Adenosine abolishes MTX-induced suppression of osteoclastogenesis and inflammatory bone destruction in adjuvant-induced arthritis

Junpei Teramachi, Akiko Kukita, Yin Ji Li, Yuki Ushijima, Hiroshi Ohkuma, Naohisa Wada, Toshiyuki Watanabe, Seiji Nakamura, Toshio Kukita

研究成果: ジャーナルへの寄稿記事

15 引用 (Scopus)

抄録

Methotrexate (MTX) is widely utilized for the treatment of patients with rheumatoid arthritis (RA); however, recent observation of the MTX-resistant patients proposed some difficulty in MTX-dependent therapeutic approach for RA. To access cellular events related to MTX resistance in RA in respect to inflammatory bone destruction, we investigated on an involvement of the potent inflammatory mediator adenosine in the regulation of osteoclastogenesis and inflammatory bone destruction. In rats with adjuvant-induced arthritis (AA rats), MTX efficiently suppressed bone destruction when it was administrated within 3 days after adjuvant injection, while it could not suppress inflammatory bone destruction if MTX was injected at the time of onset of inflammation (at day 10 after adjuvant injection). Time-course change in the level of plasma adenosine of AA rats was estimated by use of high-performance liquid chromatography and elucidated that adenosine level was markedly elevated till 10 days after adjuvant injection. In vitro bone marrow culture system for evaluating osteoclastogenesis, MTX markedly suppressed osteoclastogenesis in a stromal cell-dependent manner. This MTX-induced suppression of osteoclastogenesis was abrogated by the addition of adenosine. MTX suppressed the expression of mRNA for the receptor activator NF-B ligand (RANKL), but it did not suppress the expression of osteoprotegerin (OPG). The addition of MTX and adenosine together markedly suppressed the level of OPG expression. Abolishment of MTX action by adenosine was significantly blocked by MRS1754, a highly selective antagonist for the A 2b adenosine receptor (A 2b AR), but not by caffeine, an antagonist for A 1, A 2a, A 3 AR (A 1 AR, A 2a AR, and A 3 AR), which suggests that adenosine acts through A 2b AR. Immunohistochemical studies showed abundant expression of A 2b AR in cells localized in the bone-bone marrow boundary of the distal tibia in AA rats but not in control rats. When adenosine was injected in the ankle joints of MTX-treated AA rats, the suppressive effects of MTX on bone destruction was abolished. The current data therefore suggest that upregulation of adenosine production abolished the suppressive effect of MTX on osteoclastic bone destruction. Involvement of the adenosine-A 2b AR system may explain MTX resistance in RA.

元の言語英語
ページ(範囲)719-731
ページ数13
ジャーナルLaboratory Investigation
91
発行部数5
DOI
出版物ステータス出版済み - 5 1 2011

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Experimental Arthritis
Osteogenesis
Methotrexate
Adenosine
Bone and Bones
Adenosine A2B Receptors
Rheumatoid Arthritis
Osteoprotegerin
Injections
Bone Marrow
Ankle Joint
Stromal Cells
Caffeine
Tibia

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

これを引用

Adenosine abolishes MTX-induced suppression of osteoclastogenesis and inflammatory bone destruction in adjuvant-induced arthritis. / Teramachi, Junpei; Kukita, Akiko; Li, Yin Ji; Ushijima, Yuki; Ohkuma, Hiroshi; Wada, Naohisa; Watanabe, Toshiyuki; Nakamura, Seiji; Kukita, Toshio.

:: Laboratory Investigation, 巻 91, 番号 5, 01.05.2011, p. 719-731.

研究成果: ジャーナルへの寄稿記事

Teramachi, Junpei ; Kukita, Akiko ; Li, Yin Ji ; Ushijima, Yuki ; Ohkuma, Hiroshi ; Wada, Naohisa ; Watanabe, Toshiyuki ; Nakamura, Seiji ; Kukita, Toshio. / Adenosine abolishes MTX-induced suppression of osteoclastogenesis and inflammatory bone destruction in adjuvant-induced arthritis. :: Laboratory Investigation. 2011 ; 巻 91, 番号 5. pp. 719-731.
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abstract = "Methotrexate (MTX) is widely utilized for the treatment of patients with rheumatoid arthritis (RA); however, recent observation of the MTX-resistant patients proposed some difficulty in MTX-dependent therapeutic approach for RA. To access cellular events related to MTX resistance in RA in respect to inflammatory bone destruction, we investigated on an involvement of the potent inflammatory mediator adenosine in the regulation of osteoclastogenesis and inflammatory bone destruction. In rats with adjuvant-induced arthritis (AA rats), MTX efficiently suppressed bone destruction when it was administrated within 3 days after adjuvant injection, while it could not suppress inflammatory bone destruction if MTX was injected at the time of onset of inflammation (at day 10 after adjuvant injection). Time-course change in the level of plasma adenosine of AA rats was estimated by use of high-performance liquid chromatography and elucidated that adenosine level was markedly elevated till 10 days after adjuvant injection. In vitro bone marrow culture system for evaluating osteoclastogenesis, MTX markedly suppressed osteoclastogenesis in a stromal cell-dependent manner. This MTX-induced suppression of osteoclastogenesis was abrogated by the addition of adenosine. MTX suppressed the expression of mRNA for the receptor activator NF-B ligand (RANKL), but it did not suppress the expression of osteoprotegerin (OPG). The addition of MTX and adenosine together markedly suppressed the level of OPG expression. Abolishment of MTX action by adenosine was significantly blocked by MRS1754, a highly selective antagonist for the A 2b adenosine receptor (A 2b AR), but not by caffeine, an antagonist for A 1, A 2a, A 3 AR (A 1 AR, A 2a AR, and A 3 AR), which suggests that adenosine acts through A 2b AR. Immunohistochemical studies showed abundant expression of A 2b AR in cells localized in the bone-bone marrow boundary of the distal tibia in AA rats but not in control rats. When adenosine was injected in the ankle joints of MTX-treated AA rats, the suppressive effects of MTX on bone destruction was abolished. The current data therefore suggest that upregulation of adenosine production abolished the suppressive effect of MTX on osteoclastic bone destruction. Involvement of the adenosine-A 2b AR system may explain MTX resistance in RA.",
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AU - Kukita, Akiko

AU - Li, Yin Ji

AU - Ushijima, Yuki

AU - Ohkuma, Hiroshi

AU - Wada, Naohisa

AU - Watanabe, Toshiyuki

AU - Nakamura, Seiji

AU - Kukita, Toshio

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N2 - Methotrexate (MTX) is widely utilized for the treatment of patients with rheumatoid arthritis (RA); however, recent observation of the MTX-resistant patients proposed some difficulty in MTX-dependent therapeutic approach for RA. To access cellular events related to MTX resistance in RA in respect to inflammatory bone destruction, we investigated on an involvement of the potent inflammatory mediator adenosine in the regulation of osteoclastogenesis and inflammatory bone destruction. In rats with adjuvant-induced arthritis (AA rats), MTX efficiently suppressed bone destruction when it was administrated within 3 days after adjuvant injection, while it could not suppress inflammatory bone destruction if MTX was injected at the time of onset of inflammation (at day 10 after adjuvant injection). Time-course change in the level of plasma adenosine of AA rats was estimated by use of high-performance liquid chromatography and elucidated that adenosine level was markedly elevated till 10 days after adjuvant injection. In vitro bone marrow culture system for evaluating osteoclastogenesis, MTX markedly suppressed osteoclastogenesis in a stromal cell-dependent manner. This MTX-induced suppression of osteoclastogenesis was abrogated by the addition of adenosine. MTX suppressed the expression of mRNA for the receptor activator NF-B ligand (RANKL), but it did not suppress the expression of osteoprotegerin (OPG). The addition of MTX and adenosine together markedly suppressed the level of OPG expression. Abolishment of MTX action by adenosine was significantly blocked by MRS1754, a highly selective antagonist for the A 2b adenosine receptor (A 2b AR), but not by caffeine, an antagonist for A 1, A 2a, A 3 AR (A 1 AR, A 2a AR, and A 3 AR), which suggests that adenosine acts through A 2b AR. Immunohistochemical studies showed abundant expression of A 2b AR in cells localized in the bone-bone marrow boundary of the distal tibia in AA rats but not in control rats. When adenosine was injected in the ankle joints of MTX-treated AA rats, the suppressive effects of MTX on bone destruction was abolished. The current data therefore suggest that upregulation of adenosine production abolished the suppressive effect of MTX on osteoclastic bone destruction. Involvement of the adenosine-A 2b AR system may explain MTX resistance in RA.

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