{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:39:49Z","timestamp":1785436789346,"version":"3.56.0"},"posted":{"date-parts":[[2026,2,14]]},"group-title":"Cell Biology","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T00:00:00Z","timestamp":1771027200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["AR073156, AR08176, and AR 083374"],"award-info":[{"award-number":["AR073156, AR08176, and AR 083374"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Inflammation is associated with an influx of inflammatory macrophages and increased activation and differentiation of osteoclasts. Receptor activator of NF-kB ligand (RANKL) is a key driver for osteoclast differentiation. However, the pathogenic mechanisms augmenting RANKL-induced osteoclast differentiation in inflammatory conditions are not fully elucidated. Here, we show that TNF-\u03b1 converting enzyme (TACE) plays a critical role in pathological bone erosion and enhances osteoclast differentiation in inflammatory conditions. Myeloid cell-specific TACE deletion in a murine arthritis model attenuates joint inflammation and bone destruction. TACE deficiency suppresses distal RANKL signaling in macrophages by increasing IRF3 activation, while enhancing proximal RANKL signaling, leading to the suppression of osteoclast differentiation. Mechanistically, IRF3 activation limits macrophage reprogramming by suppressing NFATc1 and HB-EGF in response to RANKL through a non-canonical pathway. HB-EGF, a TACE substrate, activates EGFR signaling and promotes osteoclastogenesis by inhibiting IRF3 activation. TACE regulates the reciprocal inhibition of the IRF3-HBEGF axis. Our study highlights a role for TACE as a rheostat, balancing both pro- and anti-osteoclastogenic signals.<\/jats:p>","DOI":"10.64898\/2026.02.11.705073","type":"posted-content","created":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T11:10:11Z","timestamp":1771067411000},"source":"Crossref","is-referenced-by-count":0,"title":["TACE reprograms RANKL-mediated differentiation of macrophages by activating the non-canonical pathway of IRF3"],"prefix":"10.64898","author":[{"given":"Se Hwan","family":"Mun","sequence":"first","affiliation":[{"name":"The SHORE Program,"},{"name":"Research Institute of Women\u2019s Health, Sookmyung Women\u2019s University, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Oh","sequence":"additional","affiliation":[{"name":"The SHORE Program,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunichi","family":"Yokota","sequence":"additional","affiliation":[{"name":"The SHORE Program,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Umemoto","sequence":"additional","affiliation":[{"name":"The SHORE Program,"},{"name":"Department of Medicine, Weill Cornell Medical College, New York, New York, 10065 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Suh","sequence":"additional","affiliation":[{"name":"The SHORE Program,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyuho","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju 28644, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woojung","family":"Kim","sequence":"additional","affiliation":[{"name":"The SHORE Program,"},{"name":"Research Institute of Women\u2019s Health, Sookmyung Women\u2019s University, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Oliver","sequence":"additional","affiliation":[{"name":"David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Pannellini","sequence":"additional","affiliation":[{"name":"The SHORE Program,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geunho","family":"Kwon","sequence":"additional","affiliation":[{"name":"The SHORE Program,"},{"name":"Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju 28644, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young","family":"Yang","sequence":"additional","affiliation":[{"name":"Research Institute of Women\u2019s Health, Sookmyung Women\u2019s University, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5388-3411","authenticated-orcid":false,"given":"Liang","family":"Deng","sequence":"additional","affiliation":[{"name":"Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA"},{"name":"Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York 10065, USA"},{"name":"Department of Dermatology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung-Hyun","family":"Park-Min","sequence":"additional","affiliation":[{"name":"The SHORE Program,"},{"name":"David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York 10021, USA"},{"name":"Department of Medicine, Weill Cornell Medical College, New York, New York, 10065 USA"},{"name":"BCMB Allied Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026021705501264000_2026.02.11.705073v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmra2103726"},{"key":"2026021705501264000_2026.02.11.705073v1.2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.rheumatology.a005707"},{"key":"2026021705501264000_2026.02.11.705073v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3669"},{"key":"2026021705501264000_2026.02.11.705073v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nature01658"},{"key":"2026021705501264000_2026.02.11.705073v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nri2062"},{"key":"2026021705501264000_2026.02.11.705073v1.6","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1007\/s00018-018-2817-9","article-title":"Mechanisms involved in normal and pathological osteoclastogenesis","volume":"75","year":"2018","journal-title":"Cell Mol Life Sci"},{"key":"2026021705501264000_2026.02.11.705073v1.7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1004965"},{"key":"2026021705501264000_2026.02.11.705073v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0178-8"},{"key":"2026021705501264000_2026.02.11.705073v1.9","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pathmechdis.3.121806.151431"},{"key":"2026021705501264000_2026.02.11.705073v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0378-1"},{"key":"2026021705501264000_2026.02.11.705073v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0526-7"},{"key":"2026021705501264000_2026.02.11.705073v1.12","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1038\/s41467-025-57361-0","article-title":"Single cell immunoprofile of synovial fluid in rheumatoid arthritis with TNF\/JAK inhibitor treatment","volume":"16","year":"2025","journal-title":"Nat Commun"},{"key":"2026021705501264000_2026.02.11.705073v1.13","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41413-021-00162-0","article-title":"Augmenting MNK1\/2 activation by c-FMS proteolysis promotes osteoclastogenesis and arthritic bone erosion","volume":"9","year":"2021","journal-title":"Bone Res"},{"key":"2026021705501264000_2026.02.11.705073v1.14","doi-asserted-by":"publisher","DOI":"10.14348\/molcells.2017.0225"},{"key":"2026021705501264000_2026.02.11.705073v1.15","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1084\/jem.190.12.1741","article-title":"Suda T Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-fms and receptor activator of nuclear factor kB (RANK) receptors","volume":"190","year":"1999","journal-title":"J Experimental Medicine"},{"key":"2026021705501264000_2026.02.11.705073v1.16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.7.3597"},{"key":"2026021705501264000_2026.02.11.705073v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/36593"},{"key":"2026021705501264000_2026.02.11.705073v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2009.175"},{"key":"2026021705501264000_2026.02.11.705073v1.19","doi-asserted-by":"publisher","DOI":"10.1172\/JCI11176"},{"key":"2026021705501264000_2026.02.11.705073v1.20","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050978"},{"key":"2026021705501264000_2026.02.11.705073v1.21","first-page":"799575","article-title":"The Efficacy of Denosumab in Patients With Rheumatoid Arthritis: A Systematic Review and Pooled Analysis of Randomized or Matched Data","volume":"12","year":"2021","journal-title":"Front Immunol"},{"key":"2026021705501264000_2026.02.11.705073v1.22","doi-asserted-by":"publisher","DOI":"10.1002\/art.23417"},{"key":"2026021705501264000_2026.02.11.705073v1.23","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.jbspin.2015.07.010","article-title":"The roles of interferons in osteoclasts and osteoclastogenesis","volume":"83","year":"2016","journal-title":"Joint Bone Spine"},{"key":"2026021705501264000_2026.02.11.705073v1.24","doi-asserted-by":"publisher","DOI":"10.1186\/ar581"},{"key":"2026021705501264000_2026.02.11.705073v1.25","doi-asserted-by":"crossref","first-page":"127660","DOI":"10.1016\/j.micres.2024.127660","article-title":"Gut microbiota and metabolites as predictors of biologics response in inflammatory bowel disease: A comprehensive systematic review","volume":"282","year":"2024","journal-title":"Microbiol Res"},{"key":"2026021705501264000_2026.02.11.705073v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/nri1900"},{"key":"2026021705501264000_2026.02.11.705073v1.27","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1002\/jbmr.3701","article-title":"Cyclic Dinucleotides Inhibit Osteoclast Differentiation Through STING-Mediated Interferon-beta Signaling","volume":"34","year":"2019","journal-title":"J Bone Miner Res"},{"key":"2026021705501264000_2026.02.11.705073v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/nature08476"},{"key":"2026021705501264000_2026.02.11.705073v1.29","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1038\/s43018-022-00468-w","article-title":"The cGAS-STING pathway and cancer","volume":"3","year":"2022","journal-title":"Nat Cancer"},{"key":"2026021705501264000_2026.02.11.705073v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2011.05.005"},{"key":"2026021705501264000_2026.02.11.705073v1.31","doi-asserted-by":"publisher","DOI":"10.2174\/138161209788682398"},{"key":"2026021705501264000_2026.02.11.705073v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2014.08.008"},{"key":"2026021705501264000_2026.02.11.705073v1.33","doi-asserted-by":"publisher","DOI":"10.1172\/jci66168"},{"key":"2026021705501264000_2026.02.11.705073v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(03)01022-6"},{"key":"2026021705501264000_2026.02.11.705073v1.35","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1186\/s12964-024-01690-y","article-title":"Downregulation of the metalloproteinases ADAM10 or ADAM17 promotes osteoclast differentiation","volume":"22","year":"2024","journal-title":"Cell Commun Signal"},{"key":"2026021705501264000_2026.02.11.705073v1.36","doi-asserted-by":"publisher","DOI":"10.1007\/s00774-006-0725-9"},{"key":"2026021705501264000_2026.02.11.705073v1.37","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200109)44:9<2009::AID-ART349>3.0.CO;2-L"},{"key":"2026021705501264000_2026.02.11.705073v1.38","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200105)44:5<1003::AID-ANR179>3.0.CO;2-#"},{"key":"2026021705501264000_2026.02.11.705073v1.39","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1002\/art.1780380614","article-title":"Osteoporosis in rheumatoid arthritis. A monozygotic co-twin control study","volume":"38","year":"1995","journal-title":"Arthritis Rheum"},{"key":"2026021705501264000_2026.02.11.705073v1.40","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"2026021705501264000_2026.02.11.705073v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/ng1180"},{"key":"2026021705501264000_2026.02.11.705073v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/416744a"},{"key":"2026021705501264000_2026.02.11.705073v1.43","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gene.6364449"},{"key":"2026021705501264000_2026.02.11.705073v1.44","doi-asserted-by":"publisher","DOI":"10.1172\/JCI89935"},{"key":"2026021705501264000_2026.02.11.705073v1.45","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg264"},{"key":"2026021705501264000_2026.02.11.705073v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/J.AJPATH.2018.07.016"},{"key":"2026021705501264000_2026.02.11.705073v1.47","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/S0952-7915(05)80017-2","article-title":"Immunotherapy in autoimmune diseases","volume":"3","year":"1991","journal-title":"Curr Opin Immunol"},{"key":"2026021705501264000_2026.02.11.705073v1.48","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0939-8"},{"key":"2026021705501264000_2026.02.11.705073v1.49","doi-asserted-by":"crossref","unstructured":"Kuo D , et al. HBEGF(+) macrophages in rheumatoid arthritis induce fibroblast invasiveness. Sci Transl Med 11, (2019).","DOI":"10.1126\/scitranslmed.aau8587"},{"key":"2026021705501264000_2026.02.11.705073v1.50","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1038\/s41467-024-45213-2","article-title":"Single-cell insights into immune dysregulation in rheumatoid arthritis flare versus drug-free remission","volume":"15","year":"2024","journal-title":"Nat Commun"},{"key":"2026021705501264000_2026.02.11.705073v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2012.153"},{"key":"2026021705501264000_2026.02.11.705073v1.52","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/s41392-024-01980-4","article-title":"The multiple roles of interferon regulatory factor family in health and disease","volume":"9","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"2026021705501264000_2026.02.11.705073v1.53","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2210409120"},{"key":"2026021705501264000_2026.02.11.705073v1.54","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.23094"},{"key":"2026021705501264000_2026.02.11.705073v1.55","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M403114200"},{"key":"2026021705501264000_2026.02.11.705073v1.56","doi-asserted-by":"crossref","first-page":"5418","DOI":"10.1038\/ncomms6418","article-title":"Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation","volume":"5","year":"2014","journal-title":"Nature communications"},{"key":"2026021705501264000_2026.02.11.705073v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.11.010"},{"key":"2026021705501264000_2026.02.11.705073v1.58","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.immuni.2017.06.018","article-title":"Hypoxia-Sensitive COMMD1 Integrates Signaling and Cellular Metabolism in Human Macrophages and Suppresses Osteoclastogenesis","volume":"47","year":"2017","journal-title":"Immunity"},{"key":"2026021705501264000_2026.02.11.705073v1.59","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1991.tb04978.x"},{"key":"2026021705501264000_2026.02.11.705073v1.60","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.5.2686"},{"key":"2026021705501264000_2026.02.11.705073v1.61","doi-asserted-by":"crossref","unstructured":"Baldon LVR , et al. AG129 Mice as a Comprehensive Model for the Experimental Assessment of Mosquito Vector Competence for Arboviruses. Pathogens 11, (2022).","DOI":"10.3390\/pathogens11080879"},{"key":"2026021705501264000_2026.02.11.705073v1.62","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.141"},{"key":"2026021705501264000_2026.02.11.705073v1.63","doi-asserted-by":"publisher","DOI":"10.1172\/JCI69443"},{"key":"2026021705501264000_2026.02.11.705073v1.64","doi-asserted-by":"publisher","DOI":"10.1002\/art.24619"},{"key":"2026021705501264000_2026.02.11.705073v1.65","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/jbmr.5650020617","article-title":"Bone histomorphometry:stardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee","volume":"2","year":"1987","journal-title":"J Bone Mineral Research"},{"key":"2026021705501264000_2026.02.11.705073v1.66","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.07.017"},{"key":"2026021705501264000_2026.02.11.705073v1.67","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0939-8"},{"key":"2026021705501264000_2026.02.11.705073v1.68","doi-asserted-by":"crossref","unstructured":"Zhang B , et al. CD127 imprints functional heterogeneity to diversify monocyte responses in inflammatory diseases. J Exp Med 219, (2022).","DOI":"10.1084\/jem.20211191"},{"key":"2026021705501264000_2026.02.11.705073v1.69","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-021-00881-3"},{"key":"2026021705501264000_2026.02.11.705073v1.70","doi-asserted-by":"crossref","first-page":"112502","DOI":"10.1016\/j.isci.2025.112502","article-title":"Epigenomic landscapes define differential Janus kinases inhibitor sensitivity in IFN-gamma-primed human macrophages","volume":"28","year":"2025","journal-title":"iScience"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.02.11.705073","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T13:50:22Z","timestamp":1771336222000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.02.11.705073"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,14]]},"references-count":70,"URL":"https:\/\/doi.org\/10.64898\/2026.02.11.705073","relation":{},"subject":[],"published":{"date-parts":[[2026,2,14]]},"subtype":"preprint"}}