Myeloid deletion of SIRT1 suppresses collagen-induced arthritis in mice by modulating dendritic cell maturation

The type III histone deacetylase silent information regulator 1 (SIRT1) is an enzyme that is critical for the modulation of immune and inflammatory responses. However, the data on its role in rheumatoid arthritis (RA) are limited and controversial. To better understand how SIRT1 regulates adaptive immune responses in RA, we evaluated collagen-induced arthritis (CIA) in myeloid cell-specific SIRT1 knockout (mSIRT1 KO) and wild-type (WT) mice. Arthritis severity was gauged on the basis of clinical, radiographic and pathologic scores. Compared with their WT counterparts, the mSIRT1 KO mice exhibited less severe arthritis, which was less destructive to the joints. The expression levels of inflammatory cytokines, matrix metalloproteinases and ROR-γT were also reduced in the mSIRT1 KO mice compared with the WT mice and were paralleled by reductions in the numbers of Th1 and Th17 cells and CD80- or CD86-positive dendritic cells (DCs). In addition, impaired DC maturation and decreases in the Th1/Th17 immune response were observed in the mSIRT1 KO mice. T-cell proliferation was also investigated in co-cultures with antigen-pulsed DCs. In the co-cultures, the DCs from the mSIRT1 KO mice showed decreases in T-cell proliferation and the Th1/Th17 immune response. In this study, myeloid cell-specific deletion of SIRT1 appeared to suppress CIA by modulating DC maturation. Thus, a careful investigation of DC-specific SIRT1 downregulation is needed to gauge the therapeutic utility of agents targeting SIRT1 in RA.

Inhibitory Effects for Rheumatoid Arthritis of Dietary Supplementation with Resveratrol in Collagen-induced Arthritis

OBJECTIVE: Resveratrol is well-known for its anti-inflammatory, anti-oxidant effects on several diseases. We investigated whether dietary supplementation with resveratrol may suppress joint inflammation and destruction in a mouse model of collagen-induced arthritis (CIA). METHODS: Mice were randomly divided into two groups; CIA mice with normal diet-fed and CIA mice fed a 0.05% resveratrol diet. The effect of resveratrol on arthritis was assessed by clinical scoring system. The plain radiographs of paws were obtained to evaluate the effects on preventing bone destruction. Joint inflammation, cartilage damage, and osteoclastic bone resorption were checked by staining with H&E, Safranin-O, and tartrate resistant acid phosphatase (TRAP). Levels of pro-inflammatory cytokines were checked by enzyme-linked immunosorbent assay. The level of expression of nuclear factor (NF)-kappaB was measured by electrophoretic mobility shift assay (EMSA). RESULTS: Dietary supplementation with resveratrol led to mitigated severity of arthritis compared to the normal diet group (6.7+/-0.8 vs. 2.7+/-0.6, p<0.01). Resveratrol-fed mice showed decreased bone destruction on radiograph (3.4+/-0.3 vs. 2.0+/-0.2, p<0.01), and showed significantly inhibited pathological changes (inflammation 2.0+/-0.3 vs.3.2+/-0.2, p<0.01; cartilage damage 1.5+/-0.3 vs. 3.2+/-0.2, p<0.01; pannus formation 1.4+/-0.3 vs. 3.0+/-0.3, p<0.01; erosion; 1.4+/-0.2 vs. 3.3+/-0.3, p<0.01). Generation of TRAP-positive osteoclasts was inhibited in the resveratrol-fed mice (55.3+/-12.7 vs. 3.27+/-0.8, p<0.01). Resveratrol-fed mice showed decreased levels of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6,monocyte chemoattractant protein 1, and the soluble receptor activator of NF-kappaB ligand in joint tissues and sera. Expression of NF-kappaB, measured by EMSA, was decreased in resveratrol-fed mice. CONCLUSION: Dietary supplementation with resveratrol mitigates inflammation and bone destruction in CIA mice.

COMP-Angiopoietin-1 Stimulates Synovial Proliferation but Suppresses Osteoclast by Enhancing Angiogenesis and Osteoblast Maturation in Collagen-Induced Arthritis

OBJECTIVE: Angiopoietin-1 (Ang1) is a potent angiogenic factor that can increase synovial angiogenesis and also enhance osteoblast maturation and bone formation. However, its role in rheumatoid arthritis (RA) has not been well documented. Thus, we investigated roles of Ang1 in collagen-induced arthritis (CIA). METHODS: A recombinant adenovirus carrying the gene that encodes either cartilage oligomeric matrix protein (AdCOMP)-Ang1 (a modified form of Ang1) or LacZ (AdLacZ) was injected intravenously into CIA mice. Clinical, radiological, histopathological, and immunofluorescent analyses were performed. Serum levels of receptor activators of nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) and expression of osteoblast maturation genes were analyzed. RESULTS: AdCOMP-Ang1-injected mice developed more severe inflammation than the AdLacZ-injected mice. However, there were no significant differences in cartilage damage and bone erosion. More PECAM-1-positive blood vessels were seen in the synovium of the AdCOMP-Ang1-injected mice than in those injected with AdLacZ. Interestingly, a lower number of TRAP-positive osteoclasts were observed in AdCOMP-Ang1-injected CIA mice than in the AdLacZ group when comparing sections obtained from joints showing similar synovial proliferation. The serum OPG/RANKL ratio and expression of osteoblast maturation genes, such as runt-related transcription factor 2, bone sialoprotein, type 1 collagen, osteopontin, and osterix, were significantly upregulated in the AdCOMP-Ang1 group. CONCLUSION: COMP-Ang1 facilitates arthritis onset and increases synovial inflammation, but enhances osteoblast maturation, which in turn inhibits osteoclastogenesis by increasing the OPG/RANKL ratio in CIA. Our results suggest that careful investigation is necessary to delineate the possible therapeutic use of COMP-Ang1 as an adjunctive agent, in combination with anti-inflammatory therapies, for the prevention of bone destruction in RA.