{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:14:56Z","timestamp":1791231296477,"version":"4.1.0"},"reference-count":32,"publisher":"National Academy of Sciences","issue":"16","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2004,4,20]]},"abstract":"<jats:p>\n                    Osteoclasts, the only bone-resorbing cells, are central to the pathogenesis of osteoporosis, yet their development and regulation are incompletely understood. Multiple receptors of the immune system use a common signaling paradigm whereby phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) within receptor-associated adapter proteins recruit the Syk tyrosine kinase. Here we demonstrate that a similar mechanism is required for development of functional osteoclasts. Mice lacking two ITAM-bearing adapters, DAP12 and the Fc receptor \u03b3-chain (FcR\u03b3), are severely osteopetrotic.\n                    <jats:italic>DAP12<\/jats:italic>\n                    <jats:sup>-\/-<\/jats:sup>\n                    <jats:italic>FcR<\/jats:italic>\n                    \u03b3\n                    <jats:sup>-\/-<\/jats:sup>\n                    bone marrow cells fail to differentiate into multinucleated osteoclasts or resorb bone\n                    <jats:italic>in vitro<\/jats:italic>\n                    and show impaired phosphorylation of the Syk tyrosine kinase.\n                    <jats:italic>syk<\/jats:italic>\n                    <jats:sup>-\/-<\/jats:sup>\n                    progenitors are similarly defective in osteoclast development and bone resorption. Intact SH2-domains of Syk, introduced by retroviral transduction, are required for functional reconstitution of\n                    <jats:italic>syk<\/jats:italic>\n                    <jats:sup>-\/-<\/jats:sup>\n                    osteoclasts, whereas intact ITAM-domains on DAP12 are required for reconstitution of\n                    <jats:italic>DAP12<\/jats:italic>\n                    <jats:sup>-\/-<\/jats:sup>\n                    <jats:italic>FcR<\/jats:italic>\n                    \u03b3\n                    <jats:sup>-\/-<\/jats:sup>\n                    cells. These data indicate that recruitment of Syk to phosphorylated ITAMs is critical for osteoclastogenesis. Although DAP12 appears to be primarily responsible for osteoclast differentiation in cultures directly stimulated with macrophage-colony stimulating factor and receptor activator of NF-\u03baB ligand cytokines, DAP12 and FcR\u03b3 have overlapping roles in supporting osteoclast development in osteoblast\u2013osteoclast cocultures, which mirrors their overlapping functions\n                    <jats:italic>in vivo<\/jats:italic>\n                    . These results provide new insight into the biology of osteoclasts and suggest novel therapeutic targets in diseases of bony remodeling.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0401602101","type":"journal-article","created":{"date-parts":[[2004,4,8]],"date-time":"2004-04-08T20:13:45Z","timestamp":1081455225000},"page":"6158-6163","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":417,"title":["The immunomodulatory adapter proteins DAP12 and Fc receptor \u03b3-chain (FcR\u03b3) regulate development of functional osteoclasts through the Syk tyrosine kinase"],"prefix":"10.1073","volume":"101","author":[{"given":"Attila","family":"M\u00f3csai","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Department of Medicine and Department of Veterans Affairs Medical Center, Magnetic Resonance Science Center, Department of Radiology, andDepartment of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, CA 94143; and Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Beth","family":"Humphrey","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Department of Medicine and Department of Veterans Affairs Medical Center, Magnetic Resonance Science Center, Department of Radiology, andDepartment of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, CA 94143; and Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica A. G.","family":"Van Ziffle","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Department of Medicine and Department of Veterans Affairs Medical Center, Magnetic Resonance Science Center, Department of Radiology, andDepartment of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, CA 94143; and Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongmei","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Department of Medicine and Department of Veterans Affairs Medical Center, Magnetic Resonance Science Center, Department of Radiology, andDepartment of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, CA 94143; and Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Burghardt","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Department of Medicine and Department of Veterans Affairs Medical Center, Magnetic Resonance Science Center, Department of Radiology, andDepartment of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, CA 94143; and Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven C.","family":"Spusta","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Department of Medicine and Department of Veterans Affairs Medical Center, Magnetic Resonance Science Center, Department of Radiology, andDepartment of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, CA 94143; and Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharmila","family":"Majumdar","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Department of Medicine and Department of Veterans Affairs Medical Center, Magnetic Resonance Science Center, Department of Radiology, andDepartment of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, CA 94143; and Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lewis L.","family":"Lanier","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Department of Medicine and Department of Veterans Affairs Medical Center, Magnetic Resonance Science Center, Department of Radiology, andDepartment of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, CA 94143; and Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clifford A.","family":"Lowell","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Department of Medicine and Department of Veterans Affairs Medical Center, Magnetic Resonance Science Center, Department of Radiology, andDepartment of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, CA 94143; and Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary C.","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Department of Medicine and Department of Veterans Affairs Medical Center, Magnetic Resonance Science Center, Department of Radiology, andDepartment of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, CA 94143; and Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2004,4,8]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01658"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-5699(99)01574-1"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-5699(00)01745-X"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90115-5"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/77153"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20022220"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030027"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI16923"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.10694"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1359\/JBMR.0301234"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.49.32934"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)00034-0"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/378298a0"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(02)00303-5"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2818.1997.1340694.x"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1080\/01495739708936692"},{"key":"e_1_3_2_17_2","first-page":"19","volume":"80","year":"2003","unstructured":"Bakker, A. & Klein-Nulend, J. (2003) Methods Mol. Med. 80, 19-28.12728707","journal-title":"Methods Mol. Med."},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90499-O"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/16852"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200316924"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200212082"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.21.6414"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.194.8.1111"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(01)00221-7"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200112113"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(02)00420-X"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1007\/s007740070007"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207657200"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.152.1.181"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/383528a0"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M206579200"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(02)00369-6"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0401602101","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T22:19:02Z","timestamp":1650925142000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0401602101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,4,8]]},"references-count":32,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2004,4,20]]}},"alternative-id":["10.1073\/pnas.0401602101"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0401602101","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,4,8]]},"assertion":[{"value":"2004-01-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2004-04-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}