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


CONCLUSIONS
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.
Getting
Stephen J
SJ
Immunopharmacology Unit, The William Harvey Research Institute, St Bartholomew's/Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK.
Christian
Helen C
HC
Flower
Roderick J
RJ
Perretti
Mauro
M
D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000818:Animals; D015210:Arthritis, Gouty / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D004195:Disease Models, Animal; D007719:Knee Joint / Q000166:cytology / Q000276:immunology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin / Q000378:metabolism*; D015203:Reproducibility of Results; D014527:Uric Acid; D019825:gamma-MSH / Q000494:pharmacology
D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin; D019825:gamma-MSH; D014527:Uric Acid; D000324:Adrenocorticotropic Hormone