CTLA4-Ig Directly Inhibits Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations in Bone Marrow Macrophages

Hiroyuki Okada, Hiroshi Kajiya, Yasunori Omata, Takumi Matsumoto, Yuiko Sato, Tami Kobayashi, Satoshi Nakamura, Yosuke Kaneko, Shinya Nakamura, Takuma Koyama, Shunichi Sudo, Masashi Shin, Fujio Okamoto, Hisato Watanabe, Naohiro Tachibana, Jun Hirose, Taku Saito, Toshiyuki Takai, Morio Matsumoto, Masaya Nakamura & 3 others Koji Okabe, Takeshi Miyamoto, Sakae Tanaka

Research output: Contribution to journalArticle

Abstract

CTLA4-Ig (cytotoxic T-lymphocyte antigen 4-immunoglobulin; Abatacept) is a biologic drug for rheumatoid arthritis. CTLA4 binds to the CD80/86 complex of antigen-presenting cells and blocks the activation of T cells. Although previous reports showed that CTLA4-Ig directly inhibited osteoclast differentiation, the whole inhibitory mechanism of CTLA4-Ig for osteoclast differentiation is unclear. Bone marrow macrophages (BMMs) from WT mice were cultured with M-CSF and RANKL with or without the recombinant mouse chimera CTLA4-Ig. Intracellular calcium oscillations of BMMs with RANKL were detected by staining with calcium indicator fura-2 immediately after administration of CTLA4-Ig or after one day of treatment. Calcium oscillations were analyzed using Fc receptor gamma- (FcRγ-) deficient BMMs. CTLA4-Ig inhibited osteoclast differentiation and reduced the expression of the nuclear factor of activated T cells NFATc1 in BMMs in vitro. Calcium oscillations in BMMs were suppressed by CTLA4-Ig both immediately after administration and after one day of treatment. CTLA4-Ig did not affect osteoclastogenesis and did not cause remarkable changes in calcium oscillations in FcRγ-deficient BMMs. Finally, to analyze the effect of CTLA4-Ig in vivo, we used an LPS-induced osteolysis model. CTLA4-Ig suppressed LPS-induced bone resorption in WT mice, not in FcRγ-deficient mice. In conclusion, CTLA4-Ig inhibits intracellular calcium oscillations depending on FcRγ and downregulates NFATc1 expression in BMMs.

Original languageEnglish
JournalJournal of Bone and Mineral Research
DOIs
Publication statusPublished - 2019 Jan 1

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Calcium Signaling
Osteogenesis
Bone Marrow
Macrophages
IgG Receptors
Osteoclasts
Abatacept
CTLA-4 Antigen
NFATC Transcription Factors
Osteolysis
Macrophage Colony-Stimulating Factor
Fura-2
Antigen-Presenting Cells
Bone Resorption
Immunoglobulins
Rheumatoid Arthritis
Down-Regulation
Staining and Labeling
Calcium
T-Lymphocytes

Keywords

  • ABATACEPT
  • CALCIUM OSCILLATION
  • CTLA4
  • OSTEOCLAST DIFFERENTIATION

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

CTLA4-Ig Directly Inhibits Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations in Bone Marrow Macrophages. / Okada, Hiroyuki; Kajiya, Hiroshi; Omata, Yasunori; Matsumoto, Takumi; Sato, Yuiko; Kobayashi, Tami; Nakamura, Satoshi; Kaneko, Yosuke; Nakamura, Shinya; Koyama, Takuma; Sudo, Shunichi; Shin, Masashi; Okamoto, Fujio; Watanabe, Hisato; Tachibana, Naohiro; Hirose, Jun; Saito, Taku; Takai, Toshiyuki; Matsumoto, Morio; Nakamura, Masaya; Okabe, Koji; Miyamoto, Takeshi; Tanaka, Sakae.

In: Journal of Bone and Mineral Research, 01.01.2019.

Research output: Contribution to journalArticle

Okada, H, Kajiya, H, Omata, Y, Matsumoto, T, Sato, Y, Kobayashi, T, Nakamura, S, Kaneko, Y, Nakamura, S, Koyama, T, Sudo, S, Shin, M, Okamoto, F, Watanabe, H, Tachibana, N, Hirose, J, Saito, T, Takai, T, Matsumoto, M, Nakamura, M, Okabe, K, Miyamoto, T & Tanaka, S 2019, 'CTLA4-Ig Directly Inhibits Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations in Bone Marrow Macrophages', Journal of Bone and Mineral Research. https://doi.org/10.1002/jbmr.3754
Okada, Hiroyuki ; Kajiya, Hiroshi ; Omata, Yasunori ; Matsumoto, Takumi ; Sato, Yuiko ; Kobayashi, Tami ; Nakamura, Satoshi ; Kaneko, Yosuke ; Nakamura, Shinya ; Koyama, Takuma ; Sudo, Shunichi ; Shin, Masashi ; Okamoto, Fujio ; Watanabe, Hisato ; Tachibana, Naohiro ; Hirose, Jun ; Saito, Taku ; Takai, Toshiyuki ; Matsumoto, Morio ; Nakamura, Masaya ; Okabe, Koji ; Miyamoto, Takeshi ; Tanaka, Sakae. / CTLA4-Ig Directly Inhibits Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations in Bone Marrow Macrophages. In: Journal of Bone and Mineral Research. 2019.
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AU - Okada, Hiroyuki

AU - Kajiya, Hiroshi

AU - Omata, Yasunori

AU - Matsumoto, Takumi

AU - Sato, Yuiko

AU - Kobayashi, Tami

AU - Nakamura, Satoshi

AU - Kaneko, Yosuke

AU - Nakamura, Shinya

AU - Koyama, Takuma

AU - Sudo, Shunichi

AU - Shin, Masashi

AU - Okamoto, Fujio

AU - Watanabe, Hisato

AU - Tachibana, Naohiro

AU - Hirose, Jun

AU - Saito, Taku

AU - Takai, Toshiyuki

AU - Matsumoto, Morio

AU - Nakamura, Masaya

AU - Okabe, Koji

AU - Miyamoto, Takeshi

AU - Tanaka, Sakae

PY - 2019/1/1

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N2 - CTLA4-Ig (cytotoxic T-lymphocyte antigen 4-immunoglobulin; Abatacept) is a biologic drug for rheumatoid arthritis. CTLA4 binds to the CD80/86 complex of antigen-presenting cells and blocks the activation of T cells. Although previous reports showed that CTLA4-Ig directly inhibited osteoclast differentiation, the whole inhibitory mechanism of CTLA4-Ig for osteoclast differentiation is unclear. Bone marrow macrophages (BMMs) from WT mice were cultured with M-CSF and RANKL with or without the recombinant mouse chimera CTLA4-Ig. Intracellular calcium oscillations of BMMs with RANKL were detected by staining with calcium indicator fura-2 immediately after administration of CTLA4-Ig or after one day of treatment. Calcium oscillations were analyzed using Fc receptor gamma- (FcRγ-) deficient BMMs. CTLA4-Ig inhibited osteoclast differentiation and reduced the expression of the nuclear factor of activated T cells NFATc1 in BMMs in vitro. Calcium oscillations in BMMs were suppressed by CTLA4-Ig both immediately after administration and after one day of treatment. CTLA4-Ig did not affect osteoclastogenesis and did not cause remarkable changes in calcium oscillations in FcRγ-deficient BMMs. Finally, to analyze the effect of CTLA4-Ig in vivo, we used an LPS-induced osteolysis model. CTLA4-Ig suppressed LPS-induced bone resorption in WT mice, not in FcRγ-deficient mice. In conclusion, CTLA4-Ig inhibits intracellular calcium oscillations depending on FcRγ and downregulates NFATc1 expression in BMMs.

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