{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:39:55Z","timestamp":1791398395944,"version":"4.3.3"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2008,10,1]],"date-time":"2008-10-01T00:00:00Z","timestamp":1222819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Osteoclasts, multinucleated cells of myeloid-monocytic origin, are responsible for bone resorption, which is crucial for maintenance of bone homeostasis in concert with bone-forming osteoblasts of nonhematopoietic, mesenchymal origin. Receptor activator of NF-\u03baB ligand (RANKL) and M-CSF, expressed on the surface of and secreted by osteoblasts, respectively, are essential factors that facilitate osteoclast formation. In contrast to the activation processes for osteoclast formation, inhibitory mechanisms for it are poorly understood. Herein we demonstrate that inhibitory Ig-like receptors recruiting Src homology 2 domain-containing tyrosine phosphatase 1 (SHP-1) are expressed on osteoclast precursor cells like other myeloid cells, and that they play a regulatory role in the development of osteoclasts. We detected cell-surface expression of paired Ig-like receptor (PIR)-B and four isoforms of leukocyte Ig-like receptor (LILR)B on cultured osteoclast precursor cells of mouse and human origin, respectively, and showed that all of these ITIM-harboring inhibitory receptors constitutively recruit SHP-1 in the presence of RANKL and M-CSF, and that some of them can suppress osteoclast development in vitro. Fluorescence energy transfer analyses have suggested that the constitutive binding of either murine PIR-B or its human ortholog LILRB1 to MHC class I molecules on the same cell surface comprises one of the mechanisms for developmental regulation. These results constitute the first evidence of the regulation of osteoclast formation by cell-surface, ITIM-harboring Ig-like receptors. Modulation of these regulatory receptors may be a novel way to control various skeletal system disorders and inflammatory arthritis.<\/jats:p>","DOI":"10.4049\/jimmunol.181.7.4742","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T23:07:10Z","timestamp":1397862430000},"page":"4742-4751","source":"Crossref","is-referenced-by-count":118,"title":["Inhibitory Immunoglobulin-Like Receptors LILRB and PIR-B Negatively Regulate Osteoclast Development"],"prefix":"10.1093","volume":"181","author":[{"given":"Yu","family":"Mori","sequence":"first","affiliation":[{"name":"Department of Experimental Immunology, Institute of Development, Aging, and Cancer, and Center of Excellence Program for Innovative Therapeutic Development Towards the Conquest of Signal Transduction Diseases, Tohoku University, Sendai, Japan, and the Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency , Saitama,","place":["Japan"]},{"name":"Department of Orthopedic Surgery, Tohoku University Graduate School of Medicine , Sendai,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sukenao","family":"Tsuji","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Institute of Development, Aging, and Cancer, and Center of Excellence Program for Innovative Therapeutic Development Towards the Conquest of Signal Transduction Diseases, Tohoku University, Sendai, Japan, and the Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency , Saitama,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Inui","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Institute of Development, Aging, and Cancer, and Center of Excellence Program for Innovative Therapeutic Development Towards the Conquest of Signal Transduction Diseases, Tohoku University, Sendai, Japan, and the Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency , Saitama,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuzuru","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Institute of Development, Aging, and Cancer, and Center of Excellence Program for Innovative Therapeutic Development Towards the Conquest of Signal Transduction Diseases, Tohoku University, Sendai, Japan, and the Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency , Saitama,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shota","family":"Endo","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Institute of Development, Aging, and Cancer, and Center of Excellence Program for Innovative Therapeutic Development Towards the Conquest of Signal Transduction Diseases, Tohoku University, Sendai, Japan, and the Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency , Saitama,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumi","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Institute of Development, Aging, and Cancer, and Center of Excellence Program for Innovative Therapeutic Development Towards the Conquest of Signal Transduction Diseases, Tohoku University, Sendai, Japan, and the Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency , Saitama,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shion","family":"Fujimura","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Institute of Development, Aging, and Cancer, and Center of Excellence Program for Innovative Therapeutic Development Towards the Conquest of Signal Transduction Diseases, Tohoku University, Sendai, Japan, and the Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency , Saitama,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takako","family":"Koga","sequence":"additional","affiliation":[{"name":"Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University and Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Institute of Development, Aging, and Cancer, and Center of Excellence Program for Innovative Therapeutic Development Towards the Conquest of Signal Transduction Diseases, Tohoku University, Sendai, Japan, and the Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency , Saitama,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Takayanagi","sequence":"additional","affiliation":[{"name":"Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University and Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiji","family":"Itoi","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Tohoku University Graduate School of Medicine , Sendai,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiyuki","family":"Takai","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Institute of Development, Aging, and Cancer, and Center of Excellence Program for Innovative Therapeutic Development Towards the Conquest of Signal Transduction Diseases, Tohoku University, Sendai, Japan, and the Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency , Saitama,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2008,10,1]]},"reference":[{"key":"2025032700303207500_R1","first-page":"1504","article-title":"Bone resorption by osteoclasts","volume-title":"Science","year":"2000"},{"key":"2025032700303207500_R2","first-page":"345","article-title":"Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families","volume-title":"Endocr. Rev.","year":"1999"},{"key":"2025032700303207500_R3","first-page":"304","article-title":"Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand","volume-title":"Nature","year":"1999"},{"key":"2025032700303207500_R4","first-page":"1291","article-title":"Essential role of macrophage colony-stimulating factor in the osteoclast differentiation supported by stromal cells","volume-title":"J. Exp. Med.","year":"1991"},{"key":"2025032700303207500_R5","first-page":"889","article-title":"Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts","volume-title":"Dev. Cell","year":"2002"},{"key":"2025032700303207500_R6","first-page":"337","article-title":"Osteoclast differentiation and activation","volume-title":"Nature","year":"2003"},{"key":"2025032700303207500_R7","first-page":"758","article-title":"Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis","volume-title":"Nature","year":"2004"},{"key":"2025032700303207500_R8","first-page":"323","article-title":"Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice","volume-title":"J. Clin. Invest.","year":"2003"},{"key":"2025032700303207500_R9","first-page":"224","article-title":"The signaling adapter protein DAP12 regulates multinucleation during osteoclast development","volume-title":"J. Bone Miner. Res.","year":"2004"},{"key":"2025032700303207500_R10","first-page":"6158","article-title":"The immunomodulatory adapter proteins DAP12 and Fc receptor \u03b3-chain (FcR\u03b3) regulate development of functional osteoclasts through the Syk tyrosine kinase","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2004"},{"key":"2025032700303207500_R11","first-page":"237","article-title":"TREM2, a DAP12-associated receptor, regulates osteoclast differentiation and function","volume-title":"J. Bone Miner. Res.","year":"2006"},{"key":"2025032700303207500_R12","first-page":"1260","article-title":"Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification","volume-title":"Genes Dev.","year":"1998"},{"key":"2025032700303207500_R13","first-page":"943","article-title":"SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts","volume-title":"Nat. Med.","year":"2002"},{"key":"2025032700303207500_R14","first-page":"223","article-title":"Deficiency of SHP-1 protein-tyrosine phosphatase activity results in heightened osteoclast function and decreased bone density","volume-title":"Am. J. Pathol.","year":"1999"},{"key":"2025032700303207500_R15","first-page":"309","article-title":"Osteoprotegerin: a novel secreted protein involved in the regulation of bone density","volume-title":"Cell","year":"1997"},{"key":"2025032700303207500_R16","first-page":"3307","article-title":"Src homology 2 (SH2)-containing 5\u2032-inositol phosphatase localizes to podosomes, and the SH2 domain is implicated in the attenuation of bone resorption in osteoclasts","volume-title":"Endocrinology","year":"2006"},{"key":"2025032700303207500_R17","first-page":"3620","article-title":"Receptor activator of NF-\u03baB ligand stimulates recruitment of SHP-1 to the complex containing TNFR-associated factor 6 that regulates osteoclastogenesis","volume-title":"J. Immunol.","year":"2003"},{"key":"2025032700303207500_R18","first-page":"2721","article-title":"Lipopolysaccharide-induced osteoclastogenesis in Src homology 2-domain phosphatase-1-deficient viable motheaten mice","volume-title":"Endocrinology","year":"2004"},{"key":"2025032700303207500_R19","first-page":"1809","article-title":"A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells","volume-title":"J. Exp. Med.","year":"1997"},{"key":"2025032700303207500_R20","first-page":"273","article-title":"A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules","volume-title":"Immunity","year":"1997"},{"key":"2025032700303207500_R21","first-page":"615","article-title":"A new human gene complex encoding the killer cell inhibitory receptors and related monocyte\/macrophage receptors","volume-title":"Curr. Biol.","year":"1997"},{"key":"2025032700303207500_R22","first-page":"32493","article-title":"Signal regulatory proteins negatively regulate immunoreceptor-dependent cell activation","volume-title":"J. Biol. Chem.","year":"1999"},{"key":"2025032700303207500_R23","first-page":"7320","article-title":"Molecular cloning of a novel murine cell-surface glycoprotein homologous to killer cell inhibitory receptors","volume-title":"J. Biol. Chem.","year":"1997"},{"key":"2025032700303207500_R24","first-page":"5261","article-title":"A novel pair of immunoglobulin-like receptors expressed by B cells and myeloid cells","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1997"},{"key":"2025032700303207500_R25","first-page":"10809","article-title":"Mouse mast cell gp49B1 contains two immunoreceptor tyrosine-based inhibition motifs and suppresses mast cell activation when coligated with the high-affinity Fc receptor for IgE","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1996"},{"key":"2025032700303207500_R26","first-page":"1070","article-title":"Association of tyrosine phosphatases SHP-1 and SHP-2, inositol 5-phosphatase SHIP with gp49B1, and chromosomal assignment of the gene","volume-title":"J. Biol. Chem.","year":"1998"},{"key":"2025032700303207500_R27","first-page":"521","article-title":"How do inhibitory phosphatases work?","volume-title":"Mol. Immunol.","year":"2002"},{"key":"2025032700303207500_R28","first-page":"3742","article-title":"The CD85\/LIR-1\/ILT2 inhibitory receptor is expressed by all human T lymphocytes and down-regulates their functions","volume-title":"J. Immunol.","year":"2000"},{"key":"2025032700303207500_R29","first-page":"84","article-title":"Immune inhibitory receptors","volume-title":"Science","year":"2000"},{"key":"2025032700303207500_R30","first-page":"161","article-title":"A novel recognition system for MHC class I molecules constituted by PIR","volume-title":"Adv. Immunol.","year":"2005"},{"key":"2025032700303207500_R31","first-page":"542","article-title":"Impaired dendritic cell maturation and increased TH2 responses in PIR-B\u2212\/\u2212 mice","volume-title":"Nat. Immunol.","year":"2002"},{"key":"2025032700303207500_R32","first-page":"307","article-title":"Cytoplasmic protein tyrosine phosphatases SHP-1 and SHP-2: regulators of B cell signal transduction","volume-title":"Curr. Opin. Immunol.","year":"2000"},{"key":"2025032700303207500_R33","first-page":"209","article-title":"LIRs\/ILTs\/MIRs, inhibitory and stimulatory Ig-superfamily receptors expressed in myeloid and lymphoid cells","volume-title":"Cytokine Growth Factor Rev.","year":"2000"},{"key":"2025032700303207500_R34","first-page":"1743","article-title":"A novel inhibitory receptor (ILT3) expressed on monocytes, macrophages, and dendritic cells involved in antigen processing","volume-title":"J. Exp. Med.","year":"1997"},{"key":"2025032700303207500_R35","first-page":"215","article-title":"The LILR family: modulators of innate and adaptive immune pathways in health and disease","volume-title":"Tissue Antigens","year":"2004"},{"key":"2025032700303207500_R36","first-page":"623","article-title":"Exacerbated graft-versus-host disease in Pirb\u2212\/\u2212 mice","volume-title":"Nat. Immunol.","year":"2004"},{"key":"2025032700303207500_R37","first-page":"913","article-title":"Crystal structure of HLA-A2 bound to LIR-1, a host and viral major histocompatibility complex receptor","volume-title":"Nat. Immunol.","year":"2003"},{"key":"2025032700303207500_R38","first-page":"907","article-title":"Cis binding between inhibitory receptors and MHC class I can regulate mast cell activation","volume-title":"J. Exp. Med.","year":"2007"},{"key":"2025032700303207500_R39","first-page":"148","article-title":"Selecting the right fluorophores and flow cytometer for fluorescence resonance energy transfer measurements","volume-title":"Cytometry A","year":"2005"},{"key":"2025032700303207500_R40","first-page":"15086","article-title":"Constitutive tyrosine phosphorylation of the inhibitory paired Ig-like receptor PIR-B","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1999"},{"key":"2025032700303207500_R41","first-page":"1","article-title":"Fc receptors and their role in immune regulation and autoimmunity","volume-title":"J. Clin. Immunol.","year":"2005"},{"key":"2025032700303207500_R42","first-page":"5543","article-title":"Cutting edge: Leukocyte receptor complex-encoded immunomodulatory receptors show differing specificity for alternative HLA-B27 structures","volume-title":"J. Immunol.","year":"2001"},{"key":"2025032700303207500_R43","first-page":"101","article-title":"The CMRF-35H gene structure predicts for an independently expressed member of an ITIM\/ITAM pair of molecules localized to human chromosome 17","volume-title":"Tissue Antigens","year":"2000"},{"key":"2025032700303207500_R44","first-page":"6541","article-title":"CMRF-35-like molecule-1, a novel mouse myeloid receptor, can inhibit osteoclast formation","volume-title":"J. Immunol.","year":"2003"},{"key":"2025032700303207500_R45","first-page":"2469","article-title":"Extensive polymorphisms of LILRB1 (ILT2, LIR1) and their association with HLA-DRB1 shared epitope negative rheumatoid arthritis","volume-title":"Hum. Mol. Genet.","year":"2005"},{"key":"2025032700303207500_R46","first-page":"121","article-title":"Common polymorphisms and alternative splicing in the ILT3 gene are not associated with atopy","volume-title":"Eur. J. Immunogenet.","year":"2000"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/7\/4742\/62580034\/7811.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/7\/4742\/62580034\/7811.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T21:34:16Z","timestamp":1743284056000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/181\/7\/4742\/8008086"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,10,1]]},"references-count":46,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2008,10,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.181.7.4742","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2008,10]]},"published":{"date-parts":[[2008,10,1]]}}}