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

Hiroyuki Okada1, Hiroshi Kajiya2, Yasunori Omata1

  • 1Department of Orthopaedic Surgery, The University of Tokyo, Tokyo, Japan.

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research
|May 9, 2019
PubMed

Insights

Cytotoxic T-lymphocyte antigen 4-immunoglobulin (CTLA4-Ig) inhibits osteoclast differentiation by suppressing intracellular calcium oscillations dependent on Fc receptor gamma (FcRγ). This mechanism downregulates NFATc1 expression in bone marrow macrophages.

Area of Science:

  • Immunology
  • Cell Biology
  • Rheumatology

Background:

  • Rheumatoid arthritis is treated with CTLA4-Ig (Abatacept), which blocks T cell activation.
  • Previous studies suggest CTLA4-Ig inhibits osteoclast differentiation, but the mechanism remains unclear.

Purpose of the Study:

  • To elucidate the inhibitory mechanism of CTLA4-Ig on osteoclast differentiation.
  • To investigate the role of Fc receptor gamma (FcRγ) in CTLA4-Ig's effects on osteoclastogenesis.

Main Methods:

  • Bone marrow macrophages (BMMs) from wild-type (WT) and FcRγ-deficient mice were cultured with M-CSF and RANKL, with or without CTLA4-Ig.
  • Intracellular calcium oscillations were measured using fura-2 staining.
  • Osteoclast differentiation and NFATc1 expression were assessed.
  • An LPS-induced osteolysis model was used to evaluate in vivo effects.

Main Results:

  • CTLA4-Ig inhibited osteoclast differentiation and reduced NFATc1 expression in WT BMMs.
  • CTLA4-Ig suppressed intracellular calcium oscillations in BMMs.
  • These effects were dependent on FcRγ, as CTLA4-Ig did not significantly impact osteoclastogenesis or calcium oscillations in FcRγ-deficient BMMs.
  • In vivo, CTLA4-Ig suppressed LPS-induced bone resorption in WT mice but not in FcRγ-deficient mice.

Conclusions:

  • CTLA4-Ig inhibits osteoclast differentiation by suppressing FcRγ-dependent intracellular calcium oscillations.
  • This mechanism involves the downregulation of NFATc1 expression in bone marrow macrophages.
  • FcRγ is crucial for the osteoclast inhibitory effects of CTLA4-Ig both in vitro and in vivo.

Keywords:
ABATACEPTCALCIUM OSCILLATIONCTLA4OSTEOCLAST DIFFERENTIATION

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