Suppression of NF-κB activity by sulfasalazine is mediated by direct inhibition of IκB kinases α and β

Objective

To demonstrate the effects of disease-modifying antirheumatic drugs and antiinflammatory cytokines on human osteoclastogenesis through their effects on receptor activator of nuclear factor κB (RANK), osteoprotegerin (OPG), and RANK ligand (RANKL).



Methods

Peripheral blood mononuclear cells (PBMCs) and rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) were cocultured in the presence of macrophage colony-stimulating factor, 1,25-dihydroxyvitamin D3, and various concentrations of methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ), anti–tumor necrosis factor α monoclonal antibody (infliximab), interleukin-4 (IL-4), and IL-10. Osteoclast formation was assayed by counting cells after staining for tartrate-resistant acid phosphatase. RANKL expression in RA FLS and RANK expression in PBMCs were assayed by Western blotting, reverse transcription–polymerase chain reaction (RT-PCR), and real-time PCR. OPG expression was measured by enzyme-linked immunosorbent assay, RT-PCR, and real-time PCR in cultures of RA FLS.



Results

MTX, SSZ, infliximab, and IL-4, but not IL-10 and HCQ, each inhibited osteoclast formation in a dose-dependent manner. We observed no evidence of synergistic inhibition of osteoclast formation by IL-4 and IL-10. High doses of infliximab suppressed the expression of RANK in PBMCs. MTX, SSZ, infliximab, and IL-4 each inhibited the expression of RANKL in RA FLS in a dose-dependent manner, and also increased the secretion of OPG in RA FLS supernatants.



Conclusion

MTX, SSZ, infliximab, and IL-4 inhibit human osteoclastogenesis by modulating the interaction of RANKL, RANK, and OPG. These results are indicative of the underlying mechanisms of the antiresorptive effects of these 4 agents.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.20637

Effects of disease-modifying antirheumatic drugs and antiinflammatory cytokines on human osteoclastogenesis through interaction with receptor activator of nuclear factor κB, osteoprotegerin, and receptor activator of nuclear factor κB ligand

A target-identification strategy based on the yeast three-hybrid system and the SNAP-tag labeling technique identifies new targets for three small-molecule drugs and helps identify a new mechanism for the activity of the anti-inflammatory drug sulfasalazine involving inhibition of sepiapterin reductase.

/pdf/a-yeast-based-screen-reveals-that-sulfasalazine-inhibits-1snkw25mf8.pdf

A yeast-based screen reveals that sulfasalazine inhibits tetrahydrobiopterin biosynthesis

1 Rheumatoid arthritis (RA) is probably the most common source of treatable disability A major problem in modern rheumatology is that the mechanism(s) of action of the currently used disease-modifying antirheumatic drugs (DMARDs) remain unclear Many of these drugs entered rheumatology mainly through clinical intuition and have been used for decades 2 The former T-cell-centered paradigm of rheumatoid inflammation has given way to a model of inflammation highlighting the macrophage and its proinflammatory cytokines In particular, tumor necrosis factor alpha (TNF-alpha) has gained prominence as a central proinflammatory mediator in RA, and antibodies against TNF-alpha have been successfully used in patients with RA 3 This review will summarize the recent advances in determining the mechanisms of action of the currently used DMARDs, with particular emphasis on their effects on the induction of TNF-alpha and interleukin 1 (IL-1) in mononuclear phagocytes Although some DMARDs, such as auranofin, antimalarials and tenidap, act as inhibitors of the induction of these cytokines in monocytes or macrophages or both, other drugs, such as methotrexate, D-penicillamine and aurothiomalate, do not seem to affect either TNF-alpha or IL-1 4 The drugs' effects on proinflammatory cytokine induction are correlated to those on other macrophage responses

The mechanisms of action of disease-modifying antirheumatic drugs: A review with emphasis on macrophage signal transduction and the induction of proinflammatory cytokines

Sulfasalazine was first used for rheumatic polyarthritis in the 1940s and in the past 2 decades has become firmly established as a disease-modifying antirheumatic drug (DMARD). The drug is split by the action of bacterial azoreductases in the large intestine into sulfapyridine and mesalazine (mesalamine, 5-aminosalicylic acid), although whether the parent molecule or the sulfapyridine moiety, or both, is the active principle remains uncertain. Sulfasalazine is an effective treatment for rheumatoid arthritis (RA), producing improvements in disease parameters similar to those seen with penicillamine, hydroxychloroquine or oral or parenteral gold in comparative clinical trials. However, there are no direct comparisons of the drug with methotrexate. Most adverse events associated with sulfasalazine are minor and tend to occur within 3 months of starting therapy. A meta-analysis of studies investigating DMARD therapy, which included almost 5000 evaluable patients, concluded that sulfasalazine was close to methotrexate in terms of efficacy but was slightly less well tolerated. However, unlike sulfasalazine, many DMARDs may be unsuitable for women who are, or may become, pregnant because of their potential to cause teratogenic effects. Sulfasalazine may also offer a more rapid onset of action than other DMARDs and may slow down the radiological progression of RA. Combination therapy with other DMARDs, particularly methotrexate, appears more effective than single DMARD therapy. If the safety of these regimens is shown in large numbers of patients they are likely to become more widely used in the future. Sulfasalazine is a therapy of first choice in patients with RA and may be the DMARD of choice in women who are, or may become, pregnant.

/pdf/sulfasalazine-a-review-of-its-pharmacological-properties-and-140yv251op.pdf

Sulfasalazine. A review of its pharmacological properties and therapeutic efficacy in the treatment of rheumatoid arthritis.

A study was made of plasma and synovial fluid levels of sulphasalazine, one of its dissociation products — sulphapyridine and a metabolite of the latter — acetyl sulphapyridine in patients with rheumatoid arthritis (RA) who were in a steady state on sulphasalazine therapy. Combined sulphapyridine levels were significantly higher than those of sulphasalazine both in plasma and synovial fluid. Synovial fluid levels of both drugs correlated with their plasma levels and were generally slightly lower. Some patients accumulated sulphasalazine and sulphapyridine in the synovial fluid and the mean concentration of sulphasalazine was higher in the fluid than in the plasma. The explanation for this is uncertain. The concentration of combined sulphapyridine in synovial fluid was related to local joint inflammation and more active systemic disease. No consistent association was found between sulphasalazine levels and local or systemic activity. The higher sulphapyridine levels in synovial fluid found in this study suggest the possibility that this moiety could play a more active role in RA than it does in inflammatory bowel disease.

Plasma and synovial fluid concentrations of sulphasalazine and two of its metabolites in rheumatoid arthritis.

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Plasma and synovial fluid concentrations of sulphasalazine and two of its metabolites in rheumatoid arthritis.