期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 121, 期 9, 页码 3505-3516出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI45913
关键词
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资金
- Wellcome Trust
- Medical Research Council
- British Heart Foundation
- Korean Government
- NIH [R01 HL097805]
- EC
- Company of Biologists
- National Research Foundation of Korea [2009-0072758, 2011-0021771] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- British Heart Foundation [RG/09/003/27122] Funding Source: researchfish
- Medical Research Council [G0400701, G0901682, G9800943, G0500707] Funding Source: researchfish
- MRC [G0400701, G0500707, G0901682, G9800943] Funding Source: UKRI
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 gamma (FcR gamma) 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 FcR gamma-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 FcR gamma-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 microenvironrnents.
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