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

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.

Disruption of FDPS/Rac1 axis radiosensitizes pancreatic ductal adenocarcinoma by attenuating DNA damage response and immunosuppressive signalling

“… 51 Furthermore, a seminal study by Weber and colleagues demonstrated that Zol alone and in combination with surgical trauma significantly increased infiltration and shifted systemic macrophage polarization toward M1 type in spleen, lung, and skin of Wister rat model. 52 All these studies provide additional evidence of Zol contributing towards modulation of the immune system. PDAC is very difficult to treat and resistant to most conventional therapies due to dense stromal meshwork and immunosuppressive microenvironment.…”

Denosumab-Induced Medication-Related Osteonecrosis of the Jaw (DRONJ): A 5-Year Retrospective Cohort Study

“…Several hypotheses have been raised regarding the transformation of existing chronic in ammatory lesions into MRONJ, and an M1 macrophage shift is considered the most likely explanation. Kang Osteonecrosis occurs when BP or RANKL inhibitors are administered in the presence of in amed pulpal or periodontal tissue, because anti-resorptive agents affect the function of various immune cells, such as of neutrophils and polymorphonuclear leukocytes, macrophages, and dendritic cells [21][22][23][24][25][26][27] .…”

“…mediated M1/M2 macrophage alteration is related to the development of BRONJ23 , Tamaki et al reported that dynamic M1/M2 macrophage polarization was induced by the anti-RANKL antibody in a MRONJ model31 , while Weber et al analyzed MRONJ in Wistar rats and found that zoledronate induces a macrophage M1 shift24 .Human studies on macrophage function in this context have also been performed. For instance, Hoefert et al reported that patients with MRONJ had a compromised macrophage function when compared to patients with osteoradionecrosis and osteomyelitis25 , and Paschalidi et al found M1/M2 macrophage polarization in macrophages of patient tissues in MRONJ, and that macrophages shift to the M1 phenotype at stages 2 and 3, as compared to stage 1 of MRONJ 26 .…”

Evaluation of Biocompatibility of New Osteoplastic Xenomaterials Containing Zoledronic Acid and Strontium Ranelate

“…Золедроновая кислота также усиливала местное раздражающее действие ксеногенного матрикса, выражающееся в повышенной эозинофилии и фиб розировании области трансплантации. Согласно полученным ранее данным, подобный эффект мог быть следствием приобретения макрофагами фенотипа M1 под влиянием золедроновой кислоты [36], что привело к дисбалансу поляризации макрофагов между провоспалительным (М1) и противовоспалительным (М2) фенотипами, а в результате -к активизации регуляторной функции эозинофилов и локальному фиброзу.…”