ATP receptors and giant cell formation

Virgilio, Francesco Di; Falzoni, Simonetta; Chiozzi, Paola; Sanz, Jesús M.; Ferrari, Davide; Buell, Gary

doi:10.1002/jlb.66.5.723

Cited by 42 publications

(42 citation statements)

References 15 publications

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“…4, the mononuclear cells appeared to form cell aggregates indicating that they were following a pathway of activity leading to fusion, but were unable to carry out this final step when higher concentrations of P2X7R antagonists were present. This is consistent with a report describing how P2X7Rs preferentially localise to sites of cell-to-cell contact [32] and a previous observation that the formation of cell aggregates in culture was a prerequisite to cell fusion [7].…”

Section: Discussionsupporting

confidence: 93%

“…In addition, it has been demonstrated that macrophage cell clones expressing high levels of P2X7R spontaneously fuse in vitro, whereas clones lacking the P2X7R do not. Furthermore, multinucleated giant cell formation from macrophage fusion could be blocked with a monoclonal antibody directed against the extracellular domain of the P2X7R [7]. These data strongly implicate P2X7R-induced pore formation in the development of multinucleated giant cells and, more specifically, in their fusion.…”

Section: Introductionmentioning

confidence: 75%

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The effects of P2X7 receptor antagonists on the formation and function of human osteoclasts in vitro

Agrawal

Buckley

Bowers

et al. 2010

Purinergic Signalling

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The P2X7 receptor (P2X7R) has been implicated in the process of multinucleation and cell fusion. We have previously demonstrated that blockade of P2X7Rs on osteoclast precursors using a blocking antibody inhibited multinucleated osteoclast formation in vitro, but that P2X7R KO mice maintain the ability to form multinucleated osteoclasts. This apparent contradiction of the role the P2X7R plays in multinucleation has prompted us to examine the effect of the most commonly used and recently available P2X7R antagonists on osteoclast formation and function. When added to recombinant RANKL and M-CSF human blood monocytes cultures, all but one compound, decreased the formation and function of multinucleated TRAP-positive osteoclasts in a concentration-dependent manner. These data provide further evidence for the role of the P2X7R in the formation of functional human multinucleated osteoclasts and highlight the importance of selection of antagonists for use in long-term experiments.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 75%

The effects of P2X7 receptor antagonists on the formation and function of human osteoclasts in vitro

Agrawal

Buckley

Bowers

et al. 2010

Purinergic Signalling

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“…When these parameters were plotted as a function of the agonist concentration, they were well fit by standard sigmoidal dose-response equations (Fig. 1, C and D); half-maximal EC 50 values for time-to-onset and percent total cells blebbed were 33 Ϯ 2 M and 72 Ϯ 3 M, respectively. These values are within the range of EC 50 values (3-40 M) for membrane current, dye uptake or calcium entry in these cells under identical conditions (10,28,30) and thus indicate that the signaling pathway(s) underlying these rapid morphological changes are engaged over the same range as that for activation of the P2X 7 ion channel.…”

Section: Methodsmentioning

confidence: 87%

“…Results from the present study show that this is not the case for brief receptor activation. Whereas the physiological role(s) for the rapid, reversible actin filament rearrangements and subsequent zeosis induced by PS flip in response to brief P2X 7 receptor activation are not known, previous studies have linked activation of this receptor to cell proliferation in human lymphocytes and to cell-cell fusion in other immune cells (8,9,50,51), both processes of which require concerted cytoskeletal reorganization and regulated plasma membrane disruption. The pseudoapoptosis identified in the present study may provide a mechanism underlying P2X 7 R-generated giant cell formation at sites of inflammation or cell proliferation during tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Pseudoapoptosis Induced by Brief Activation of ATP-gated P2X7 Receptors

Mackenzie

Young

Adinolfi

et al. 2005

Journal of Biological Chemistry

154

160

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P2X 7 receptors are ATP-gated ion channels primarily expressed on antigen-presenting immune cells where they play a role in the acute inflammatory response. These ion channels couple not only to influx of cations, including calcium, but also to rapid alterations in cell morphology (membrane blebbing, phosphatidylserine exposure, microvesicle shedding). These features resemble the extranuclear events associated with end stages of apoptosis but cell death does not occur if receptor activation is brief. Here we delineate two signaling pathways underlying these apoptotic-like processes. Loss of membrane asymmetry occurs within seconds, which directly triggers cytoskeletal disruption and zeiotic membrane blebbing; this is readily reversible and requires both calcium influx through P2X 7 channels and mitochondrial calcium increase but is not associated with cytochrome c release. A slower, calcium-independent, ROCK-1-dependent cascade that does not involve rapid loss of membrane asymmetry but is associated with cytochrome c release is secondarily activated. The ROCK-1 pathway appears largely responsible for cell death, which occurs after prolonged stimulation of P2X 7 receptors. We suggest that the former mechanism underlies the reversible pseudoapoptotic events induced by brief activation of P2X 7 receptors.

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“…It is also the only P2 receptor subtype known to be strongly antagonized by oATP (11). Because oATP treatment attenuates multiple functions of monocytes and macrophages, autocrine activation of the P2X7 nucleotide receptor has been implicated in the fusion of monocytes into multinucleate giant cells (48) and in various sequellae of endotoxin activation, such as the release of arachidonic acid, NO, and IL-1␤ (5-7, 9, 20). However, oATP was originally developed as an affinity label for ATP-binding enzymes.…”

Section: Discussionmentioning

confidence: 99%

Endotoxin Activation of Macrophages Does Not Induce ATP Release and Autocrine Stimulation of P2 Nucleotide Receptors

Beigi

Dubyak

2000

The Journal of Immunology

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Receptors for extracellular nucleotides (P2, or purinergic receptors) have previously been implicated in the transduction of endotoxin signaling in macrophages. The most compelling evidence has been the observation that inhibitors of ionotropic nucleotide (P2X) receptors, including periodate-oxidized ATP (oATP), attenuate a subset of endotoxin-induced effects such as activation of NF-κB and up-regulation of inducible NO synthase. We investigated whether endotoxin induces ATP release from a murine macrophage cell line (BAC1.2F5) using sensitive on-line assays for extracellular ATP. These cells constitutively released ATP, producing steady-state extracellular concentrations of ∼1 nM when assayed as monolayers of 106 adherent cells bathed in 1 ml of medium. However, the macrophages did not release additional ATP during either acute or prolonged endotoxin stimulation. In addition, cellular ecto-ATPase activities were measured following prolonged endotoxin activation and were found not to be significantly altered. Although oATP treatment significantly attenuated the endotoxin-induced production of NO, this inhibitory effect was not reproduced when the cells were coincubated with apyrase, a highly effective ATP scavenger. These results indicate that activation of macrophages by endotoxin does not induce autocrine stimulation of P2 nucleotide receptors by endogenous ATP released to extracellular compartments. Moreover, the data suggest that the ability of oATP to interfere with endotoxin signaling is due to its interaction with molecular species other than ATP-binding P2 receptors.

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ATP receptors and giant cell formation

Cited by 42 publications

References 15 publications

The effects of P2X7 receptor antagonists on the formation and function of human osteoclasts in vitro

The effects of P2X7 receptor antagonists on the formation and function of human osteoclasts in vitro

Pseudoapoptosis Induced by Brief Activation of ATP-gated P2X7 Receptors

Endotoxin Activation of Macrophages Does Not Induce ATP Release and Autocrine Stimulation of P2 Nucleotide Receptors

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