an in vivo rat model. METHODS: A total of 120 animals were divided into four groups. Groups 2 and 4 were treated with 8 × 40 μg/kg body weight of the BP Zoledronate i.p. (week 0-7). Groups 3 and 4 were exposed to surgical trauma (week 8, tooth extraction + tibia fracture), whereas in Group 1 neither medication nor surgical trauma was applied. After 8, 10, 12 and 16 weeks, skin, lung and spleen were immunohistochemically examined for macrophage polarization via expression analysis of CD68, CD163 and iNOS using a tissue microarray (TMA). RESULTS: A significant shift of macrophage polarization towards M1 was observed in skin, spleen and lung tissue of animals, with and without surgical trauma, treated with BP when compared to those without BP application. Surgical trauma did not cause a significant increase towards M1 polarization. CONCLUSIONS:BP application leads to a systemic pro-inflammatory situation in vivo, independent of surgical trauma, as evidenced by the shift in macrophage polarization towards M1 in various somatic tissues. This provides a possible explanation for the clinically observed anti-tumor effect of bisphosphonates and might also contribute to pathogenesis of MRONJ.
Authors: P Hadji; R E Coleman; C Wilson; T J Powles; P Clézardin; M Aapro; L Costa; J-J Body; C Markopoulos; D Santini; I Diel; A Di Leo; D Cameron; D Dodwell; I Smith; M Gnant; R Gray; N Harbeck; B Thurlimann; M Untch; J Cortes; M Martin; U-S Albert; P-F Conte; B Ejlertsen; J Bergh; M Kaufmann; I Holen Journal: Ann Oncol Date: 2015-12-17 Impact factor: 32.976
Authors: Cornelius von Wilmowsky; Philipp Stockmann; Igor Harsch; Kerstin Amann; Philipp Metzler; Rainer Lutz; Tobias Moest; Friedrich Wilhelm Neukam; Karl Andreas Schlegel Journal: J Clin Periodontol Date: 2011-08 Impact factor: 8.728
Authors: Paul Günther Baptist Heymann; Thomas Ziebart; Peer Wolfgang Kämmerer; Robert Mandic; Akram Saydali; Andreas Braun; Andreas Neff; Guy Florian Draenert Journal: J Oral Pathol Med Date: 2016-04-28 Impact factor: 4.253
Authors: Christian Gross; Manuel Weber; Kay Creutzburg; Patrick Möbius; Raimund Preidl; Kerstin Amann; Falk Wehrhan Journal: J Transl Med Date: 2017-06-06 Impact factor: 5.531
Authors: Ingo Diel; Sonja Ansorge; David Hohmann; Christina Giannopoulou; Daniela Niepel; Michele Intorcia Journal: Support Care Cancer Date: 2020-02-21 Impact factor: 3.603