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IL-17-mediated M1/M2 macrophage alteration contributes to pathogenesis of bisphosphonate-related osteonecrosis of the jaws.

ABSTRACT: Osteonecrosis of the jaw (ONJ) is emerging as one of the important complications in cancer patients treated with antiresorptive agents. This study explored the potential role of interleukin (IL)-17-mediated M1/M2 macrophage alterations in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ).The expression of IL-17 and M1 and M2 macrophage markers at the local mucosal site of human BRONJ lesions was examined by immunofluorescence studies. BRONJ-like disease was induced in C57BL/6 mice and multiple myeloma-burdened mice by intravenous injection of zoledronate to evaluate the correlation of elevated IL-17 levels with changes in M1 and M2 macrophage phenotypes and the therapeutic effects of blocking IL-17 on pathogenesis of BRONJ-like disease.Increased T-helper (TH)17 cells and IL-17 cytokine correlate with an increase in M1/M2 macrophages ratio at the local mucosal site of both murine and human BRONJ lesion. Convincingly, in mice burdened with multiple myeloma, a combination of elevated suprabasal level and drug-induced IL-17 activity augmented the incidence of BRONJ; both systemic increase of IL-17 and disease severity could be reversed by adoptive transfer of ex vivo expanded M2 macrophages. Targeting IL-17 via specific neutralizing antibodies or a small inhibitory molecule, laquinimod, significantly decreased M1/M2 ratio and concomitantly suppressed BRONJ-like condition in mice. Mechanistically, IL-17 enhanced IFN-?-induced M1 polarization through augmenting STAT-1 phosphorylation while suppressing IL-4-mediated M2 conversion via inhibiting STAT-6 activation.These findings have established a compelling linkage between activated IL-17-mediated polarization of M1 macrophages and the development of BRONJ-like conditions in both human disease and murine models.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC5558149 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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IL-17-mediated M1/M2 macrophage alteration contributes to pathogenesis of bisphosphonate-related osteonecrosis of the jaws.

Zhang Qunzhou Q Atsuta Ikiru I Liu Shiyu S Chen Chider C Shi Shihong S Shi Songtao S Le Anh D AD

Clinical cancer research : an official journal of the American Association for Cancer Research 20130424 12

<h4>Purpose</h4>Osteonecrosis of the jaw (ONJ) is emerging as one of the important complications in cancer patients treated with antiresorptive agents. This study explored the potential role of interleukin (IL)-17-mediated M1/M2 macrophage alterations in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ).<h4>Experimental design</h4>The expression of IL-17 and M1 and M2 macrophage markers at the local mucosal site of human BRONJ lesions was examined by immunofluorescence ...[more]

PMID: 23616636

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Project description:Aging is a significant risk factor for the development of bisphosphonate-related osteonecrosis of the jaws (BRONJ). Accumulating evidence suggests that bone aging is associated with oxidative stress (OS), and OS is associated with osteonecrosis. To elucidate the mechanisms of the onset of BRONJ, the present study focused on OS and the effects of treatment with the pro-oxidant DL-buthionine-(S,R)-sulfoximine (BSO), an oxidative stressor, on healing of a surgically induced penetrating injury of the palate. Six-week-old C57BL/6J mice were randomly divided into four groups (n=5 each) and treated with or without zoledronic acid (ZOL) and with or without BSO (experimental groups: ZOL, BSO, and ZOL+BSO; control group: saline solution). A penetrating injury of the midline palate was surgically created using a root elevator. ZOL (250 µg/kg/day) was injected intraperitoneally every day from 7 days prior to the surgical treatment to 4 days following the surgical treatment. BSO (500 µg/kg/day) was administered 7 days prior to the surgical treatment as a single intraperitoneal injection. The maxillae were harvested at 5 days following the surgical treatment for histological and histochemical studies. The presence of empty osteocyte lacunae in the palatal bone was increased by ZOL and BSO treatment. The highest number of empty osteocyte lacunae was observed in the ZOL+BSO group. The number of tartrate-resistant acid phosphatase-positive cells was decreased by ZOL treatment and increased by BSO treatment. The number of canaliculi per osteocyte lacuna was significantly decreased by BSO treatment. The mineral apposition rate was significantly lower in the treatment groups than the control group. Bisphosphonates and OS suppressed bone turnover. The present study has demonstrated that BSO treatment affects osteocytes, and OS in osteocytes exacerbates impairment of the osteocytic canalicular networks. As a result, bisphosphonates and OS may induce osteonecrosis following invasive dentoalveolar surgery. OS has been identified as an additional risk factor for the development of BRONJ.

Project description:Osteonecrosis of the jaw induced by administration of bisphosphonates (BPs), BP-related osteonecrosis (BRONJ), typically develops after tooth extraction and is medically challenging. As BPs inhibit oral mucosal cell growth, we hypothesized that suppression of the wound healing-inhibiting effects could prevent BRONJ onset after tooth extraction. Since basic fibroblast growth factor (bFGF) promotes wound healing, but has a short half-life, we examined whether the initiation of BRONJ could be prevented by applying a bFGF-containing gelatin hydrogel over the extraction sockets of BRONJ model rats. Forty-three rats, received two intravenous injections of zoledronic acid 60 ?g/kg, once per week for a period of 2 weeks, underwent extraction of a unilateral lower first molar. The rats here were randomly assigned to the bFGF group (n = 15 rats, gelatin hydrogel sheets with incorporated bFGF applied over the sockets); the phosphate-buffered saline (PBS) group (n = 14 rats, gelatin hydrogel sheets without bFGF applied over the sockets); or the control group (n = 14 rats, nothing applied over the sockets). One rat in the bFGF group was sacrificed immediately after tooth extraction. Twenty-one rats were sacrificed at 3 weeks, and the remaining 21 rats were sacrificed at 8 weeks after tooth extractions. The harvested mandibles were analyzed using micro-computed tomography and sections were evaluated qualitatively for mucosal disruption and osteonecrosis. The incidence of osteonecrosis at 8 weeks after tooth extraction was 0% in the bFGF group, 100% in the PBS group, and 85.7% in the control group. The frequency of complete coverage of the extraction socket by mucosal tissue was significantly greater in the bFGF group than in the other groups. These results suggest that application of bFGF in the extraction socket promoted socket healing, which prevented BRONJ development. The growth-stimulating effects of bFGF may have offset the inhibition of wound healing by BP.

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Project description:Human amniotic mesenchymal cells (hAMTCs) possess interesting immunomodulatory properties, making them attractive candidates for regenerative medicine applications. Recent in vivo reports argue in favour of an important role for macrophages as targets of hAMTC-mediated suppression of inflammation and the enhancement of tissue repair. However, a comprehensive study of the effects of hAMTCs and their conditioned medium (CM) on human macrophage differentiation and function is unavailable. In the present study we found that hAMTCs and CM induce the differentiation of myeloid cells (U937 and monocytes) towards macrophages. We then investigated their effects on monocytes differentiated toward pro-inflammatory M1 and anti-inflammatory M2 macrophages. Monocytes treated under M1 conditions in the presence of hAMTCs or CMs shifted towards M2-like macrophages, which expressed CD14, CD209, CD23, CD163 and PM-2 K, possessed higher phagocytic activity and produced higher IL-10 and lower pro-inflammatory cytokines. They were also poor T cell stimulators and Th1 inducers, while they were able to increase activated and naïve suppressive Treg subsets. We show that prostaglandins, and not IL-6, play a role in determining the M2 activation status. Instead, monocytes treated under M2 conditions in the presence of hAMTCs or CM retained M2-like features, but with an enhanced anti-inflammatory profile, having a reduced expression of the co-stimulatory molecule CD80, reduced phagocytosis activity and decreased the secretion of inflammatory chemokines. Importantly, we provide evidence that macrophages re-educated by CM improve tissue regeneration/repair in wound-healing models. In conclusion, we identified new cell targets of hAMTCs and their bioactive factors and here provide insight into the beneficial effects observed when these cells are used in therapeutic approaches in vivo. © 2016 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons Ltd.

Dataset Information

IL-17-mediated M1/M2 macrophage alteration contributes to pathogenesis of bisphosphonate-related osteonecrosis of the jaws.

Publications

IL-17-mediated M1/M2 macrophage alteration contributes to pathogenesis of bisphosphonate-related osteonecrosis of the jaws.

Similar Datasets

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