{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:23:29Z","timestamp":1787009009117,"version":"build-2736575974"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T00:00:00Z","timestamp":1667520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K15519"],"award-info":[{"award-number":["22K15519"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K16705"],"award-info":[{"award-number":["19K16705"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19H03484"],"award-info":[{"award-number":["19H03484"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical Research and Development","award":["19cm0106363h0001"],"award-info":[{"award-number":["19cm0106363h0001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Dysregulation of osteoclasts, the multinucleated cells responsible for bone resorption, contributes to several degenerative bone disorders. Previously, we showed that blocking the leukocyte immunoglobulin (Ig)-like receptor B4 (LILRB4), a kind of inhibitory receptor that plays an important role in immune regulation, promotes osteoclast differentiation in vitro. Here, we explored whether gp49B, the murine ortholog of LILRB4, regulates osteoclastogenesis in vivo, and whether fibronectin (FN), a ligand of LILRB4\/gp49B, certainly contributes to LILRB4\/gp49B-mediated osteoclastogenesis. In comparison with wild-type mice, gp49B deficiency mice exhibited a loss of trabecular bone number and an increase in osteoclast formation. Gp49B knockout improved the bone resorptive capacity of osteoclasts derived from murine Raw264.7 cells by increasing osteoclast formation. We further revealed that gp49B deficiency increased the receptor activator of nuclear factor (NF)-\u03baB ligand (RANKL)-induced signaling transduction by increasing the phosphorylation of transforming growth factor (TGF)-activated kinase 1 (TAK1), NF-\u03baB and mitogen-activated protein kinases (MAPKs). Furthermore, the N-terminal 30 kDa proteolytic fragments of FN promoted gp49B-mediated inhibition of osteoclastogenesis by increasing Src homology-2-containing tyrosine phosphatase 1 (SHP-1) phosphorylation and tumor necrosis factor receptor-associated factor 6 (TRAF6)-SHP-1 association. In summary, the FN-LILRB4\/gp49B interaction negatively regulates RANKL-induced TRAF6\/TAK1\/NF-\u03baB\/MAPK signaling in osteoclastogenesis.<\/jats:p>","DOI":"10.1093\/intimm\/dxac051","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T15:23:44Z","timestamp":1667575424000},"page":"135-145","source":"Crossref","is-referenced-by-count":15,"title":["Fibronectin-LILRB4\/gp49B interaction negatively regulates osteoclastogenesis through inhibition of RANKL-induced TRAF6\/TAK1\/NF\u2013kB\/MAPK signaling"],"prefix":"10.1093","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0630-6126","authenticated-orcid":false,"given":"Mei-Tzu","family":"Su","sequence":"first","affiliation":[{"name":"Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dai","family":"Kezuka","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shotaro","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8225-4690","authenticated-orcid":false,"given":"Yu","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine , Sendai , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4549-7116","authenticated-orcid":false,"given":"Toshiyuki","family":"Takai","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,4]]},"reference":[{"key":"2023031408042419700_","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1096\/fba.2020-00058","article-title":"Current advances in regulation of bone homeostasis","volume":"2","author":"Al-Bari","year":"2020","journal-title":"FASEB Bioadv."},{"key":"2023031408042419700_","doi-asserted-by":"crossref","first-page":"104482","DOI":"10.1016\/j.fitote.2020.104482","article-title":"A review on osteoclast diseases and osteoclastogenesis inhibitors recently developed from natural resources","volume":"142","author":"Wang","year":"2020","journal-title":"Fitoterapia"},{"key":"2023031408042419700_","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature01658","article-title":"Osteoclast differentiation and activation","volume":"423","author":"Boyle","year":"2003","journal-title":"Nature."},{"key":"2023031408042419700_","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1152\/physrev.00036.2016","article-title":"Osteoimmunology: the conceptual framework unifying the immune and skeletal systems","volume":"97","author":"Okamoto","year":"2017","journal-title":"Physiol. 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