Zoledronic Acid Enhances Lipopolysaccharide-Stimulated Proinflammatory Reactions through Controlled Expression of SOCS1 in Macrophages

Daichi Muratsu,Tomohiro Onimura,Yoshihiro Seki,Seiji Nakamura,Daigo Yoshiga,Takaharu Taketomi,Akinobu Matsumoto,Özlem Yilmaz

doi:10.1371/journal.pone.0067906

Abstract

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious side effect of nitrogen-containing bisphosphonate (NBP) use. Many studies have shown that BRONJ is limited to the jawbone and does not occur in the other bones. We hypothesized that BRONJ is related to local bacterial iections and involves the innate immune system. To examine the relationship between BRONJ and innate immunity, we examined the effects of NBPs on macrophages, one of the important cell types in innate immunity. The expression of toll-like receptor-4 (TLR4) in cells after pretreatment with zoledronic acid (ZOL) did not considerably differ from that in untreated control cells. However, cytokine levels and nitric oxide (NO) production increased after pretreatment with ZOL. Furthermore, ZOL induced NF-κB activation by enhancing IκB-α degradation. Lipopolysaccharide (LPS)-induced apoptosis also increased after pretreatment with ZOL. This effect was mediated by a reduction of suppressor of cytokine signaling-1 (SOCS1), which is a negative regulator of myeloid differentiation primary response gene 88 (MyD 88)-dependent signaling. These results suggest that ZOL induced excessive innate immune response and proinflammatory cytokine production and that these processes may be involved in the bone destruction observed in BRONJ.

Highlights

Nitrogen-containing bisphosphonates (NBPs), which are synthetic analogs of pyrophosphate, are an effective treatment for osteoporosis, hypercalcemia of malignancy, osteolytic lesions in multiple myeloma, and bone metastases from solid tumors, including breast cancer and hormone-independent prostate cancer [1,2]
In this study, we used macrophages, which are of the same origin as osteoclasts, like all typical immune cells, and we focused on the relationship between innate immunity and bisphosphonate-related osteonecrosis of the jaw (BRONJ), the involvement of the NBP zoledronic acid (ZOL), and its effects on toll-like receptor-4 (TLR4) signaling and inflammatory cytokine production
We examined the effects of ZOL on LPS-induced iNOS release from RAW264.7 cells

Summary

Introduction

Nitrogen-containing bisphosphonates (NBPs), which are synthetic analogs of pyrophosphate, are an effective treatment for osteoporosis, hypercalcemia of malignancy, osteolytic lesions in multiple myeloma, and bone metastases from solid tumors, including breast cancer and hormone-independent prostate cancer [1,2]. NBPs are effective for the treatment of numerous metabolic bone diseases. NBPs have a high affinity for bone minerals [3] and accumulate in high concentrations in bones [4,5]. They are selectively taken up by osteoclasts and strongly inhibit bone resorption by inducing apoptosis in osteoclasts [6,7]. Serious side effects such as bisphosphonate-related osteonecrosis of the jaw (BRONJ) have been reported with the use of NBPs [8,9]. In addition to the clinical appearance of exposed necrotic bone, concomitant local infections are often observed in patients with BRONJ. Because bisphosphonates have been shown to reduce bone remodeling [10] and angiogenesis [11], the suppression of bone turnover and jaw angiogenesis resulting from bisphosphonates have been proposed as underlying mechanisms for BRONJ

Methods

Results

Conclusion