55of experimental arthritis, probably by inhibiting iNOS (Wang et al. 2004 ). From
above results and other references regarding bacterial infection-induced iNOS in
human neutrophils (Wheel et al. 1997 ) and NO-driven angiogenesis (Lala and
Chakraborty 2001 ; Muntan and De la Mat 2010 ), we proposed that NO might be a
candidate mediator initiating synovial hyperplasia.
Owing to synovial hyperplasia resembling tumor malignancy, it can be
expected to halt the synovial hyperplasia by administering apoptosis inducers.
Indeed, treatment of the adjuvant-induced rat arthritis by phytol, an inducer of
apoptosis, blocks both acute and chronic phases of arthritis by increasing oxida-
tive stress and decreasing autoimmune responses (Hultqvist et al. 2006 ). On the
other hand, ART is also evident to induce apoptosis of tumor cells (Efferth et al.
2001 , 2003 ; Du et al. 2010 ), so it is reasonable to use ART as an antiarthritic
agent. The potential of ART in antitumor has been convinced from the finding
that ART inhibits the proliferation of fibroblast-like synoviocytes by blocking the
nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the
P13 kinase/Akt signal pathway (Motzer et al. 2008 ). ART also downregulates the
angiogenesis-related functional factors, such as HIF-1α, and vascular endothelial
growth factor (VEGF) (Hess et al. 2009 ). Besides, ART is also known to ame-
liorate the experimental arthritis in DBA/1 mice by suppressing an inflammatory
Th17 response (Yao et al. 2011 ).
The mammalian target of rapamycin (mTOR) is upregulated in several types of
cancer (Xu et al. 2007 ; He et al. 2009 ; Wang et al. 2008 ), and the mTOR inhibi-
tor RAP (sirolimus or everolimus) has been approved for treatment of advanced
renal cell carcinoma (An et al. 2009 ), refractory mantle cell lymphoma (Zhou
et al. 2010 ), and progressive advanced pancreatic neuroendocrine tumors (Pantuck
et al. 2007 ). From this, we could predict that RAP is also effective on RA. Indeed,
it has been reported that the mTOR inhibitor sirolimus induces osteoclasts and
suppresses bone resorption through inhibiting the phosphorylation of S6 protein,
S6 kinase, and 4E-BP1 in osteoclasts (Glantschnig et al. 2003 ). Other reports on
RAP’s antiarthritis have also demonstrated as follows: (1) Everolimus prevents
ovariectomy-induced bone loss in rats via inhibiting cathepsin K expression and
osteoclasts activity (Kneissel et al. 2004 ). (2) RAP decreases the articular inva-
sion by fibroblast-like synoviocytes in pristine-induced arthritis rats, resulting
from an attenuation of the phosphorylation of mTOR and substrates, p70S6K1 and
4EBP (Laragione and Gulko 2010 ). (3) Sirolimus or everolimus reduces synovial
osteoclast formation and protects against local bone erosions and cartilage loss by
downregulating digestive enzymes and enhancing osteoclast apoptosis in human
TNF-transgenic mice with a chronic inflammatory and destructive arthritis (Cejka
et al. 2010 ).
We would introduce some findings that might help to answer the questions
involving the unsolved mechanisms causing RA: what is the de novo etiological
initiator of RA? Whether such an initiator can be used to replicate RA? Are there
alternative therapeutic options targeting the pathogenic initiator?