{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T09:27:21Z","timestamp":1790242041778,"version":"4.1.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2013,5,15]],"date-time":"2013-05-15T00:00:00Z","timestamp":1368576000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>\u2003<\/jats:title>\n                    <jats:p>Siglecs are a family of sialic acid\u2013binding immunoglobulin-like lectins that regulate the functions of cells in the innate and adaptive immune systems through glycan recognition. Here we show that Siglec-15 regulates osteoclast development and bone resorption by modulating receptor activator of nuclear factor \u03baB ligand (RANKL) signaling in association with DNAX-activating protein 12\u2009kDa (DAP12), an adaptor protein bearing an immunoreceptor tyrosine-based activation motif (ITAM). Among the known Siglecs expressed in myeloid lineage cells, only Siglec-15 was upregulated by RANKL in mouse primary bone marrow macrophages. Siglec-15\u2013deficient mice exhibit mild osteopetrosis resulting from impaired osteoclast development. Consistently, cells lacking Siglec-15 exhibit defective osteoclast development and resorptive activity in vitro. RANKL-induced activation of phosphatidylinositol 3-kinase (PI3K)\/Akt and Erk pathways were impaired in Siglec-15\u2013deficient cells. Retroviral transduction of Siglec-15\u2013null osteoclast precursors with wild-type Siglec-15 or mutant Siglec-15 revealed that the association of Siglec-15 with DAP12 is involved in the downstream signal transduction of RANK. Furthermore, we found that the ability of osteoclast formation is preserved in the region adjacent to the growth plate in Siglec-15\u2013deficient mice, indicating that there is a compensatory mechanism for Siglec-15\u2013mediated osteoclastogenesis in the primary spongiosa. To clarify the mechanism of this compensation, we examined whether osteoclast-associated receptor (OSCAR)\/Fc receptor common \u03b3 (FcR\u03b3) signaling, an alternative ITAM-mediated signaling pathway to DAP12, rescues impaired osteoclastogenesis in Siglec-15\u2013deficient cells. The ligands in type II collagen activate OSCAR and rescue impaired osteoclastogenesis in Siglec-15\u2013deficient cells when cultured on bone slices, indicating that Siglec-15\u2013mediated signaling can be compensated for by signaling activated by type II collagen and other bone matrix components in the primary spongiosa. Our findings indicate that Siglec-15 plays an important role in physiologic bone remodeling by modulating RANKL signaling, especially in the secondary spongiosa. \u00a9 2013 American Society for Bone and Mineral Research.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jbmr.1989","type":"journal-article","created":{"date-parts":[[2013,5,15]],"date-time":"2013-05-15T08:48:42Z","timestamp":1368607722000},"page":"2463-2475","source":"Crossref","is-referenced-by-count":120,"title":["Siglec-15 Regulates Osteoclast Differentiation by Modulating RANKL-Induced Phosphatidylinositol 3-Kinase\/Akt and Erk Pathways in Association With Signaling Adaptor DAP12"],"prefix":"10.1093","volume":"28","author":[{"given":"Yusuke","family":"Kameda","sequence":"first","affiliation":[{"name":"Department of Orthopedic SurgerySchool of MedicineHokkaido UniversitySapporoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Takahata","sequence":"additional","affiliation":[{"name":"Department of Orthopedic SurgerySchool of MedicineHokkaido UniversitySapporoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Komatsu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic SurgerySchool of MedicineHokkaido UniversitySapporoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shintaro","family":"Mikuni","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Cell DynamicsFaculty of Advanced Life ScienceHokkaido UniversitySapporoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigetsugu","family":"Hatakeyama","sequence":"additional","affiliation":[{"name":"Department of BiochemistrySchool of MedicineHokkaido UniversitySapporoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic SurgerySchool of MedicineHokkaido UniversitySapporoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Angata","sequence":"additional","affiliation":[{"name":"Glycan Recognition TeamSystems Glycobiology Research GroupRIKEN Advanced Science InstituteWakoSaitamaJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Kinjo","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Cell DynamicsFaculty of Advanced Life ScienceHokkaido UniversitySapporoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Minami","sequence":"additional","affiliation":[{"name":"Department of Orthopedic SurgerySchool of MedicineHokkaido UniversitySapporoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norimasa","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Department of Orthopedic SurgerySchool of MedicineHokkaido UniversitySapporoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,5,15]]},"reference":[{"issue":"2","key":"2024020318332723700_jbmr1989-bib-0001","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1359\/JBMR.0301234","article-title":"The signaling adapter protein DAP12 regulates multinucleation during osteoclast development","volume":"19","author":"Humphrey","year":"2004","journal-title":"J Bone Miner Res."},{"issue":"3","key":"2024020318332723700_jbmr1989-bib-0002","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1172\/JCI16923","article-title":"Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice","volume":"111","author":"Kaifu","year":"2003","journal-title":"J Clin Invest."},{"issue":"6984","key":"2024020318332723700_jbmr1989-bib-0003","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/nature02444","article-title":"Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis","volume":"428","author":"Koga","year":"2004","journal-title":"Nature."},{"issue":"16","key":"2024020318332723700_jbmr1989-bib-0004","doi-asserted-by":"crossref","first-page":"6158","DOI":"10.1073\/pnas.0401602101","article-title":"The immunomodulatory adapter proteins DAP12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase","volume":"101","author":"Mocsai","year":"2004","journal-title":"Proc Natl Acad Sci USA."},{"issue":"Pt 17","key":"2024020318332723700_jbmr1989-bib-0005","doi-asserted-by":"crossref","first-page":"2955","DOI":"10.1242\/jcs.069872","article-title":"Cytoskeletal dysfunction dominates in DAP12-deficient osteoclasts","volume":"123","author":"Zou","year":"2010","journal-title":"J Cell Sci."},{"issue":"2","key":"2024020318332723700_jbmr1989-bib-0006","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1359\/JBMR.051016","article-title":"TREM2, a DAP12-associated receptor, regulates osteoclast differentiation and function","volume":"21","author":"Humphrey","year":"2006","journal-title":"J Bone Miner Res."},{"issue":"2","key":"2024020318332723700_jbmr1989-bib-0007","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1084\/jem.20011681","article-title":"A novel member of the leukocyte receptor complex regulates osteoclast differentiation","volume":"195","author":"Kim","year":"2002","journal-title":"J Exp Med."},{"issue":"27","key":"2024020318332723700_jbmr1989-bib-0008","doi-asserted-by":"crossref","first-page":"11394","DOI":"10.1073\/pnas.0701971104","article-title":"Pathological role of osteoclast costimulation in arthritis-induced bone 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Report of the ASBMR Histomorphometry Nomenclature Committee","volume":"2","author":"Parfitt","year":"1987","journal-title":"J Bone Miner Res."},{"issue":"8","key":"2024020318332723700_jbmr1989-bib-0017","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1359\/jbmr.2000.15.8.1477","article-title":"Identification and characterization of the new osteoclast progenitor with macrophage phenotypes being able to differentiate into mature osteoclasts","volume":"15","author":"Takeshita","year":"2000","journal-title":"J Bone Miner Res."},{"issue":"8","key":"2024020318332723700_jbmr1989-bib-0018","doi-asserted-by":"crossref","first-page":"4254","DOI":"10.4049\/jimmunol.165.8.4254","article-title":"Endogenous production of TGF-beta is essential for osteoclastogenesis induced by a combination of receptor activator of NF-kappa B ligand and macrophage-colony-stimulating factor","volume":"165","author":"Kaneda","year":"2000","journal-title":"J 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