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Arthritis Rheum. 2002 Oct;46(10):2765-75.

Activation of melanocortin type 3 receptor as a molecular mechanism for adrenocorticotropic hormone efficacy in gouty arthritis.

Author information

1
Immunopharmacology Unit, The William Harvey Research Institute, St Bartholomew's/Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK.

Abstract

OBJECTIVE:

To test the hypothesis that local activation of melanocortin receptor(s) by adrenocorticotropic hormone (ACTH) could be responsible, at least in part, for its efficacy in human gouty arthritis.

METHODS:

Monosodium urate monohydrate (MSU) crystals were administered into rat knee joints either alone or with ACTH or a selective melanocortin type 3 receptor (MC3-R) agonist. Neutrophil migration, arthritis score, increases in joint size, and cytokine levels were measured over time. MC3-R expression on rat knee joint macrophages was monitored by electron microscopy and intracellular accumulation of cyclic adenosine monophosphate.

RESULTS:

MSU crystals produced a knee joint inflammation that was time dependent and was characterized by cell influx and cytokine release that was sensitive to treatment with classic anti-arthritic drugs (indomethacin, colchicine, dexamethasone). Local, but not systemic, ACTH had an antiinflammatory effect in normal rats, a dose that did not alter circulating corticosterone (5 microg). This treatment was also effective in adrenalectomized rats. Rat knee joint macrophages expressed functional MC3-R. The MC3-R antagonist (SHU9119, 10 microg) blocked ACTH antiinflammatory actions, whereas antiinflammatory activity was retained with a selective MC3-R agonist (gamma(2)-melanocyte-stimulating hormone).

CONCLUSION:

This research provides evidence for a separate mechanism of action of ACTH in experimental gouty arthritis and points to a novel antiinflammatory target (selective agonists at MC3-R) for clinical management of human gouty arthritis and possibly other chronic inflammatory conditions.

PMID:
12384937
DOI:
10.1002/art.10526
[Indexed for MEDLINE]
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