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Neutrophils involvement in osteoclastogenesis remains uncertain. Given that neutrophil extracellular traps (NETs) can act as inflammatory mediators in rheumatoid arthritis, we investigated the role of NETs in stimulating bone loss by potentiating osteoclastogenesis during arthritis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The level of NETs in synovial fluid from arthritis patients was assessed. Bone loss was evaluated by histology and micro\u2010CT in antigen\u2010induced arthritis (AIA)\u2010induced WT mice treated with DNase or in Padi4\u2010deficient mice (<jats:italic>Padi4<\/jats:italic><jats:sup>flox\/flox<\/jats:sup> <jats:italic>LysM<\/jats:italic><jats:sup>CRE<\/jats:sup>). The size and function of osteoclasts and the levels of RANKL and osteoprotegerin (OPG) released by osteoblasts that were incubated with NETs were measured. The expression of osteoclastogenic marker genes and protein levels were evaluated by qPCR and western blotting. To assess the participation of TLR4 and TLR9 in osteoclastogenesis, cells from <jats:italic>Tlr4<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and <jats:italic>Tlr9<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice were cultured with NETs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Rheumatoid arthritis patients had higher levels of NETs in synovial fluid than osteoarthritis patients, which correlated with increased levels of RANKL\/OPG. Moreover, patients with bone erosion had higher levels of NETs. Inhibiting NETs with DNase or Padi4 deletion alleviated bone loss in arthritic mice. Consistently, NETs enhanced RANKL\u2010induced osteoclastogenesis that was dependent on TLR4 and TLR9 and increased osteoclast resorptive functions <jats:italic>in vitro<\/jats:italic>. In addition, NETs stimulated the release of RANKL and inhibited osteoprotegerin in osteoblasts, favouring osteoclastogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Inhibiting NETs could be an alternative strategy to reduce bone erosion in arthritis patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16227","type":"journal-article","created":{"date-parts":[[2023,8,26]],"date-time":"2023-08-26T01:10:31Z","timestamp":1693012231000},"page":"429-446","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Neutrophil extracellular traps mediate bone erosion in rheumatoid arthritis by enhancing RANKL\u2010induced osteoclastogenesis"],"prefix":"10.1111","volume":"181","author":[{"given":"Ayda Henriques","family":"Schneider","sequence":"first","affiliation":[{"name":"Center of Research in Inflammatory Diseases, Ribeirao Preto Medical School University of Sao Paulo  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