The role of M1 and M2 macrophage polarization in progression of medication-related osteonecrosis of the jaw
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ORIGINAL ARTICLE
The role of M1 and M2 macrophage polarization in progression of medication-related osteonecrosis of the jaw Polytimi Paschalidi 1 & Ioannis Gkouveris 2 & Akrivoula Soundia 3 & Evangelos Kalfarentzos 1 & Emmanouil Vardas 4 & Maria Georgaki 2 & Georgios Kostakis 1 & Boban M. Erovic 5 & Sotirios Tetradis 3 & Christos Perisanidis 1 & Nikolaos G. Nikitakis 2 Received: 26 May 2020 / Accepted: 17 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Objectives The aim of this study was to investigate the relationship between M1 and M2 macrophage polarization and clinical stage in patients with medication-related osteonecrosis of the jaw (MRONJ) who underwent treatment with bisphosphonates or denosumab. Materials and methods M1 and M2 macrophage density and expression of interleukin (IL)-6 and IL-10 were assessed on biopsies of mucosal tissues surrounding necrotic bone in 30 MRONJ patients with stages 1–3 and controls. For identification of M1 and M2 macrophages, double CD68/iNOS and CD68/CD206 immunofluorescence staining was conducted, respectively. Computer-assisted immunofluorescence quantification of markers was performed. Results Early stage 1 MRONJ patients showed a switch toward the M2 phenotype, as indicated by the higher density of M2 macrophages, the decreased M1/M2 ratio, and the upregulation of IL-10. MRONJ patients with advanced stages 2 and 3 showed a shift toward M1-polarized macrophages, as suggested by the higher density of M1 macrophages, the increased M1/M2 ratio, and the overexpression of IL-6. The macrophage density of both M1 and M2 subsets was significantly enhanced in patients receiving bisphosphonates compared with those receiving denosumab. Conclusions The M1–M2 macrophage polarization status in mucosal tissues bordering necrotic bone correlates with clinical stage of MRONJ. Patients with early-stage MRONJ show a switch toward M2-polarized macrophages, while MRONJ patients with advanced stage demonstrate a shift toward the M1 phenotype. Clinical relevance Therapeutic molecules targeting the inflammatory microenvironment via the regulation of either M1 or M2 macrophage polarization may represent a novel strategy for treatment of MRONJ. Keywords Jaw diseases . Denosumab . Bisphosphonate-associated osteonecrosis of the jaw . Zoledronic acid . Alendronate . Macrophage . Phenotype
Sotirios Tetradis, Christos Perisanidis and Nikolaos G. Nikitakis contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00784-020-03602-z) contains supplementary material, which is available to authorized users. * Polytimi Paschalidi [email protected] 1
2
Department of Oral and Maxillofacial Surgery, School of Dentistry, National and Kapodistrian University of Athens, Thivon 2, Goudi, Athens, Greece Department of Oral Medicine and Pathology, School of Dentistry, National and Kapodistrian University of Athens, Thivon 2, Goudi, Athens, Greece
3
Division of Diagnostic and Surgical Sciences, U
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