Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: A mechanism for methotrexate-induced nodulosis in rheumatoid arthritis

Merrill, Joan T.; Shen, Charles; Schreibman, David; Coffey, Dan; Zakharenko, Olga; Fisher, Robert C.; Lahita, Robert G.; Salmon, Jane E.; Cronstein, Bruce N.

doi:10.1002/art.16

Cited by 35 publications

(44 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The biological effects of extracellular adenosine are mediated by purinergic receptors of the P1 subtype, further subdivided into 4 subfamilies: A1, A2A, A2B, and A3 (27). It has been previously suggested that A1 receptors are involved in multinucleation at foci of nodulosis in patients with rheumatoid arthritis (28). However, we found very little expression of this receptor subtype by RT-PCR, whether in quiescent or M-CSF/ RANKL-stimulated monocytes (Fig.…”

Section: Resultsmentioning

confidence: 57%

See 1 more Smart Citation

P2X7 receptor drives osteoclast fusion by increasing the extracellular adenosine concentration

et al. 2011

View full text Add to dashboard Cite

Defects in bone homeostasis are a major health problem. Osteoclast differentiation and activation have a crucial role in bone remodeling in health and disease. Osteoclasts are bone-resorbing cells derived from mononuclear phagocyte progenitors. The key event in osteoclast formation is fusion of mononucleate precursors to form mature multinucleated osteclasts. Here we provide evidence of an absolute requirement for the P2X7 receptor, ATP release, and adenosine signaling in human osteoclast formation, as shown by the following findings: macrophage-colony stimulating factor/receptor activator for nuclear factor-κB ligand (M-CSF/RANKL)-stimulated fusion of human monocytes is fully prevented by an anti-P2X7 mAb, by specific P2X7 pharmacological antagonists, or by inhibition of CD39/NTPDase; fusion-competent monocytes release ATP via the P2X7 receptor; accelerated degradation of released ATP by addition of either apyrase or hexokinase strongly increases fusion; removal of extracellular adenosine by adenosine deaminase blocks, while addition of exogenous adenosine strongly potentiates, fusion; and pharmacologic stimulation of the adenosine A2A receptor increases, while selective A2A blockade inhibits, fusion. These results show that the purinergic axis plays a crucial and as yet undescribed role in osteoclast formation and reconcile previous evidence advocating a key role for either ATP or adenosine receptors in multinucleated giant cell formation.

show abstract

Section: Resultsmentioning

confidence: 57%

“…In our view, these data identify the A2A receptor as the P1 receptor subtype involved in osteoclast fusion. Discrepancy with the findings by Cronstein and coworkers (28,43) might be due at least partially to species difference, as these researchers used mouse cells.…”

Section: Discussionmentioning

confidence: 66%

P2X7 receptor drives osteoclast fusion by increasing the extracellular adenosine concentration

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Previous studies have demonstrated that A 1 Rs play an important role in the formation of multinuclear giant cells from human peripheral blood monocytes (10). To determine whether they play a similar role in osteoclast formation, we compared the capacity of BMMs from WT and adenosine A 1 KO mice to form multinucleated osteoclasts in response to RANKL and CSF-1 in vitro.…”

Section: Osteoclast Precursors From Adenosine a 1 Ko Mice Have Reducementioning

confidence: 99%

“…Four subtypes are currently recognized: A 1 , A 2A , A 2B , and A 3 receptors, which are present in virtually every tissue (9). We have previously reported that, among other effects, adenosine A 1 receptor (A 1 R) stimulation promotes multinucleated giant cell formation by human peripheral blood monocytes (10). Moreover, we have found that deletion or blockade of adenosine A 1 Rs leads to increased bone density and prevents ovariectomy-induced bone loss without affecting bone formation (11).…”

mentioning

confidence: 99%

Adenosine A₁receptors (A₁Rs) play a critical role in osteoclast formation and function

et al. 2010

Self Cite

View full text Add to dashboard Cite

Adenosine regulates a wide variety of physiological processes via interaction with one or more G-protein-coupled receptors (A(1)R, A(2A)R, A(2B)R, and A(3)R). Because A(1)R occupancy promotes fusion of human monocytes to form giant cells in vitro, we determined whether A(1)R occupancy similarly promotes osteoclast function and formation. Bone marrow cells (BMCs) were harvested from C57Bl/6 female mice or A(1)R-knockout mice and their wild-type (WT) littermates and differentiated into osteoclasts in the presence of colony stimulating factor-1 and receptor activator of NF-kappaB ligand in the presence or absence of the A(1)R antagonist 1,3-dipropyl-8-cyclopentyl xanthine (DPCPX). Osteoclast morphology was analyzed in tartrate-resistant acid phosphatase or F-actin-stained samples, and bone resorption was evaluated by toluidine blue staining of dentin. BMCs from A(1)R-knockout mice form fewer osteoclasts than BMCs from WT mice, and the A(1)R antagonist DPCPX inhibits osteoclast formation (IC(50)=1 nM), with altered morphology and reduced ability to resorb bone. A(1)R blockade increased ubiquitination and degradation of TRAF6 in RAW264.7 cells induced to differentiate into osteoclasts. These studies suggest a critical role for adenosine in bone homeostasis via interaction with adenosine A(1)R and further suggest that A(1)R may be a novel pharmacologic target to prevent the bone loss associated with inflammatory diseases and menopause.

show abstract

“…One study used an ingenious in vitro system to investigate a proposed mechanism for methotrexate-induced accelerated nodulosis. 9 Methotrexate's antiinflammatory effects may be due in part to the increase in adenosine binding to receptors. Two adenosine receptors (A1 and A2) were observed in cultured monocytes.…”

Section: In Vitro Evidencementioning

confidence: 99%

A Review of Methotrexate‐Induced Accelerated Nodulosis

Patatanian

Thompson

2002

Pharmacotherapy

View full text Add to dashboard Cite

show abstract

Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: A mechanism for methotrexate-induced nodulosis in rheumatoid arthritis

Cited by 35 publications

References 19 publications

P2X7 receptor drives osteoclast fusion by increasing the extracellular adenosine concentration

P2X7 receptor drives osteoclast fusion by increasing the extracellular adenosine concentration

Adenosine A₁receptors (A₁Rs) play a critical role in osteoclast formation and function

A Review of Methotrexate‐Induced Accelerated Nodulosis

Contact Info

Product

Resources

About

Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: A mechanism for methotrexate-induced nodulosis in rheumatoid arthritis

Cited by 35 publications

References 19 publications

P2X7 receptor drives osteoclast fusion by increasing the extracellular adenosine concentration

P2X7 receptor drives osteoclast fusion by increasing the extracellular adenosine concentration

Adenosine A1receptors (A1Rs) play a critical role in osteoclast formation and function

A Review of Methotrexate‐Induced Accelerated Nodulosis

Contact Info

Product

Resources

About

Adenosine A₁receptors (A₁Rs) play a critical role in osteoclast formation and function