Zoledronic acid inhibits macrophage SOCS3 expression and enhances cytokine production

Abstract

Suppressor of cytokine signaling-3 (SOCS3) has multiple functions including inhibition of Janus kinase activity, regulation of protein degradation, and suppression of cytokine signaling. SOCS3 modulates macrophage response to cytokines such as IL-6 and leptin that are systemically induced in obesity. Obesity is a suspected risk factor for SOCS3-related pathology such as rheumatoid arthritis and Crohn’s disease as well as zoledronic acid (ZA)-induced osteonecrosis of the jaw (ONJ). Thus, understanding the ability of bisphosphonates to modulate SOCS3 is necessary to qualify their contribution to these disorders. ONJ occurs in up to 10% of patients using intravenous bisphosphonates and has an unknown pathogenesis that may be linked to decreased bone turnover, altered vascularity, bacterial invasion, and compromised wound healing. Given the increased risk of ONJ with obesity and importance of macrophages in wound healing, we hypothesized that amino-bisphosphonates could contribute to the pathogenesis of ONJ by regulating macrophage responses to cytokines such as leptin and IL-6. We report that zoledronic acid is a novel inhibitor of SOCS3 in primary macrophages and human ONJ biopsy specimens. Inhibition of SOCS3 by ZA resulted in significant increases in IL-6 production. SOCS3 transcription is regulated by nuclear accumulation of phosphorylated-Stat3 (P-Stat3). We found that ZA decreased phosphorylation of Stat3 in a mevalonate-pathway dependent manner. However, restoration of P-Stat3 was not sufficient to correct SOCS3 inhibition. We propose that disruption of macrophage SOCS3 expression by amino-bisphosphonates such as ZA may be a novel contributor to inflammatory phenotypes in obesity and the pathogenesis of ONJ.

IL-17–Mediated M1/M2 Macrophage Alteration Contributes to Pathogenesis of Bisphosphonate-Related Osteonecrosis of the Jaws

“…Recent studies have demonstrated that suppressor of cytokine signaling-3 (SOCS3) can repress the proinflammatory M1 macrophage phenotype, whereas SOCS3 deficiency promotes M1 macrophage polarization and inflammation via an increased production of proinflammatory cytokines IL-1β, IL-6, IL-12 and IL23, rendering a microenvironment conditioned for the differentiation of Th1 and Th17 cells (49, 50). Interestingly, zoledronic acid has been shown to induce M2-like tumor associated macrophages (TAMs) toward an M1 phenotype (51) and enhances proinflammatory cytokine production through inhibition of SOCS3 expression in macrophages (19). These findings could explain the mechanisms whereby zoledronic acid drives Th17 differentiation, at least in part, through promoting M1-macrophage polarization and activation (18).…”

“…The tumor associated macrophages (TAMs) with similar characteristics of M2 macrophages can suppress immune response and promote angiogenesis and metastasis of tumor cells, thus facilitating cancer progression, or attenuating inflammation and enhancing wound healing (54). Recently, both in vitro and in vivo studies have shown that tumor macrophages are potential targets of BPs (18, 19, 51), possibly via the manipulation of macrophage phenotypes in tumor microenvironment, and by similar mechanisms, sustain prolonged inflammation leading to an increased susceptibility to BRONJ. Epidemiologic study has identified several risk factors associated with ONJ; in cancer patients receiving high-dose intravenous BPs for the prevention and treatment of skeletal-related complications, treatment with other anti-tumor drugs including glucocorticoid (dexamethasone), chemotherapeutic or/and anti-angiogenic drugs incur additional risks; as such, it should be further explored whether BPs and these anti-tumor drugs have any cooperative effects on the immune system, specifically on the interplay between Th17 cells and M1/M2 macrophages, as these immune cells potentially function as a “double-edge” sword within the tumor microenvironment to enhance both anti-tumor immunity and inflammatory responses (18, 39).…”

“…Given the importance of macrophages in wound healing and the fact that these cells share similar cell lineage as osteoclasts, it is plausible to hypothesize that macrophage function may potentially be altered by BP treatment and therefore, contributes to the defective healing in BRONJ (17). Most recent studies have suggested a potential effect of zoledronic acid (ZA) in the polarization of tumor associated macrophages (TAMs) in vitro (18, 19); it remains to be determined comprehensively whether and how the function and phenotypes (M1 vs M2) of macrophages participate in the pathogenesis of BRONJ.…”

Activated monocytes augment TRAIL‐mediated cytotoxicity by human NK cells through release of IFN‐γ

“…Indeed, monocytes treated with ZA and IL-2 displayed an increased phosphorylation of p38 compared to monocytes treated with either IL-2 or ZA alone (data not shown). Moreover, SOCS3 inhibition by ZA [23,24] resulting in enhanced STAT1/3 signaling may contribute to increased IFN-γ production when IL-2 was added to cultures.It is well known that isopentenyl pyrophosphate (IPP) accumulates in monocytes when treated with ZA [25]. Monocytes that accumulate IPP become antigen-presenting cells and stimulate γδ T cells in peripheral blood.…”

“…Indeed, monocytes treated with ZA and IL-2 displayed an increased phosphorylation of p38 compared to monocytes treated with either IL-2 or ZA alone (data not shown). Moreover, SOCS3 inhibition by ZA [23,24] resulting in enhanced STAT1/3 signaling may contribute to increased IFN-γ production when IL-2 was added to cultures.…”