Nitrogen ‐containing bisphosphonates and lipopolysaccharide mutually augment inflammation via adenosine triphosphate (ATP)‐mediated and interleukin 1β (IL‐1β)‐mediated production of neutrophil extracellular traps (NETs)

ABSTRACTAmong the bisphosphonates (BPs), nitrogen-containing BPs (N-BPs) have much stronger anti –bone-resorptive actions than non-N–BPs. However, N-BPs have various side effects such as acute influenza-like reactions after their initial administration and osteonecrosis of the jawbones after repeated administration. The mechanisms underlying such effects remain unclear. To overcome these pr oblems, it is important to profile the inflammatory nature of N-BPs. Here, we analyzed the inflammatory reactions induced in mouse ear pinnae by the N-BPs alendronate (Ale) and zoledronate (Zol). We found the following: (i) Ale and Zol each induced two phases of inflammation (early weak and late str ong ear swelling); (ii) both phases were augmented by lipopolysaccharides (LPSs; cell-surface constituent of gram-negative bacteria, including oral bacteria), but prevented by inhibitors of the phosphate transporters of solute carrier 20/34 (SLC20/SLC34); (iii) macrophages and neutrophils were invol ved in both phases of Ale+LPS–induced ear-swelling; (iv) Ale increased or tended to increase various cytokines, and LPS augmented these effects, especially that on interleukin 1β (IL-1β); (v) adenosine triphosphate (ATP) was involved in both phases, and Ale alone or Ale+LPS increased ATP in ear pinnae; (vi) the augmented late-phase swelling induced by Ale+LPS depended on both IL-1 and neutrophil extracellular traps (NETs; neutrophil-derived net-like complexes); (vii) neutrophils, together wi...

Source: Journal of Bone and Mineral Research - June 22, 2021 Category: Orthopaedics Authors: Kanan Bando, Toshinobu Kuroishi, Hiroyuki Tada, Takefumi Oizumi, Yukinori Tanaka, Tetsu Takahashi, Itaru Mizoguchi, Shunji Sugawara, Yasuo Endo Tags: Original Article Source Type: research