Zoledronic acid enhances lipopolysaccharide-stimulated proinflammatory reactions through controlled expression of SOCS1 in macrophages

PLoS One. 2013 Jul 9;8(7):e67906. doi: 10.1371/journal.pone.0067906. Print 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / immunology
  • Cell Line
  • Cytokines / genetics
  • Cytokines / metabolism
  • Diphosphonates / pharmacology*
  • Gene Expression Regulation / drug effects*
  • Imidazoles / pharmacology*
  • Immunity, Innate
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism
  • Lipopolysaccharides / immunology*
  • Macrophage Activation / drug effects
  • Macrophage Activation / immunology
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / metabolism*
  • Mice
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / metabolism
  • Nitric Oxide / biosynthesis
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins / genetics*
  • Suppressor of Cytokine Signaling Proteins / metabolism*
  • Toll-Like Receptor 4 / metabolism
  • Zoledronic Acid

Substances

  • Cytokines
  • Diphosphonates
  • Imidazoles
  • Lipopolysaccharides
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • SOCS1 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Toll-Like Receptor 4
  • Nitric Oxide
  • Zoledronic Acid

Grants and funding

Grant number: 21890185; URL:http://www.jsps.go.jp/j-grantsinaid/03_keikaku/index.html. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.