SAT0046 Regulation of Sirt1 Maybe A Pioneering Strategy in Treatment of Rheumatoid Arthritis
Authors: S.Y. Lee, W.T. Chung, S.W. Lee, S.Y. Park
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Monocyte maybe a dual role in rheumatoid arthritis (RA) development, because of differentiation to macrophages in joint and osteoclasts in bone so, blocking of monocyte differentiation maybe effective target in RA treatment. <h3>Objectives</h3> In this study, we interrupted monocyte differentiation to macrophages and osteoclasts via SIRT1 blocking and proposed pioneering treatment of RA. <h3>Methods</h3> In this study, monocytes from synovial fluid of RA patients (RAMCs), THP-1 monocytes, bone marrow–derived monocytes (BMDCs) from mice and RAW 264.7 cells were studied. PMA-induced expression of macrophages surface markers (CD11b, CD14 and CD36), proinflammatory cytokines (TNF-α, IL-1β and IL-6) secretion and differentiation of BMDCs from SIRT1 TG mice were measured after administration of resveratrol, which was reversed by sirtinol, an inhibitor of sirtuin proteins. In addition, RANKL [receptor activator of nuclear factor kappa B (RANK) ligand]-induced RANK expression in bone marrow–derived monocyte/macrophage precursors (BMMs) and RAW 264.7 cells were treated cilostazol and this was blocked by sirtinol (a SIRT1 inhibitor) in vitro and in a mouse model of collagen-induced arthritis (CIA). <h3>Results</h3> PMA-induced expression of macrophages surface markers (CD11b, CD14 and CD36) and proinflammatory cytokines (TNF-α, IL-1β and IL-6) secretion was inhibited by resveratrol. BMDCs from SIRT1 TG mice were inhibited differentiation by PMA than control BMDCs from C57BL/6 mice. These effects were associated with decrease in proinflammatory cytokines (TNF-α, IL-1β and IL-6) secreation by decreasing mRNA expression in BMDCs from SIRT1 TG mice. Further, resveratrol suppressed the PMA-induced PU.1 activation, which is critical transcription factor for macrophages differentiation. SIRT1 inhibits monocytes to macrophages differentiation through the down-regulates PU.1 activity and cilostazol elevated SIRT1 mRNA and protein levels in 12–24 h and increased SIRT1 activity, and these effects were also inhibited by sirtinol. Furthermore, the RANKL-induced nuclear expression of PU.1 was suppressed by cilostazol. In addition, marked RANKL-induced RANK immunofluorescence staining in Raw264.7 cells was strongly attenuated by cilostazol and by rSIRT1, and these attenuations were prevented by sirtinol. Extensive RANK staining of knee synovial tissues in a mouse model of collagen-induced arthritis (CIA) was also markedly reduced by cilostazol (30 mg/kg/day), and in BMMs both RANKL- and M-CSF-induced differentiation of BMMs to multinucleated TRAP<sup>+</sup> giant cells and resorption pit formation were inhibited by cilostazol in association with a decrease in TRAP (a marker enzyme of osteoclasts) activity. <h3>Conclusions</h3> SIRT1 have dual a role in anti-osteoclast formation BMMs of RA bone and inhibiting differentiation monocyte to macrophage in RA synovium. so, SIRT1 maybe a perfect strategy for RA treatment. <h3>References</h3> Scott DL, Wolfe F, Huizinga TWJ (2010) Rheumatoid arthritis. Lancet 376(9746):1094–1108 Scott DL, Wolfe F, Huizinga TWJ (2010) Rheumatoid arthritis.Lancet 376(9746):1094–1108. <h3>Disclosure of Interest</h3> None declared