title: OSCAR is a collagen receptor that costimulates osteoclastogenesis in DAP12-deficient humans and mice.
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.
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, United Kingdom. adb44@cam.ac.uk
authors.forename: Alexander David
authors.initials: AD
authors.lastname: Barrow
authors.forename: Nicolas
authors.initials: N
authors.lastname: Raynal
authors.forename: Thomas Levin
authors.initials: TL
authors.lastname: Andersen
authors.forename: David A
authors.initials: DA
authors.lastname: Slatter
authors.forename: Dominique
authors.initials: D
authors.lastname: Bihan
authors.forename: Nicholas
authors.initials: N
authors.lastname: Pugh
authors.forename: Marina
authors.initials: M
authors.lastname: Cella
authors.forename: Taesoo
authors.initials: T
authors.lastname: Kim
authors.forename: Jaerang
authors.initials: J
authors.lastname: Rho
authors.forename: Takako
authors.initials: T
authors.lastname: Negishi-Koga
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Delaisse
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
authors.forename: Joseph
authors.initials: J
authors.lastname: Lorenzo
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: Richard W
authors.initials: RW
authors.lastname: Farndale
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.forename: John
authors.initials: J
authors.lastname: Trowsdale
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency*; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000172:deficiency; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D011485:Protein Binding; D053245:RANK Ligand / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C512828:OSCAR protein, human; C450519:Oscar protein, mouse; D053245:RANK Ligand; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; C498715:TREM2 protein, human; C110546:TYROBP protein, human; D053773:Transforming Growth Factor beta1; C484963:Tyrobp protein, mouse; D003094:Collagen