Bcl-2 Expression in Synovial Fibroblasts Is Essential for Maintaining Mitochondrial Homeostasis and Cell Viability

Perlman, Harris; Georganas, Constantinos; Pagliari, Lisa J.; Koch, Alisa E.; Haines, Kenneth; Pope, Richard M.

doi:10.4049/jimmunol.164.10.5227

Cited by 115 publications

(76 citation statements)

References 64 publications

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“…The intrinsic difference in the activation of multiple intracellular signal transduction mechanisms such as ERK may account for the higher induction of IL-6, CXCL8 and MMP-1 from RA-FLS compared to normal FLS. [42][43][44] IL-6 and other chemokines in synovial fluid and synovium of RA patients have also been reported to be significantly elevated compared with control subjects. 9,28 Uric acid crystals have been shown to activate the MAPK (p38 MAPK, JNK and ERK1/2) signaling pathway in T-cell lines 20 and also activate the ERK signaling pathway in fibroblasts, 45 but the signaling pathways downstream of uric acid crystals in FLS have not been reported.…”

Section: Discussionmentioning

confidence: 99%

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

et al. 2011

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Hyperuricemia-mediated uric acid crystal formation may cause joint inflammation and provoke the destruction of joints through the activation of inflammasome-mediated innate immune responses. However, the immunopathological effects and underlying intracellular regulatory mechanisms of uric acid crystal-mediated activation of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) have not been elucidated. Therefore, we investigated the in vitro effects of monosodium urate crystals, alone or in combination with the inflammatory cytokines tumor-necrosis factor (TNF)-a or interleukin (IL)-1b, on the activation of human FLS from RA patients and normal control subjects and the underlying intracellular signaling mechanisms of treatment with these crystals. Monosodium urate crystals were able to significantly increase the release of the inflammatory cytokine IL-6, the chemokine CXCL8 and the matrix metalloproteinase (MMP)-1 from both normal and RA-FLS (all P,0.05). Moreover, the additive or synergistic effect on the release of IL-6, CXCL8 and MMP-1 from both normal and RA-FLS was observed following the combined treatment with monosodium urate crystals and TNF-a or IL-1b. Further experiments showed that the release of the measured inflammatory cytokine, chemokine and MMP-1 stimulated by monosodium urate crystals were differentially regulated by the intracellular activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase pathways but not the p38 mitogen-activated protein kinase pathway. Our results therefore provide a new insight into the uric acid crystal-activated immunopathological mechanisms mediated by distinct intracellular signal transduction pathways leading to joint inflammation in RA. Keywords: cytokines; fibroblast-like synoviocytes; rheumatoid arthritis; signal transduction; uric acid INTRODUCTION Arthritis is the most common cause of joint pain and physical disability in developed countries and worldwide. 1 Gout is an acute inflammatory arthritis whose incidence has increased over the past decade, which is characterized by elevated serum urate concentrations and recurrent attacks by intra-articular uric acid crystal deposition. 2 Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis with 1% prevalence in industrialized countries, which is characterized by cytokinemediated inflammation of the synovium and destruction of cartilage and bone. 3 Uric acid crystal-mediated gouty attacks have also been observed in patients with RA. 4,5 Fibroblast-like synoviocytes (FLS) are resident mesenchymal cells in synovial joints that play crucial roles in both joint damage and the propagation of inflammation in arthritic diseases. 6 The ability of FLS to erode cartilage is a multistep process that includes the attachment of FLS onto cartilage and the synthesis of matrix metalloproteinases (MMPs) such as MMP-1. 7 Additionally, FLS secrete receptor activator of nuclear factor-kB ligand, which can attract macrophages from the vasculature, stimulate the differentiation of vascular-and tiss...

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Section: Discussionmentioning

confidence: 99%

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

et al. 2011

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“…In RA synovium, despite the expression of several death receptor ligands (such as tumor necrosis factor ␣ [TNF␣] and Fas ligand [FasL]) by infiltrating cells in close proximity to FLS, the net effect is toward hyperplasia rather than apoptotic elimination of FLS (5-7). Rheumatoid FLS display increased expression of several antiapoptotic proteins, but their specific function in these cells has not been completely elucidated (8)(9)(10). Whether cultured RA FLS are different from osteoarthritis (OA) FLS regarding susceptibility to Fasmediated apoptosis remains controversial (11)(12)(13).…”

Section: Objective Hyperplasia Of Fibroblast-like Synoviocytes (Fls)mentioning

confidence: 99%

Down‐regulation of FLIP sensitizes rheumatoid synovial fibroblasts to Fas‐mediated apoptosis

Palao¹,

Santiago²,

Galindo³

et al. 2004

Arthritis & Rheumatism

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“…A pathologist blinded to the study (G.K.H.) determined the number of p21-positive/CD68-negative cells in the synovial lining and the medium synovial lining thickness by analyzing multiple sections to avoid sampling error for each tissue as previously described (21)(22)(23)(24). Fifty cells per area were analyzed for RA synovial tissue sections (n ϭ 4), and 20 cells/area were examined for OA synovial tissue sections (n ϭ 4).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…p21 was introduced into cells using replication-defective E1 Ϫ E3 Ϫ adenovirus vector (Ad-p21), which readily and uniformly infects synovial fibroblasts (22). Ad-␤-Gal was used as a negative control.…”

Section: Ad-p21 Induces Cell Cycle Arrest In Ra Synovial Fibroblastsmentioning

confidence: 99%

“…Synoviocytes were used from passages 3-9 in these experiments. A homogenous population was determined by flow cytometry (Ͻ1% CD11b, Ͻ1% phagocytic, and Ͻ1% Fc␥RII receptor positive) (22,25,28,29). Whole-cell extracts were prepared from serum-starved quiescent (0.5% FBS) and serum-stimulated (10% FBS) RA and OA synovial fibroblasts (SF).…”

Section: Expression Of P21 Is Reduced In Ramentioning

confidence: 99%

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IL-6 and Matrix Metalloproteinase-1 Are Regulated by the Cyclin-Dependent Kinase Inhibitor p21 in Synovial Fibroblasts

Perlman

Bradley

Liu

et al. 2003

The Journal of Immunology

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During the pathogenesis of rheumatoid arthritis (RA), the synovial fibroblasts increase in number and produce proinflammatory cytokines and matrix metalloproteinases (MMPs) that function to promote inflammation and joint destruction. Recent investigations have suggested that cell cycle activity and inflammation may be linked. However, little is known about the mechanisms responsible for the coordinate regulation of proliferation and the expression of proinflammatory molecules in RA synovial fibroblasts. Here, we demonstrate a 50 ± 10% decrease in the expression of p21, a cell cycle inhibitor, in the synovial fibroblast population from RA compared with osteoarthritis (OA) synovial tissue. Moreover, p21 positivity in the synovial fibroblasts inversely correlates with medium synovial lining thickness (r = −0.76; p < 0.02). The expression of p21 is also reduced in isolated RA synovial fibroblasts compared with OA synovial fibroblasts. Adenovirus-mediated delivery of p21 (Ad-p21) arrests both RA and OA synovial fibroblasts in the G0/G1 phase of the cell cycle without inducing cytotoxicity. However, the spontaneous production of IL-6 and MMP-1 is suppressed only in the Ad-p21-infected RA synovial fibroblasts, indicating a novel role for p21 in RA. Analyses of p21-deficient mouse synovial fibroblasts reveal a 100-fold increase in IL-6 protein and enhance IL-6 and MMP-3 mRNA. Restoration of p21, but not overexpression of Rb, which also induces G0/G1 cell cycle arrest, decreases IL-6 synthesis in p21-null synovial fibroblasts. Furthermore, in RA synovial fibroblasts the ectopic expression of p21 reduces activation of the AP-1 transcription factor. Additionally, p21-null synovial fibroblasts display enhanced activation of AP-1 compared with wild-type synovial fibroblasts. These data suggest that alterations in p21 expression may activate AP-1 leading to enhanced proinflammatory cytokine and MMP production and development of autoimmune disease.

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Bcl-2 Expression in Synovial Fibroblasts Is Essential for Maintaining Mitochondrial Homeostasis and Cell Viability

Cited by 115 publications

References 64 publications

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

Down‐regulation of FLIP sensitizes rheumatoid synovial fibroblasts to Fas‐mediated apoptosis

IL-6 and Matrix Metalloproteinase-1 Are Regulated by the Cyclin-Dependent Kinase Inhibitor p21 in Synovial Fibroblasts

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