Sotirios Tetradis1, Christos Perisanidis2, Nikolaos G Nikitakis3, Polytimi Paschalidi4, Ioannis Gkouveris3, Akrivoula Soundia1, Evangelos Kalfarentzos2, Emmanouil Vardas5, Maria Georgaki3, Georgios Kostakis2, Boban M Erovic6. 1. Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA, 90095, USA. 2. Department of Oral and Maxillofacial Surgery, School of Dentistry, National and Kapodistrian University of Athens, Thivon 2, Goudi, Athens, Greece. 3. Department of Oral Medicine and Pathology, School of Dentistry, National and Kapodistrian University of Athens, Thivon 2, Goudi, Athens, Greece. 4. Department of Oral and Maxillofacial Surgery, School of Dentistry, National and Kapodistrian University of Athens, Thivon 2, Goudi, Athens, Greece. polina_paschal@hotmail.com. 5. Clinic of Hospital Dentistry, School of Dentistry, National and Kapodistrian University of Athens, Thivon 2, Goudi, Athens, Greece. 6. Institute of Head and Neck Diseases, Evangelical Hospital Vienna, Hans-Sachs Gasse 10-12, 1180, Vienna, Austria.
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.
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.
Entities:
Keywords:
Alendronate; Bisphosphonate-associated osteonecrosis of the jaw; Denosumab; Jaw diseases; Macrophage; Phenotype; Zoledronic acid
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