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PMID:21841309

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Citation

Barrow, AD, Raynal, N, Andersen, TL, Slatter, DA, Bihan, D, Pugh, N, Cella, M, Kim, T, Rho, J, Negishi-Koga, T, Delaisse, JM, Takayanagi, H, Lorenzo, J, Colonna, M, Farndale, RW, Choi, Y and Trowsdale, J (2011) OSCAR is a collagen receptor that costimulates osteoclastogenesis in DAP12-deficient humans and mice. J. Clin. Invest. 121:3505-16

Abstract

Osteoclasts are terminally differentiated leukocytes that erode the mineralized bone matrix. Osteoclastogenesis requires costimulatory receptor signaling through adaptors containing immunoreceptor tyrosine-based activation motifs (ITAMs), such as Fc receptor common γ (FcRγ) and DNAX-activating protein of 12 kDa. Identification of these ITAM-containing receptors and their ligands remains a high research priority, since the stimuli for osteoclastogenesis are only partly defined. Osteoclast-associated receptor (OSCAR) was proposed to be a potent FcRγ-associated costimulatory receptor expressed by preosteoclasts in vitro, but OSCAR lacks a cognate ligand and its role in vivo has been unclear. Using samples from mice and patients deficient in various ITAM signaling pathways, we show here that OSCAR costimulates one of the major FcRγ-associated pathways required for osteoclastogenesis in vivo. Furthermore, we found that OSCAR binds to specific motifs within fibrillar collagens in the ECM that become revealed on nonquiescent bone surfaces in which osteoclasts undergo maturation and terminal differentiation in vivo. OSCAR promoted osteoclastogenesis in vivo, and OSCAR binding to its collagen motif led to signaling that increased numbers of osteoclasts in culture. Thus, our results suggest that ITAM-containing receptors can respond to exposed ligands in collagen, leading to the functional differentiation of leukocytes, which provides what we believe to be a new concept for ITAM regulation of cytokine receptors in different tissue microenvironments.

Links

PubMed PMC3163954 Online version:10.1172/JCI45913

Keywords

Adaptor Proteins, Signal Transducing/deficiency; Amino Acid Sequence; Animals; Cells, Cultured; Collagen/metabolism; Humans; Membrane Glycoproteins/deficiency; Membrane Proteins/deficiency; Mice; Mice, Knockout; Molecular Sequence Data; Monocytes/cytology; Monocytes/physiology; Osteoclasts/cytology; Osteoclasts/physiology; Protein Binding; RANK Ligand/metabolism; Receptors, Cell Surface/genetics; Receptors, Cell Surface/metabolism; Receptors, Immunologic/deficiency; Receptors, Immunologic/metabolism; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Sequence Alignment; Transforming Growth Factor beta1/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:TNF11

acts_upstream_of_or_within

GO:0036035: osteoclast development

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FCERG

acts_upstream_of_or_within

GO:0030316: osteoclast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857165

P

Seeded From UniProt

complete

MOUSE:OSCAR

acts_upstream_of_or_within

GO:0030316: osteoclast differentiation

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q8IYS5

P

Seeded From UniProt

complete

MOUSE:OSCAR

acts_upstream_of_or_within

GO:0030316: osteoclast differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:OSCAR

acts_upstream_of_or_within

GO:0030316: osteoclast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5301430

P

Seeded From UniProt

complete

MOUSE:OSCAR

acts_upstream_of_or_within

GO:0030316: osteoclast differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:98725

P

Seeded From UniProt

complete

MOUSE:OSCAR

acts_upstream_of_or_within

GO:0030316: osteoclast differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1277211

P

Seeded From UniProt

complete

MOUSE:OSCAR

enables

GO:0038064: collagen receptor activity

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q8IYS5

F

Seeded From UniProt

complete

MOUSE:OSCAR

enables

GO:0038064: collagen receptor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5301430

F

Seeded From UniProt

complete

MOUSE:OSCAR

acts_upstream_of_or_within

GO:0038094: Fc-gamma receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5301430

P

Seeded From UniProt

complete

MOUSE:TREM2

acts_upstream_of_or_within

GO:0030316: osteoclast differentiation

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q9NZC2

P

Seeded From UniProt

complete

MOUSE:TGFB1

acts_upstream_of_or_within

GO:0030316: osteoclast differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TGFB1

acts_upstream_of_or_within

GO:0030316: osteoclast differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2179720

P

Seeded From UniProt

complete

MOUSE:TYOBP

acts_upstream_of_or_within

GO:0030316: osteoclast differentiation

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:O43914

P

Seeded From UniProt

complete

MOUSE:TYOBP

acts_upstream_of_or_within

GO:0030316: osteoclast differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TYOBP

acts_upstream_of_or_within

GO:0030316: osteoclast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2450834

P

Seeded From UniProt

complete

MOUSE:TYOBP

acts_upstream_of_or_within

GO:0030316: osteoclast differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2179720

P

Seeded From UniProt

complete

Notes

See also

References

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