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Abstract Number: 2569

Regulation of SIRT1 Maybe a Perfect Strategy in Treatment of Rheumatoid Arthritis

Sang-Yeob Lee1, Sung Won Lee2, Won Tae Chung2, Jae Ho Bae3, So Youn Park4 and Chi Dae Kim4, 1Division of Rheumatology, Department of Internal Medicine, Dong-A University College of Medicine, Busan, South Korea, 2Rheumatology, Dong-A University Hospital, Busan, South Korea, 3Biochemistry, Pusan national university, Yong -San, South Korea, 4Medical Research Center for Ischemic Tissue Regeneration, Pusan national university, Yong -San, South Korea

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Macrophage, monocytes, osteoclasts, rheumatoid arthritis (RA) and synovial cells, synovial fluid

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Session Information

Date: Tuesday, November 10, 2015

Title: Rheumatoid Arthritis - Animal Models Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Monocyte may differentiate to osteoclasts in bone and macrophages in joint. so, blocking of monocyte differentiation maybe effective target in RA (rheumatoid arthritis) treatment. in this study, we interrupted monocyte differentiation via SIRT1 and proposed potential strategy in 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. Expression of macrophages surface markers (CD11b, CD14 and CD36) were analysis by real-time PCR. TNF-α, IL-1β and IL-6 levels were measured in the conditioned medium by ELISA. The effects of SIRT1 on osteoclast formation were detected TRAP activity and pit formation. 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 measured using western blot. Anti-arthritic effects of SIRT1were evaluated in CIA mice.

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, SIRT1 activator in RAMCs. 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 activity and expression were elevated by cilostazol. Cilostazol 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, a SIRT1 inhibitor. Furthermore, the RANKL-induced nuclear expression of PU.1 was suppressed by cilostazol, a SIRT1 activator. 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.

Conclusion: SIRT1 have dual a role in anti-osteoclast formation BMMs of RA bone and inhibiting differentiation monocyte to macrophage in RA synovium. so, regulation of SIRT1 maybe a potential strategy for perfect RA treatment.


Disclosure: S. Y. Lee, None; S. W. Lee, None; W. T. Chung, None; J. H. Bae, None; S. Y. Park, None; C. D. Kim, None.

To cite this abstract in AMA style:

Lee SY, Lee SW, Chung WT, Bae JH, Park SY, Kim CD. Regulation of SIRT1 Maybe a Perfect Strategy in Treatment of Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/regulation-of-sirt1-maybe-a-perfect-strategy-in-treatment-of-rheumatoid-arthritis/. Accessed .
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