Methotrexate—how does it really work?

Chan, Edwin S. L.; Cronstein, Bruce N.

doi:10.1038/nrrheum.2010.5

Cited by 345 publications

(270 citation statements)

References 33 publications

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“…Since RANKL, the principal stimulus for osteoclast differentiation, is primarily expressed on osteoblasts, which have been previously shown to express A 2b receptors which affect their function [50][51][52], the most likely explanation for the observed effects of A 2b receptor ligation on osteoclastogenesis is inhibition of osteoblast-mediated stimulation of osteoclastogenesis. It is also interesting to note that it is likely that the inhibitory effects of methotrexate on osteoclast-mediated bone destruction are mediated by the higher levels of adenosine released by methotrexate-treated cells and tissues which interact with A 2A and A 3 receptors [53]. Indeed, in the adjuvant arthritis model studied by Teramachi and colleagues, the adenosine receptor antagonists theophylline and caffeine reverse the anti-inflammatory effects of methotrexate [54].…”

Section: Discussionmentioning

confidence: 99%

Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling

Cronstein

2012

Purinergic Signalling

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Adenosine is an endogenous nucleoside that modulates many physiological processes through four receptor subtypes (A 1 , A 2a , A 2b , A 3 ). Previous work from our laboratory has uncovered a critical role for adenosine A 1 receptor (A 1 R) in osteoclastogenesis both in vivo and in vitro. Our current work focuses on understanding the details of how A 1 R modulates the receptor activator of NF-κB ligand (RANKL)-induced signaling in osteoclastogenesis. Osteoclasts were generated from mouse bone marrow precursors in the presence of RANKL and macrophage-colony stimulating factor. A pharmacological antagonist of A 1 R (DPCPX) inhibited RANKL-induced osteoclast differentiation, including osteoclast-specific genes (Acp5, MMP9, β 3 Integrin, α v Integrin, and CTSK) and osteoclast-specific transcription factors such as c-fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) expression in a dose-dependent manner. DPCPX also inhibited RANKL-induced activation of NF-κB and JNK/ c-Jun but had little effect on other mitogen-activated protein kinases (p38 and Erk). Finally, immunoprecipitation analysis showed that blockade of A 1 R resulted in disruption of the association of tumor necrosis factor receptor-associated factor 6 (TRAF6) and transforming growth factor-β-activated kinase 1 (TAK1), a signaling event that is important for activation of NF-κB and JNK, suggesting the participation of adenosine/ A 1 R in early signaling of RANKL. Collectively, these data demonstrated an important role of adenosine, through A 1 R in RANKL-induced osteoclastogenesis.

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Section: Discussionmentioning

confidence: 99%

Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling

Cronstein

2012

Purinergic Signalling

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“…Notably adenosine, which can act via G s coupled GPCRs, has been suggested to synergize with TLR agonists to induce IL-10 (59). Interestingly, one of the mechanisms of action suggested for methotrexate, a commonly used drug in autoimmunity, is to elevate extracellular adenosine levels (60). In addition PDE4 inhibitors, which would promote PKA signaling in macrophages, have also generated interest as immunosuppressive agents and one such inhibitor, roflumilast, has been approved for use in some forms of chronic obstructive pulmonary disease (61).…”

Section: Discussionmentioning

confidence: 99%

PGE2 Induces Macrophage IL-10 Production and a Regulatory-like Phenotype via a Protein Kinase A–SIK–CRTC3 Pathway

MacKenzie

Clark

Naqvi

et al. 2013

The Journal of Immunology

204

196

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The polarization of macrophages into a regulatory-like phenotype and the production of IL-10 plays an important role in the resolution of inflammation. We show in this study that PGE2, in combination with LPS, is able to promote an anti-inflammatory phenotype in macrophages characterized by high expression of IL-10 and the regulatory markers SPHK1 and LIGHT via a protein kinase A–dependent pathway. Both TLR agonists and PGE2 promote the phosphorylation of the transcription factor CREB on Ser133. However, although CREB regulates IL-10 transcription, the mutation of Ser133 to Ala in the endogenous CREB gene did not prevent the ability of PGE2 to promote IL-10 transcription. Instead, we demonstrate that protein kinase A regulates the phosphorylation of salt-inducible kinase 2 on Ser343, inhibiting its ability to phosphorylate CREB-regulated transcription coactivator 3 in cells. This in turn allows CREB-regulated transcription coactivator 3 to translocate to the nucleus where it serves as a coactivator with the transcription factor CREB to induce IL-10 transcription. In line with this, we find that either genetic or pharmacological inhibition of salt-inducible kinases mimics the effect of PGE2 on IL-10 production.

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“…Besides clinical and genetic determinants, phenotypic markers (metabolites/proteins) could also be potential predictors of MTX nonresponse. MTX is a folate antagonist that uses the same transport mechanisms as folate (7). MTX, as well as food-derived folate or supplemented folates, are taken up intracellularly via solute carrier 19A1 and incorporated into the folate pathway (one-carbon metabolism).…”

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confidence: 99%

Association of Low Baseline Levels of Erythrocyte Folate With Treatment Nonresponse at Three Months in Rheumatoid Arthritis Patients Receiving Methotrexate

Rotte

Jong

Pluijm

et al. 2013

Arthritis & Rheumatism

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Objective. To investigate whether baseline concentrations of one-carbon metabolism biomarkers are associated with treatment nonresponse and adverse events in rheumatoid arthritis (RA) patients receiving methotrexate (MTX).Methods. A prospective derivation cohort (n ‫؍‬ 285) and validation cohort (n ‫؍‬ 102) of RA patients receiving MTX were studied. Concentrations of plasma homocysteine, serum vitamin B 12 , serum folate, erythrocyte vitamin B 6 , and erythrocyte folate were determined at baseline and after 3 months of treatment. Nonresponse after 3 months was assessed using the Disease Activity Score in 28 joints (DAS28) and the European League Against Rheumatism (EULAR) response criteria. Adverse events at 3 months were assessed using biochemical parameters and health status questionnaires. Analyses were corrected for baseline DAS28, age, sex, MTX dose, comedications, and presence of the methylenetetrahydrofolate reductase 677TT genotype.Results. In the derivation cohort, the mean DAS28 scores at baseline and 3 months were 4.94 and 3.12, respectively, and 78% of patients experienced adverse events. This was similar between the 2 cohorts, despite a lower MTX dose in the validation cohort. Patients with lower levels of erythrocyte folate at baseline had a higher DAS28 at 3 months in both the derivation cohort (␤ ‫؍‬ ؊0.15, P ‫؍‬ 0.037) and the validation cohort (␤ ‫؍‬ ؊0.20, P ‫؍‬ 0.048). In line with these results, lower baseline erythrocyte folate levels were linearly associated with a 3-month DAS28 of >3.2 in both cohorts (derivation cohort, P ‫؍‬ 0.049; validation cohort, P ‫؍‬ 0.021) and with nonresponse according to the EULAR criteria (derivation cohort, P ‫؍‬ 0.066; validation cohort, P ‫؍‬ 0.027). None of the other biomarkers (levels at baseline or changes over 3 months) were associated with the DAS28 or treatment nonresponse. Baseline levels of the biomarkers and changes in levels after 3 months were not associated with incidence of adverse events.Conclusion. A low baseline concentration of erythrocyte folate is associated with high disease activity and nonresponse at 3 months after the start of MTX treatment and could be used in prediction models for MTX outcome. None of the investigated one-carbon metabolism biomarkers were associated with incidence of adverse events at 3 months.

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Methotrexate—how does it really work?

Cited by 345 publications

References 33 publications

Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling

Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling

PGE2 Induces Macrophage IL-10 Production and a Regulatory-like Phenotype via a Protein Kinase A–SIK–CRTC3 Pathway

Association of Low Baseline Levels of Erythrocyte Folate With Treatment Nonresponse at Three Months in Rheumatoid Arthritis Patients Receiving Methotrexate

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