Influence of heme oxygenase 1 modulation on the progression of murine collagen-induced arthritis.
OBJECTIVE
Heme oxygenase 1 (HO-1) can be induced by inflammatory mediators as an adaptive response. The objective of the present study was to determine the consequences of HO-1 modulation in the murine collagen-induced arthritis (CIA) model.


METHODS
DBA/1J mice were treated with an inhibitor of HO-1, tin protoporphyrin IX (SnPP), or with an inducer of HO-1, cobalt protoporphyrin IX (CoPP), from day 22 to day 29 after CIA induction. The clinical evolution of disease was monitored visually. At the end of the experiment, joints were examined for histopathologic changes. Cytokine levels in paws were measured by enzyme-linked immunosorbent assay. Levels of HO-1, cyclooxygenase 2 (COX-2), and prostaglandin E2 (PGE2) were determined. Effects of treatments on the early phase of disease and after prophylactic administration were also assessed.


RESULTS
CoPP strongly induced HO-1, resulting in the inhibition of cartilage erosion accompanied by extensive fibrosis in the joint. Levels of tumor necrosis factor alpha (TNFalpha), interleukin-2 (IL-2), and IL-10 were inhibited by CoPP, whereas levels of vascular endothelial growth factor were increased. Treatment with SnPP significantly reduced the severity of CIA, with inhibition of joint inflammation and cartilage destruction. The levels of PGE2, IL-1beta, and TNFalpha were also significantly reduced by SnPP treatment, which did not modify COX-2 protein expression. SnPP was more effective than CoPP in preventing the development of CIA (prophylactic administration).


CONCLUSIONS
HO-1 is induced during CIA. Although overexpression of this protein causes some beneficial effects, strategies aimed at HO-1 overexpression cannot slow the progression of the chronic inflammatory disease, whereas treatment with SnPP, which inhibits HO-1, exerts prophylactic and therapeutic effects.
Devesa
Isabel
I
University of Valencia, Burjassot, Valencia, Spain.
Ferrándiz
Maria Luisa
ML
Terencio
María Carmen
MC
Joosten
Leo A B
LA
van den Berg
Wim B
WB
Alcaraz
María José
MJ
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D002908:Chronic Disease; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051547:Heme Oxygenase-1; D007596:Joints / Q000201:enzymology / Q000473:pathology; D008565:Membrane Proteins; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D008811:Mice, Inbred DBA; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D008665:Metalloporphyrins; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases