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Article

Zoledronate Causes a Systemic Shift of Macrophage Polarization towards M1 In Vivo

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
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Department of Nephropathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
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Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
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Department of Oral and Maxillofacial Surgery, University of Mainz, 55122 Mainz, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Hiroshi Nakase
Int. J. Mol. Sci. 2021, 22(3), 1323; https://doi.org/10.3390/ijms22031323
Received: 29 November 2020 / Revised: 21 January 2021 / Accepted: 22 January 2021 / Published: 28 January 2021
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. View Full-Text
Keywords: bisphosphonate; Zoledronate; antiresorptives; macrophage polarization; M1; M2; immune modulation bisphosphonate; Zoledronate; antiresorptives; macrophage polarization; M1; M2; immune modulation
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MDPI and ACS Style

Weber, M.; Homm, A.; Müller, S.; Frey, S.; Amann, K.; Ries, J.; Geppert, C.; Preidl, R.; Möst, T.; Kämmerer, P.W.; Kesting, M.; Wehrhan, F. Zoledronate Causes a Systemic Shift of Macrophage Polarization towards M1 In Vivo. Int. J. Mol. Sci. 2021, 22, 1323. https://doi.org/10.3390/ijms22031323

AMA Style

Weber M, Homm A, Müller S, Frey S, Amann K, Ries J, Geppert C, Preidl R, Möst T, Kämmerer PW, Kesting M, Wehrhan F. Zoledronate Causes a Systemic Shift of Macrophage Polarization towards M1 In Vivo. International Journal of Molecular Sciences. 2021; 22(3):1323. https://doi.org/10.3390/ijms22031323

Chicago/Turabian Style

Weber, Manuel, Andi Homm, Stefan Müller, Silke Frey, Kerstin Amann, Jutta Ries, Carol Geppert, Raimund Preidl, Tobias Möst, Peer W. Kämmerer, Marco Kesting, and Falk Wehrhan. 2021. "Zoledronate Causes a Systemic Shift of Macrophage Polarization towards M1 In Vivo" International Journal of Molecular Sciences 22, no. 3: 1323. https://doi.org/10.3390/ijms22031323

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