72 5 ART for Anti-inflammation
relationship between NO and SpO 2 established in our study strongly supports that
NO is a driver to hypoxia. Besides, a recent study has demonstrated that IL-17A
is a key mediator in inflammatory arthritis, and an association of hypoxia with
IL-17A expression appears to be indirect, probably through hypoxia-induced pro-
inflammatory pathways and leukocyte influx within the joint microenvironment
(Moran et al. 2011 ).
In the present study, we also found that SNP does not upregulate any hypoxia
signaling pathway genes, otherwise downregulates NOS2 gene. In contrast,
CFA/CII-CFA injection can upregulate a lot of hypoxia signaling pathway genes
including NOS2. It is possible that the activation of hypoxia pathway genes needs
the perpetual NO production, and the induction of NOS2 is the prerequisite medi-
ating hypoxia signaling activation. Nevertheless, frequent SNP injections can
upregulate both HIF-1α and VEGF. Under a hypoxic condition, HIF-1α and VEGF
were found to be upregulated, thereby initiating angiogenesis (Xu et al. 2005 ),
during which Toll-like receptor 2 promotes angiogenesis, cell adhesion, and inva-
sion (Saber et al. 2011 ). As a similar observation in the present study, serum LA
levels were found to be affected by angiogenesis progression. At first, LA levels
elevate due to NO-driven hypoxia, and then LA levels decline after angiogenesis.
It can be interpreted that hypoxia leads to enhanced glycolysis and overproduced
LA, whereas angiogenesis results in compromised hypoxia, suppressed glycolysis,
and lowered LA levels. Besides, CFA not only triggers NO production, but also
promotes 3-nitrotyrosine formation, suggesting CFA also enhances the synchro-
nous production of O 2 −. Interestingly, we noticed that the anti-3-nitrotyrosine
antibody levels are reversely proportional to the anti-CCP antibody levels.
Although anti-TNFα-based biologic therapies are approved for clinic use in
patients with RA (Biniecka et al. 2011 ), as many as 40 % RA patients are nonre-
sponders to anti-TNFα antibodies (Schett et al. 2011 ). Why is there nonresponders
to anti-TNFα? As known, NO initiates synovial angiogenesis and hyperplasia, and
leads to acute synovitis and finally to chronic arthritis. Because NO is triggered
by not only TNFα, but also IL-1β and other proinflammatory cytokines (Bakker
et al. 2009 ), inhibition of TNFα alone but not others should be partially responsive
among patients with RA. Based on such a consideration, it can be predicted that
blockage of TNFR by engineered peptides (Tang et al. 2011 ) or antisense technol-
ogies (Paquet et al. 2011 ) may also provide a restrictive protection from RA even
among responders.
The novel concept of ‘treating synovitis as tumor’ suggested by ours seems
supported by the evaluation of potential antitumor agents, ART (Zhou et al.
2007 ), RAP (Motzer et al. 2008 ; Hess et al. 2009 ; Yao et al. 2011 ), and BLA
(Zuco et al. 2002 ; Robert and Samir 2004 ), as candidate antisynovitic drugs.
Actually, ART (Wang et al. 2008 ) and RAP (Kneissel et al. 2004 ; Laragione and
Gulko 2010 ; Cejka et al. 2010 ) exhibit certain antiarthritic roles, but no docu-
ments describing BLA’s antiarthritic effects. We found that CFA-induced syno-
vitis can be considerably ameliorated by preadministration or postadministration
with ART or RAP through reversing the inflammation-triggered NO signaling
process. Pretreatment by ART or RAP can block the onset of synovitis, whereas