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

Cited 70 time in Web of Science Cited 71 time in Scopus
Authors

Lee, Hak-Yong; Jeon, Hyun-Soon; Song, Eun-Kyung; Han, Myung-Kwan; Park, Sung-Il; Lee, Sang-Il; Yun, Hee-Jin; 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

Issue Date
2006-06
Publisher
John Wiley & Sons Inc.
Citation
Arthritis and Rheumatism, Vol.54 No.6, pp.1747-1758
Abstract
Objective. To determine whether CD40 ligation of rheumatoid arthritis synovial fibroblasts (RASFs) is able to induce RANKL expression and osteoclastogenesis in RASFs, and to identify its mechanism of action in patients with RA. Methods. CD40 of RASFs was ligated with CD40 ligand (CD40L)-transfected L cells or activated T cells. The formation of osteoclasts in cocultures of CD40-ligated RASFs and T lymphocyte-depleted peripheral blood mononuclear cells was evaluated by tartrate-resistant acid phosphatase staining, detection of calcitonin receptor, and resorption pit formation assay. The expression of NF-kappa B, I kappa B alpha, ERK-1/2, phospho-ERK1/2, p38, phospho-p38, and RANKL was examined by immunoblotting and/or semiquantitative reverse transcription-polymerase chain reaction. Results. CD40 ligation of RASFs by CD40L-transfected L cells or activated T cells induced RANKL expression and enhanced osteoclastogenesis. CD40 ligation of RASFs also induced activation of ERK-1/2, p38 MAPK, and NF-kappa B and up-regulation of CD40 ligation-induced RANKL expression, whereas osteoclastogenesis was reduced in RASFs transfected with a dominant-negative mutant of I kappa B alpha or by an NF-kappa B inhibitor. However, specific inhibitors,of MAMERK-1/2 and p38 MAPK partially blocked the induction of RANKL expression and osteoclastogenesis. Monoclonal antibodies against interleukin-1 and tumor necrosis factor a partially inhibited CD40 ligation-mediated osteoclastogenesis. Conclusion. These results indicate that CD40 ligation of RASFs induces RANKL expression mainly via NF-kappa B activation and also results in enhanced osteoclast formation, both of which might play important roles in bone and cartilage destruction in RA. Inhibition of the CD40-CD40L interaction is a potential strategy for the prevention of bone damage in RA.
ISSN
0004-3591
URI
https://hdl.handle.net/10371/202703
DOI
https://doi.org/10.1002/art.21873
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Research Area Function, Immune modulation by metabolites, T-cell anergy, differentiation of memory CD8+ T cells, metabolism

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