Influence of dichloromethylene diphosphonate on reactive oxygen species production by human neutrophils

Abstract

Biphosphonates suppress bone destruction in various diseases. Several studies have demonstrated the potential use of biphosphonate in arthritis. The results of these studies indicate that the effectiveness of the biphosphonates, for inhibiting the arthritic process, is related to their antiresorptive properties. It has been shown that the generation of reactive oxygen species is associated with the formation of new osteoclasts and enhanced bone resorption. We studied the effects of the dichloromethylene diphosphonate on the reactive oxygen species production by activated polymorphonuclear leucocytes, measured by chemiluminescence. Our results indicate a dose-dependent inhibitory effect of dichloromethylene diphosphonate on reactive oxygen species production by polymorphonuclear leucocytes stimulated with N-formil-methionyl-leucyl-phenylalanine, the calcium ionophore A23187 and phorbol myristate acetate. The mechanisms by which this biphosphonate inhibits the reactive oxygen species production by activated polymorphonuclear leucocytes are discussed.

Dynamics of macrophage polarization reveal new mechanism to inhibit IL-1β release through pyrophosphates

“…We hypothesized that the inhibition of IL-1β processing and release by ATP and PPi that was not reversed by treatment with CB (i.e. the actin-independent inhibition) may result from reduced ROS production because P2X 7 R stimulation of M1 polarized macrophages is known to increase ROS production and is associated with NLRP3-inflammasome activation ( Dostert et al , 2008 ; Hewinson et al , 2008 ) ( Supplementary Figure S4D ) and ATP, PPi and bisphosphonates may act directly or indirectly as oxygen radical scavengers ( Serretti et al , 1993 ; Kachur et al , 1997 ; Dombrecht et al , 2006 ). Both ATP and MTX induced similar rapid (within 2–3 min) increases in ROS production from M1 polarized macrophages ( Figure 7A and E ) but in M2 polarized macrophages the enhanced ROS production was significantly delayed (no significant increase occurred before 8–10 min) and reduced ( Figure 7B and E ).…”

Novel macrophage polarization model: from gene expression to identification of new anti-inflammatory molecules

“…The PPi actions to inhibit the inflammasome [8] and NF-jB gene transcription identified in the present study may well underlie these anti-inflammatory actions of bisphosphonates. Both PPi and clodronate have been shown to directly or indirectly act as oxygen radical scavengers [42][43][44], and they also inhibit ROS production in macrophages [8]. Redox balance has been extensively implicated in NF-jB activation [45], as ROSs contribute to the cytoplasmic signaling pathways leading to NF-jB nuclear translocation.…”

Zoledronate and pamidronate depress neutrophil functions and survival in mice

“…The presence of infection appears to be a consistent finding among histological reports of BRONJ (Marx et al ., 2007) with Actinomyces being a common, if not universal, finding (Hansen et al ., 2006). In addition, there are reports that some bisphosphonates affect the innate immune system, including inhibition of neutrophil enzymes that affect wound healing, such as matrix metalloproteinase 8 (Teronen et al ., 1997), increased risk of neutropenia (Coukell and Markham, 1998) and decreased generation of reactive oxygen species formation (Serretti et al ., 1993). This is not surprising in view of the mechanism of action of bisphosphonates, which target small GTPases that are signalling proteins integral to neutrophil differentiation and function (Dinauer, 2003).…”