Concomitant Treatment with Etanercept and Tacrolimus Synergistically Attenuates Arthritis Progression via Inhibition of Matrix Metalloproteinase-3 Production and Osteoclastogenesis in Human TNF-α Transgenic Mice
In the present study, we investigated the effects and mechanisms of action of a combined treatment with etanercept, a soluble tumor necrosis factor receptor (p75) Fc fusion protein, and tacrolimus, a calcineurin inhibitor on the progression of arthritis in human tumor necrosis factor-α (TNF-α) trans...
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| Format: | Article |
| Language: | English |
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Wiley
2019-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2019/4176974 |
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| author | Iwao Seki Miwa Takai-Imamura Tomomi Kohara-Tanaka Satoshi Shirae Minoru Sasano Hiroaki Matsuno Hiroyuki Aono |
| author_facet | Iwao Seki Miwa Takai-Imamura Tomomi Kohara-Tanaka Satoshi Shirae Minoru Sasano Hiroaki Matsuno Hiroyuki Aono |
| author_sort | Iwao Seki |
| collection | DOAJ |
| description | In the present study, we investigated the effects and mechanisms of action of a combined treatment with etanercept, a soluble tumor necrosis factor receptor (p75) Fc fusion protein, and tacrolimus, a calcineurin inhibitor on the progression of arthritis in human tumor necrosis factor-α (TNF-α) transgenic (hTNF-Tg) mice. Single-drug treatments with etanercept and tacrolimus attenuated the clinical signs but not the radiographic changes associated with the development of arthritis in mice. On the contrary, combined treatment significantly suppressed the radiographic progression and also improved the clinical signs. The combined treatment exhibited synergistic effects of the two drugs in reducing the serum matrix metalloproteinase-3 level and the number of peripheral CD11bhigh osteoclast precursor cells. Moreover, tacrolimus inhibited the cytokine-induced osteoclast differentiation in synergy with etanercept in an in vitro assay. Interestingly, tacrolimus did not inhibit the production of antidrug antibodies (ADAs) against etanercept in the hTNF-Tg mice. This result implies that the synergistic effects of etanercept and tacrolimus are not due to secondary effects derived from the suppression of ADA production by tacrolimus but are due to their primary effects. These findings suggest that concomitant treatment with etanercept and tacrolimus may be one of preferable treatment options to control disease activities for patients with rheumatoid arthritis, especially for those with bone resorption. |
| format | Article |
| id | doaj-art-9a36ee8a65d843469aff6adaeb06fa00 |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
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| series | Mediators of Inflammation |
| spelling | doaj-art-9a36ee8a65d843469aff6adaeb06fa002025-02-03T05:46:12ZengWileyMediators of Inflammation0962-93511466-18612019-01-01201910.1155/2019/41769744176974Concomitant Treatment with Etanercept and Tacrolimus Synergistically Attenuates Arthritis Progression via Inhibition of Matrix Metalloproteinase-3 Production and Osteoclastogenesis in Human TNF-α Transgenic MiceIwao Seki0Miwa Takai-Imamura1Tomomi Kohara-Tanaka2Satoshi Shirae3Minoru Sasano4Hiroaki Matsuno5Hiroyuki Aono6Research and Development Department, AYUMI Pharmaceutical Corporation, 8F Shijyo-Karasuma FT Square, 20 Naginatahoko-cho, Shimogyo-ku, Kyoto 600-8008, JapanResearch and Development Department, AYUMI Pharmaceutical Corporation, 8F Shijyo-Karasuma FT Square, 20 Naginatahoko-cho, Shimogyo-ku, Kyoto 600-8008, JapanResearch and Development Department, AYUMI Pharmaceutical Corporation, 8F Shijyo-Karasuma FT Square, 20 Naginatahoko-cho, Shimogyo-ku, Kyoto 600-8008, JapanResearch and Development Department, AYUMI Pharmaceutical Corporation, 8F Shijyo-Karasuma FT Square, 20 Naginatahoko-cho, Shimogyo-ku, Kyoto 600-8008, JapanResearch and Development Department, AYUMI Pharmaceutical Corporation, 8F Shijyo-Karasuma FT Square, 20 Naginatahoko-cho, Shimogyo-ku, Kyoto 600-8008, JapanMatsuno Clinic for Rheumatic Disease, 7187-2, Kureha-cho, Toyama-shi, Toyama 930-0138, JapanResearch and Development Department, AYUMI Pharmaceutical Corporation, 8F Shijyo-Karasuma FT Square, 20 Naginatahoko-cho, Shimogyo-ku, Kyoto 600-8008, JapanIn the present study, we investigated the effects and mechanisms of action of a combined treatment with etanercept, a soluble tumor necrosis factor receptor (p75) Fc fusion protein, and tacrolimus, a calcineurin inhibitor on the progression of arthritis in human tumor necrosis factor-α (TNF-α) transgenic (hTNF-Tg) mice. Single-drug treatments with etanercept and tacrolimus attenuated the clinical signs but not the radiographic changes associated with the development of arthritis in mice. On the contrary, combined treatment significantly suppressed the radiographic progression and also improved the clinical signs. The combined treatment exhibited synergistic effects of the two drugs in reducing the serum matrix metalloproteinase-3 level and the number of peripheral CD11bhigh osteoclast precursor cells. Moreover, tacrolimus inhibited the cytokine-induced osteoclast differentiation in synergy with etanercept in an in vitro assay. Interestingly, tacrolimus did not inhibit the production of antidrug antibodies (ADAs) against etanercept in the hTNF-Tg mice. This result implies that the synergistic effects of etanercept and tacrolimus are not due to secondary effects derived from the suppression of ADA production by tacrolimus but are due to their primary effects. These findings suggest that concomitant treatment with etanercept and tacrolimus may be one of preferable treatment options to control disease activities for patients with rheumatoid arthritis, especially for those with bone resorption.http://dx.doi.org/10.1155/2019/4176974 |
| spellingShingle | Iwao Seki Miwa Takai-Imamura Tomomi Kohara-Tanaka Satoshi Shirae Minoru Sasano Hiroaki Matsuno Hiroyuki Aono Concomitant Treatment with Etanercept and Tacrolimus Synergistically Attenuates Arthritis Progression via Inhibition of Matrix Metalloproteinase-3 Production and Osteoclastogenesis in Human TNF-α Transgenic Mice Mediators of Inflammation |
| title | Concomitant Treatment with Etanercept and Tacrolimus Synergistically Attenuates Arthritis Progression via Inhibition of Matrix Metalloproteinase-3 Production and Osteoclastogenesis in Human TNF-α Transgenic Mice |
| title_full | Concomitant Treatment with Etanercept and Tacrolimus Synergistically Attenuates Arthritis Progression via Inhibition of Matrix Metalloproteinase-3 Production and Osteoclastogenesis in Human TNF-α Transgenic Mice |
| title_fullStr | Concomitant Treatment with Etanercept and Tacrolimus Synergistically Attenuates Arthritis Progression via Inhibition of Matrix Metalloproteinase-3 Production and Osteoclastogenesis in Human TNF-α Transgenic Mice |
| title_full_unstemmed | Concomitant Treatment with Etanercept and Tacrolimus Synergistically Attenuates Arthritis Progression via Inhibition of Matrix Metalloproteinase-3 Production and Osteoclastogenesis in Human TNF-α Transgenic Mice |
| title_short | Concomitant Treatment with Etanercept and Tacrolimus Synergistically Attenuates Arthritis Progression via Inhibition of Matrix Metalloproteinase-3 Production and Osteoclastogenesis in Human TNF-α Transgenic Mice |
| title_sort | concomitant treatment with etanercept and tacrolimus synergistically attenuates arthritis progression via inhibition of matrix metalloproteinase 3 production and osteoclastogenesis in human tnf α transgenic mice |
| url | http://dx.doi.org/10.1155/2019/4176974 |
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