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B7-H3 regulates osteoclast differentiation via type I interferon-dependent IDO induction
Younseo Oh1,2, Robin Park3, So Yeon Kim1,4
1Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea.
Cell Death & Disease
|October 21, 2021
Summary
B7-H3 protein regulates bone remodeling by promoting osteoclast differentiation. Its deficiency inhibits osteoclast formation via the type-I IFN-IDO signaling pathway, revealing a new role in bone metabolism.
Area of Science:
- Immunology
- Bone Biology
- Cell Signaling
Background:
- B7-family proteins, including B7-H3, are known immune checkpoint molecules.
- B7-H3 also regulates bone remodeling, with established roles in osteoblast differentiation.
- The specific role of B7-H3 in osteoclast differentiation was previously unclear.
Purpose of the Study:
- To investigate the role of B7-H3 in osteoclast differentiation.
- To elucidate the molecular mechanisms underlying B7-H3's function in osteoclastogenesis.
Main Methods:
- Analysis of B7-H3 expression in mature osteoclasts.
- Assessment of osteoclastogenesis in B7-H3 deficient human osteoclast precursors (OCPs).
- High-throughput transcriptomic analysis to identify downstream signaling pathways.
- Pharmacological inhibition of type-I IFN and IDO knockdown experiments.
Main Results:
- B7-H3 is highly expressed in mature osteoclasts.
- B7-H3 deficiency significantly inhibits osteoclastogenesis in OCPs.
- Transcriptomic analysis revealed that B7-H3 inhibition upregulates type-I IFN signaling and IFN-inducible genes like IDO.
- Reversal of osteoclastogenesis suppression was observed upon type-I IFN inhibition or IDO knockdown.
- B7-H3 inhibition did not affect osteoclastogenesis in rheumatoid arthritis synovial fluid macrophages.
Conclusions:
- B7-H3 acts as a physiological positive regulator of osteoclast differentiation.
- Type-I IFN-IDO signaling pathway is a key downstream mechanism for B7-H3's role in osteoclastogenesis.
- These findings offer new insights into the regulation of bone remodeling by immune checkpoint molecules.
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