Background 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.
Objectives In this study, we interrupted monocyte differentiation to macrophages and osteoclasts via SIRT1 blocking and proposed pioneering treatment of RA.
Methods 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).
Results 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+ giant cells and resorption pit formation were inhibited by cilostazol in association with a decrease in TRAP (a marker enzyme of osteoclasts) activity.
Conclusions 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.
Scott DL, Wolfe F, Huizinga TWJ (2010) Rheumatoid arthritis.
Scott DL, Wolfe F, Huizinga TWJ (2010) Rheumatoid arthritis.Lancet 376(9746):1094–1108.
Disclosure of Interest None declared