Back to Search Start Over

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

Authors :
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
Source :
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2019 Sep; Vol. 34 (9), pp. 1744-1752. Date of Electronic Publication: 2019 Jul 16.
Publication Year :
2019

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. © 2019 American Society for Bone and Mineral Research.<br /> (© 2019 American Society for Bone and Mineral Research.)

Details

Language :
English
ISSN :
1523-4681
Volume :
34
Issue :
9
Database :
MEDLINE
Journal :
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Publication Type :
Academic Journal
Accession number :
31067348
Full Text :
https://doi.org/10.1002/jbmr.3754