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Hokkaido University Collection of Scholarly and Academic Papers >
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Role of Chondrocytes in the Development of Rheumatoid Arthritis Via Transmembrane Protein 147-Mediated NF-kappa B Activation
| Title: | Role of Chondrocytes in the Development of Rheumatoid Arthritis Via Transmembrane Protein 147-Mediated NF-kappa B Activation |
| Authors: | Ota, Mitsutoshi Browse this author | | Tanaka, Yuki Browse this author →KAKEN DB | | Nakagawa, Ikuma Browse this author | | Jiang, Jing-Jing Browse this author | | Arima, Yasunobu Browse this author →KAKEN DB | | Kamimura, Daisuke Browse this author →KAKEN DB | | Onodera, Tomohiro Browse this author →KAKEN DB | | Iwasaki, Norimasa Browse this author →KAKEN DB | | Murakami, Masaaki Browse this author →KAKEN DB |
| Issue Date: | Jun-2020 |
| Publisher: | John Wiley & Sons |
| Journal Title: | Arthritis & rheumatology |
| Volume: | 72 |
| Issue: | 6 |
| Start Page: | 931 |
| End Page: | 942 |
| Publisher DOI: | 10.1002/art.41182 |
| Abstract: | Objective We have previously reported that the coactivation of NF-kappa B and STAT3 in nonimmune cells, including synovial fibroblasts, enhances the expression of NF-kappa B target genes and plays a role in chronic inflammation and rheumatoid arthritis (RA). This study was undertaken to examine the role of NF-kappa B activation in chondrocytes and better understand the pathogenesis of RA. Furthermore, transmembrane protein 147 (TMEM147) was investigated as a representative NF-kappa B activator in chondrocytes. Methods Clinical samples from RA patients were analyzed by immunohistochemistry. Specimens obtained from patients with polydactyly were used as control samples. The functional contribution of chondrocytes and TMEM147 to arthritis was examined in several murine models of RA. In vitro experiments (quantitative polymerase chain reaction, RNA interference, immunoprecipitation, and confocal microscopy) were performed to investigate the mechanism of action of TMEM147 in chondrocytes. Results Samples obtained from RA patients and mouse models of RA showed coactivation of NF-kappa B and STAT3 in chondrocytes (P < 0.001). This coactivation induced a synergistic expression of NF-kappa B targets in vitro (P < 0.01). Chondrocyte-specific deletion of STAT3 significantly suppressed the development of cytokine-induced RA (P < 0.01). TMEM147 was highly expressed in chondrocytes from RA patient samples and the mouse models of RA. Gene silencing of TMEM147 or anti-TMEM147 antibody treatment inhibited the cytokine-mediated activation of NF-kappa B in vitro (P < 0.01) and suppressed cytokine-induced RA in vivo (P < 0.01). Mechanistically, TMEM147 molecules acted as scaffold proteins for the NF-kappa B complex, which included breakpoint cluster region and casein kinase 2, and enhanced NF-kappa B activity. Conclusion These results suggest that chondrocytes play a role in the development of RA via TMEM147-mediated NF-kappa B activation and indicate a novel therapeutic strategy for RA. |
| Rights: | This is the peer reviewed version of the following article: Ota, M., Tanaka, Y., Nakagawa, I., Jiang, J.‐J., Arima, Y., Kamimura, D., Onodera, T., Iwasaki, N. and Murakami, M. (2020), Role of Chondrocytes in the Development of Rheumatoid Arthritis Via Transmembrane Protein 147-Mediated NF ‐κB Activation. Arthritis Rheumatol, 72: 931-942, which has been published in final form at https://doi.org/10.1002/art.41182. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/81699 |
| Appears in Collections: | 遺伝子病制御研究所 (Institute for Genetic Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 村上 正晃
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