Pharmacologic induction of heme oxygenase 1 reduces acute inflammatory arthritis in mice.
OBJECTIVE
To determine the consequences of pharmacologic up-regulation of heme oxygenase 1 (HO-1), and inhibition of HO-1 by injection of an anti-HO-1 small interfering RNA (siRNA), in vivo in the acute phase of a mouse model of nonautoimmune arthritis.


METHODS
In the K/BxN mouse serum transfer model, which mimics human inflammatory arthritis without lymphocyte influence, HO-1 was up-regulated by intraperitoneal injection of cobalt protoporphyrin IX (CoPP), a potent pharmacologic inducer, and was inhibited using a specific siRNA. The clinical progress of arthritis was monitored by measurement of paw thickness. Interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNFalpha), serum antioxidant, and nitric oxide (NO) levels, prostaglandin E(2) (PGE(2)) production, and matrix metalloproteinase 9 (MMP-9) activity were measured in serum. At the end of the experiments, joints were examined for immunohistopathologic changes.


RESULTS
Intraperitoneal injection of CoPP alleviated disease symptoms, such as joint swelling, cartilage degradation, and proliferation of inflammatory tissue in joints, in the acute phase of inflammatory arthritis. The CoPP-induced expression of HO-1 in the joints and liver was associated with marked decreases in IL-1beta, IL-6, and TNFalpha levels, PGE(2) secretion, and MMP-9 activity in serum, and with a marked increase in systemic antioxidant activity. In contrast, NO production in serum and inducible NO synthase expression in chondrocytes were not affected by HO-1 induction. Specific inhibition of HO-1 by in vivo delivery of anti-HO-1 siRNA repressed the protective effects.


CONCLUSIONS
Our data provide the first evidence that pharmacologically induced up-regulation of HO-1 triggers a robust protective antiinflammatory response in a model of nonautoimmune arthritis in mice. This suggests that exogenously induced HO-1 may have potential as therapy in the acute phase of inflammatory arthritis in humans.
INSERM U 747, and Université Paris Descartes, 45 Rue des Saintes Pères, 75006 Paris, France.
Mourad
M
Benallaoua
Mathias
M
François
Frédéric
F
Batteux
Natacha
N
Thelier
John Y-J
JY
Shyy
Catherine
C
Fitting
Lydia
L
Tsagris
Jorge
J
Boczkowski
Jean-François
JF
Savouret
Marie-Thérèse
MT
Corvol
Serge
S
Poiraudeau
François
F
Rannou
D000818:Animals; D001169:Arthritis, Experimental / Q000097:blood / Q000201:enzymology* / Q000628:therapy*; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology; D007274:Injections, Intraperitoneal; D007596:Joints / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011524:Protoporphyrins / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015854:Up-Regulation
D015415:Biomarkers; D004791:Enzyme Inhibitors; D011524:Protoporphyrins; D034741:RNA, Small Interfering; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1