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; Koji Okabe; Takeshi Miyamoto; Sakae Tanaka

doi:10.1002/jbmr.3754

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 NakamuraKoji Okabe, Takeshi Miyamoto, Sakae Tanaka

IDAC - Division of Aging Science

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

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 language	English
Pages (from-to)	1744-1752
Number of pages	9
Journal	Journal of Bone and Mineral Research
Volume	34
Issue number	9
DOIs	https://doi.org/10.1002/jbmr.3754
Publication status	Published - 2019 Sept 1

Keywords

ABATACEPT
CALCIUM OSCILLATION
CTLA4
OSTEOCLAST DIFFERENTIATION

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/jbmr.3754

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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., ... Tanaka, S. (2019). CTLA4-Ig Directly Inhibits Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations in Bone Marrow Macrophages. Journal of Bone and Mineral Research, 34(9), 1744-1752. https://doi.org/10.1002/jbmr.3754

@article{c806217d3e714357bb941f4350625a4b,

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

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.",

keywords = "ABATACEPT, CALCIUM OSCILLATION, CTLA4, OSTEOCLAST DIFFERENTIATION",

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

note = "Funding Information: This work was supported in part by JSPS KAKENHI grant numbers JP 18K09017, and the Private University Research Branding Project at Fukuoka Dental College. Authors{\textquoteright} Roles: Conceptualization: YO, Taku M, JH, ST; Data curation: HO, HK, Take M, ST; Formal Analysis: HO, HK; Funding acquisition: HK, TS, MM, MN, KO, Take M, ST; Investigation: HO, HK, Sa N, YK, Sh N, Taku K, SS, HW; Methodology: HO, HK, YO, Taku M, MS, FO, NT, JH; Project administration: Take M, ST; Resources, YS, Tami K, TS, TT, MM, MN, KO, Take M, ST; Software: HO, HK; Supervision: KO, Take M, ST; Validation: HO, HK, KO; Visualization: HO, HK; Writing – Original Draft: HO; Writing – Review & Editing: HK, KO, Take M, ST. All authors have revised the manuscript and approved the final version. HO takes responsibility for the integrity of the data analysis. Publisher Copyright: {\textcopyright} 2019 American Society for Bone and Mineral Research",

year = "2019",

month = sep,

day = "1",

doi = "10.1002/jbmr.3754",

language = "English",

volume = "34",

pages = "1744--1752",

journal = "Journal of Bone and Mineral Research",

issn = "0884-0431",

publisher = "Wiley-Blackwell",

number = "9",

}

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, vol. 34, no. 9, pp. 1744-1752. https://doi.org/10.1002/jbmr.3754

TY - JOUR

T1 - CTLA4-Ig Directly Inhibits Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations in Bone Marrow Macrophages

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

N1 - Funding Information: This work was supported in part by JSPS KAKENHI grant numbers JP 18K09017, and the Private University Research Branding Project at Fukuoka Dental College. Authors’ Roles: Conceptualization: YO, Taku M, JH, ST; Data curation: HO, HK, Take M, ST; Formal Analysis: HO, HK; Funding acquisition: HK, TS, MM, MN, KO, Take M, ST; Investigation: HO, HK, Sa N, YK, Sh N, Taku K, SS, HW; Methodology: HO, HK, YO, Taku M, MS, FO, NT, JH; Project administration: Take M, ST; Resources, YS, Tami K, TS, TT, MM, MN, KO, Take M, ST; Software: HO, HK; Supervision: KO, Take M, ST; Validation: HO, HK, KO; Visualization: HO, HK; Writing – Original Draft: HO; Writing – Review & Editing: HK, KO, Take M, ST. All authors have revised the manuscript and approved the final version. HO takes responsibility for the integrity of the data analysis. Publisher Copyright: © 2019 American Society for Bone and Mineral Research

PY - 2019/9/1

Y1 - 2019/9/1

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.

AB - 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.

KW - ABATACEPT

KW - CALCIUM OSCILLATION

KW - CTLA4

KW - OSTEOCLAST DIFFERENTIATION

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U2 - 10.1002/jbmr.3754

DO - 10.1002/jbmr.3754

M3 - Article

C2 - 31067348

AN - SCOPUS:85069895033

SN - 0884-0431

VL - 34

SP - 1744

EP - 1752

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

IS - 9

ER -

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

Abstract

Keywords

UN SDGs

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