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

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.

[1]  R. Hess,et al.  Tumor‐Associated Macrophages (TAM) are recruited to the aging prostate epithelial lesions and become intermingled with basal cells , 2020, Andrology.

[2]  Xikun Zhou,et al.  Tumor-Associated Macrophages: Recent Insights and Therapies , 2020, Frontiers in Oncology.

[3]  M. Intorcia,et al.  Real-world use of denosumab and bisphosphonates in patients with solid tumours and bone metastases in Germany , 2020, Supportive Care in Cancer.

[4]  C. Ries,et al.  CD163+ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes , 2020, Clinical & translational immunology.

[5]  M. Kesting,et al.  Malignant transformation of oral leukoplakia is associated with macrophage polarization , 2020, Journal of Translational Medicine.

[6]  M. Kesting,et al.  Osseous ingrowth in allogeneic bone blocks applied for vertical bone augmentation: a preclinical randomised controlled study , 2019, Clinical Oral Investigations.

[7]  A. Varzi,et al.  Macrophage polarization in wound healing: role of aloe vera/chitosan nanohydrogel , 2019, Drug Delivery and Translational Research.

[8]  N. Pannacciulli,et al.  Efficacy and safety of denosumab vs. bisphosphonates in postmenopausal women previously treated with oral bisphosphonates , 2019, Osteoporosis International.

[9]  K. Kregel,et al.  Aging results in accumulation of M1 and M2 hepatic macrophages and a differential response to gadolinium chloride , 2019, Histochemistry and Cell Biology.

[10]  X. Che,et al.  M2 macrophage infiltration into tumor islets leads to poor prognosis in non-small-cell lung cancer , 2019, Cancer management and research.

[11]  S. Patntirapong,et al.  Inhibition of macrophage viability by bound and free bisphosphonates. , 2019, Acta histochemica.

[12]  M. Kesting,et al.  Osteoclastic expression of higher-level regulators NFATc1 and BCL6 in medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy: a comparison with osteoradionecrosis and osteomyelitis , 2019, Journal of Translational Medicine.

[13]  Meera G. Nair,et al.  Macrophages in wound healing: activation and plasticity , 2019, Immunology and cell biology.

[14]  Yu Fu,et al.  Zoledronic acid promotes TLR‐4‐mediated M1 macrophage polarization in bisphosphonate‐related osteonecrosis of the jaw , 2019, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  M. Najafi,et al.  Contribution of regulatory T cells to cancer: A review , 2018, Journal of cellular physiology.

[16]  S. Patntirapong,et al.  Alteration of macrophage viability, differentiation, and function by bisphosphonates. , 2018, Oral diseases.

[17]  D. Yoshiga,et al.  Zoledronic acid exacerbates inflammation through M1 macrophage polarization , 2018, Inflammation and regeneration.

[18]  N. Raje,et al.  Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. , 2018, The Lancet. Oncology.

[19]  Ilijana Muratovska,et al.  In vivo effects of geranylgeraniol on the development of bisphosphonate-related osteonecrosis of the jaws. , 2017, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[20]  Qiaojun He,et al.  Macrophage Polarization: Anti‐Cancer Strategies to Target Tumor‐Associated Macrophage in Breast Cancer , 2017, Journal of cellular biochemistry.

[21]  R. Z. Murray,et al.  Macrophage Phenotypes Regulate Scar Formation and Chronic Wound Healing , 2017, International journal of molecular sciences.

[22]  K. Amann,et al.  Osteoclast profile of medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy: a comparison with osteoradionecrosis and osteomyelitis , 2017, Journal of Translational Medicine.

[23]  F. Neukam,et al.  Macrophage and osteoclast polarization in bisphosphonate associated necrosis and osteoradionecrosis. , 2017, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[24]  A. Etges,et al.  Microscopic Evaluation of the Effect of Oral Microbiota on the Development of Bisphosphonate-Related Osteonecrosis of the Jaws in Rats , 2016, Journal of oral & maxillofacial research.

[25]  R. Mandic,et al.  The enhancing effect of a laser photochemotherapy with cisplatin or zolendronic acid in primary human osteoblasts and osteosarcoma cells in vitro. , 2016, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[26]  R. Gray,et al.  Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[27]  M. Zandi,et al.  Introducing a protocol to create bisphosphonate-related osteonecrosis of the jaw in rat animal model. , 2016, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[28]  Amitava Das,et al.  Monocyte and macrophage plasticity in tissue repair and regeneration. , 2015, The American journal of pathology.

[29]  P. Kronqvist,et al.  Human breast cancer cells educate macrophages toward the M2 activation status , 2015, Breast Cancer Research.

[30]  K. Amann,et al.  BRONJ-related jaw bone is associated with increased Dlx-5 and suppressed osteopontin—implication in the site-specific alteration of angiogenesis and bone turnover by bisphosphonates , 2015, Clinical Oral Investigations.

[31]  K. Amann,et al.  Macrophage polarisation changes within the time between diagnostic biopsy and tumour resection in oral squamous cell carcinomas—an immunohistochemical study , 2015, British Journal of Cancer.

[32]  K. Schlegel,et al.  Extra-oral defect augmentation using autologous, bovine and equine bone blocks: A preclinical histomorphometrical comparative study. , 2015, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[33]  T. Tamura,et al.  Functions and development of red pulp macrophages , 2015, Microbiology and immunology.

[34]  P. Svider,et al.  iNOS Expression in CD4+ T Cells Limits Treg Induction by Repressing TGFβ1: Combined iNOS Inhibition and Treg Depletion Unmask Endogenous Antitumor Immunity , 2014, Clinical Cancer Research.

[35]  F. Neukam,et al.  Small oral squamous cell carcinomas with nodal lymphogenic metastasis show increased infiltration of M2 polarized macrophages--an immunohistochemical analysis. , 2014, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[36]  E. Nkenke,et al.  The outcome after surgical therapy of bisphosphonate-associated osteonecrosis of the jaw—results of a clinical case series with an average follow-up of 20 months , 2013, Clinical Oral Investigations.

[37]  O. Olopade,et al.  The role of tumor-associated macrophages in breast cancer , 2015 .

[38]  S. Shi,et al.  IL-17–Mediated M1/M2 Macrophage Alteration Contributes to Pathogenesis of Bisphosphonate-Related Osteonecrosis of the Jaws , 2013, Clinical Cancer Research.

[39]  C. Wilmowsky,et al.  Osseointegration of SLActive implants in diabetic pigs. , 2013, Clinical oral implants research.

[40]  A. Sica,et al.  Macrophage plasticity and polarization in tissue repair and remodelling , 2013, The Journal of pathology.

[41]  Zhi-ren Zhang,et al.  Macrophages in Tumor Microenvironments and the Progression of Tumors , 2012, Clinical & developmental immunology.

[42]  Alberto Mantovani,et al.  Macrophage plasticity and polarization: in vivo veritas. , 2012, The Journal of clinical investigation.

[43]  K. Schlegel,et al.  Diabetes mellitus negatively affects peri-implant bone formation in the diabetic domestic pig. , 2011, Journal of clinical periodontology.

[44]  E. Nkenke,et al.  Msx-1 is suppressed in bisphosphonate-exposed jaw bone analysis of bone turnover-related cell signalling after bisphosphonate treatment. , 2011, Oral diseases.

[45]  Cord Sunderkötter,et al.  An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. , 2011, The Journal of clinical investigation.

[46]  M. Ellis,et al.  Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. , 2010, The Lancet. Oncology.

[47]  E. Nkenke,et al.  Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: a prospective clinical study with 12 months follow-up , 2010, Supportive Care in Cancer.

[48]  A. Sica,et al.  New vistas on macrophage differentiation and activation , 2007, European journal of immunology.

[49]  F. Neukam,et al.  Prognostic significance of macrophage polarization in early stage oral squamous cell carcinomas. , 2016, Oral oncology.

[50]  M. Stockler,et al.  Bisphosphonates and other bone agents for breast cancer. , 2012, The Cochrane database of systematic reviews.