Abstract
While their function, as immune checkpoint molecules, is well known, B7-family proteins also function as regulatory molecules in bone remodeling. B7-H3 is a receptor ligand of the B7 family that functions primarily as a negative immune checkpoint. While the regulatory function of B7-H3 in osteoblast differentiation has been established, its role in osteoclast differentiation remains unclear. Here we show that B7-H3 is highly expressed in mature osteoclasts and that B7-H3 deficiency leads to the inhibition of osteoclastogenesis in human osteoclast precursors (OCPs). High-throughput transcriptomic analyses reveal that B7-H3 inhibition upregulates IFN signaling as well as IFN-inducible genes, including IDO. Pharmacological inhibition of type-I IFN and IDO knockdown leads to reversal of B7-H3-deficiency-mediated osteoclastogenesis suppression. Although synovial-fluid macrophages from rheumatoid-arthritis patients express B7-H3, inhibition of B7-H3 does not affect their osteoclastogenesis. Thus, our findings highlight B7-H3 as a physiologic positive regulator of osteoclast differentiation and implicate type-I IFN-IDO signaling as its downstream mechanism.
© 2021. The Author(s).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Neutralizing / pharmacology
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Arthritis, Rheumatoid / pathology
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B7 Antigens / deficiency
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B7 Antigens / genetics
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B7 Antigens / metabolism*
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Cell Differentiation*
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Enzyme Induction / drug effects
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Humans
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Indoleamine-Pyrrole 2,3,-Dioxygenase / biosynthesis*
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Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
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Interferon Type I / metabolism*
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Interferon-beta / metabolism
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Macrophage Colony-Stimulating Factor / pharmacology
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Macrophages / drug effects
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Macrophages / metabolism
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Macrophages / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Monocytes / drug effects
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Monocytes / metabolism
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Nitric Oxide Synthase Type II / metabolism
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Osteoclasts / metabolism*
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Osteoclasts / pathology*
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Osteogenesis / drug effects
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Proto-Oncogene Proteins c-fos / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Signal Transduction / drug effects
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Stem Cells / drug effects
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Stem Cells / metabolism
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Suppressor of Cytokine Signaling 1 Protein / metabolism
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Synovial Fluid / metabolism
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Tryptophan / metabolism
Substances
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Antibodies, Neutralizing
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B7 Antigens
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CD276 protein, human
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Cd276 protein, mouse
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IDO1 protein, human
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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Interferon Type I
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Proto-Oncogene Proteins c-fos
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RNA, Messenger
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SOCS1 protein, human
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Suppressor of Cytokine Signaling 1 Protein
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Interferon-beta
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Macrophage Colony-Stimulating Factor
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Tryptophan
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Nitric Oxide Synthase Type II