CD40 ligation of rheumatoid synovial fibroblasts regulates RANKL‐medicated osteoclastogenesis: Evidence of NF‐κB–dependent, CD40‐mediated bone destruction in rheumatoid arthritis

Lee, Hak Yong; Jeon, Hyun Sun; Song, Eun Kyung; Han, Myung‐Kwan; Park, Sung Il; Lee, Sang Il; Yun, Hae-Eun; Kim, Jung Ryul; Kim, Jong‐Suk; Lee, Yong Chul; Kim, Sung Il; Kim, Hang Rae; Choi, Jin Young; Kang, Insoo; Kim, Ho Youn; Yoo, Wan Hee

doi:10.1002/art.21873

Cited by 77 publications

(49 citation statements)

References 48 publications

(48 reference statements)

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“…In particular, several previous studies in RA as well as SpA, but not PsA (10), were able to detect RANKL expression only in infiltrating T lymphocytes, although it is well documented that this factor is also expressed by fibroblastlike synoviocytes (9,27).…”

Section: Discussionmentioning

confidence: 94%

“…Therefore, major questions are as follows: what drives the expression of these factors during active synovitis, and how can this be modulated? In vitro, RANKL is expressed by activated but not resting T cells and by synovial fibroblasts after stimulation by inflammatory cytokines such as TNF␣, interleukin-1␤ (IL-1␤), and IL-17 (28), by CD40 ligand (27), as well as by Toll-like receptor 2 (TLR-2) and TLR-4 ligands (31). Moreover, synovial RANKL expression in vivo was suggested to be higher in active versus nonactive RA (11).…”

Section: Discussionmentioning

confidence: 99%

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The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation

Vandooren

Cantaert

Noordenbos

et al. 2008

Arthritis & Rheumatism

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Objective. Spondylarthritis (SpA) and rheumatoid arthritis (RA) have different patterns of bone damage, with more pronounced bone erosions in RA. The RANK/RANKL/osteoprotegerin (OPG) system plays a central role in bone resorption by promoting the maturation and activation of osteoclasts. To assess the potential role of this system in the distinct bone phenotype, we studied the synovial expression of these mediators in SpA and RA peripheral synovitis.Methods. Synovial biopsy specimens were obtained from the actively inflamed peripheral joints of 35 patients with SpA and 19 patients with RA. Paired synovial biopsy samples were obtained from 24 patients with SpA after tumor necrosis factor ␣ (TNF␣) blockade. Synovial tissue sections were immunostained for RANKL, OPG, RANK, and TRAP and assessed by semiquantitative scoring and digital image analysis.Results. After extensive validation of the reactivity and specificity of the antibodies, we demonstrated the abundant expression of RANKL and OPG in SpA synovitis. RANKL was expressed by both fibroblast-like synoviocytes and sublining T lymphocytes. RANKpositive osteoclast precursors but no mature TRAPpositive osteoclasts were present in the inflamed tissue. The expression of these mediators was not different between patients with nonpsoriatic SpA, patients with psoriatic SpA, and patients with RA, was not related to the degree of systemic or local inflammation, and was not significantly modulated by highly effective treatment with TNF␣ blockers. Only the subset of patients with the best systemic response to TNF␣ blockade had decreased RANKL expression in the intimal lining layer.Conclusion. The relative protection against bone erosions in SpA cannot be explained by qualitative or quantitative differences in the synovial expression of RANKL, OPG, and RANK. The abundant expression of these factors in SpA peripheral synovitis is largely disconnected from systemic and local inflammation.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation

Vandooren

Cantaert

Noordenbos

et al. 2008

Arthritis & Rheumatism

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“…The cells were collected by centrifugation and the pellets were lysed in RIPA lysis buffer containing protease inhibitor cocktail for 30 min on ice. To determine the cytoplasmic IkB, cytoplasmic extracts were prepared (Lee et al, 2006). To analyze NF-kB (p65), nuclear extract was prepared using a previously described method (Lee et al, 2006).…”

Section: Western Blottingmentioning

confidence: 99%

“…To determine the cytoplasmic IkB, cytoplasmic extracts were prepared (Lee et al, 2006). To analyze NF-kB (p65), nuclear extract was prepared using a previously described method (Lee et al, 2006). Protein concentration was determined by Bio-Rad protein assay kit (BioRad Laboratories, USA).…”

Section: Western Blottingmentioning

confidence: 99%

Fisetin, a dietary flavonoid induces apoptosis via modulating the MAPK and PI3K/Akt signalling pathways in human osteosarcoma (U-2 OS) cells

Huang

et al. 2015

Bangladesh J Pharmacol

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Human osteosarcoma is the most prevalent primary malignant bone tumor with high frequency of invasion and metastasis. Strong resistance coupled with toxicity of the currently available chemotherapeutic drugs poses challenge in treatment. The study aimed to investigate if fisetin, a dietary flavonoid induced apoptosis in human osteosarcoma (U-2 OS) cells. Fisetin at 20-100 µM effectively reduced the viability of OS cells, and induced apoptosis by significantly inducing the expression of caspases (Caspases-3,-8 and -9) and proapoptotic proteins (Bax and Bad) with subsequent down-regulation of Bcl-xL and Bcl-2. While fisetin inhibited PI3K/Akt pathway and ERK1/2, it caused enhanced expressions of p-JNK, p-c-Jun and p-p38. Fisetin-induced ROS generation and decrease in mitochondrial membrane potential would have also contributed to rise in apoptotic cell counts. The observations suggest that fisetin was able to effectively induce apoptosis of U-2 OS cells through ROS generation and modulation of MAPK and PI3K/Akt signalling cascades. Article Info

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“…Isolated SFs from RA patient express both type of receptor, CD40 and CD154 (28). A recent study demonstrates that the direct interaction of T cells and RA-SF via CD40/CD154 induces the expression of RANKL, a key regulator of osteoclastogenesis (29). Furthermore, other cell types such as dendritic, endothelial, epithelial, and NK cells express CD154 (30), and thus, even in the absence of T cells, joint destruction in the LS48-SCID-mouse model can also be induced by CD40 ligation.…”

Section: Original Articlementioning

confidence: 99%

Characterization of fibroblasts responsible for cartilage destruction in arthritis

et al. 2008

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In the pathogenesis of rheumatoid arthritis (RA), synovial fibroblasts (SF) play a key role as they secrete distinct patterns of cytokines and express variable levels of costimulatory and adhesion molecules. The murine fibroblast cell line LS48 has been shown to be invasive in the cartilage destruction models in vivo and in vitro. The purpose of this study was to examine in detail the LS48 phenotype, to obtain a better understanding of the SF-mediated cartilage destruction in RA. The destructive fibroblasts line LS48 and the nondestructive 3T3 cells were cultured and characterized with slide-based and flow cytometry, using antibodies against several adhesion molecules, immunological acting molecules, and marker proteins. The invasive LS48 fibroblasts are characterized by significantly higher expression of adhesion molecules such as CD47 (IAP), CD51 (integrin aV), CD61 (GPIIIa), and CD147 (EMMPRIN), and immunological acting molecules such as CD40 (Bp50), CD55 (DAF), and TLR-2. The results from the slide-based and flow cytometry analyses were exactly the same, except for the selected CD147 and TLR-2. This study demonstrated that the destructive fibroblast cell line LS48 has the characteristics of RA SFs. The high expression of specific costimulatory and adhesion molecules underlines the aberrant phenotype of these cells when compared with noninvasive fibroblasts. Furthermore, slide-based and flow cytometry complement each other in fibroblast phenotyping. Overall, this study shows that LS48 is an excellent tool to gain a deeper understanding of SF in RA. '

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CD40 ligation of rheumatoid synovial fibroblasts regulates RANKL‐medicated osteoclastogenesis: Evidence of NF‐κB–dependent, CD40‐mediated bone destruction in rheumatoid arthritis

Cited by 77 publications

References 48 publications

The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation

The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation

Fisetin, a dietary flavonoid induces apoptosis via modulating the MAPK and PI3K/Akt signalling pathways in human osteosarcoma (U-2 OS) cells

Characterization of fibroblasts responsible for cartilage destruction in arthritis

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