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The aim of this study was to investigate whether\n                    <jats:italic>Pg-<\/jats:italic>\n                    derived EVs can be transported and exacerbate bone destruction in RA by promoting osteoclastogenesis and to elucidate the underlying mechanisms involved. EVs derived from\n                    <jats:italic>Porphyromonas endodontalis<\/jats:italic>\n                    (\n                    <jats:italic>Pe<\/jats:italic>\n                    ), which is weakly associated with PD or RA, were used as controls.\n                    <jats:italic>Pg<\/jats:italic>\n                    and\n                    <jats:italic>Pe<\/jats:italic>\n                    EVs interact with osteoclasts after translocating into the marrow and metacarpal joints of mice. In vitro,\n                    <jats:italic>Pg<\/jats:italic>\n                    EVs induce osteoclastogenesis via various components, such as lipopolysaccharide, proteins, lipoproteins, and proteases. TNF-\u03b1, IL-1\u03b2, and IL-6 promote but cannot independently control\n                    <jats:italic>Pg<\/jats:italic>\n                    EV-induced osteoclastogenesis. RNA sequencing and verification experiments further demonstrated that\n                    <jats:italic>Pg<\/jats:italic>\n                    EVs induced osteoclastogenesis by promoting the phosphorylation of spleen tyrosine kinase (Syk). In vivo,\n                    <jats:italic>Pg<\/jats:italic>\n                    EVs exacerbated RA-induced bone destruction by activating Syk-dependent osteoclastogenesis. R406, a Syk inhibitor, significantly attenuated\n                    <jats:italic>Pg<\/jats:italic>\n                    EV-induced RA osteoclastogenesis and bone destruction. However,\n                    <jats:italic>Pe-<\/jats:italic>\n                    derived EVs presented an extremely weak ability to promote osteoclastogenesis and RA. Our findings reveal a new mechanism by which\n                    <jats:italic>Pg<\/jats:italic>\n                    EVs can exacerbate RA via transport through the circulation and the promote Syk-dependent osteoclastogenesis. This study deepens our understanding of the significant pathogenic role of EVs derived from oral bacterial in RA and explores targeted therapeutic strategies by inhibiting the activation of Syk.\n                  <\/jats:p>","DOI":"10.1038\/s41368-025-00416-1","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:03:37Z","timestamp":1770249817000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Porphyromonas gingivalis-derived extracellular vesicles aggravate bone destruction in rheumatoid arthritis by promoting Syk-dependent osteoclastogenesis"],"prefix":"10.1038","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4116-6512","authenticated-orcid":false,"given":"Jiajie","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4180-0883","authenticated-orcid":false,"given":"Qiujing","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyuan","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiyue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengcheng","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirohiko","family":"Okamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaya","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongchen","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihong","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"416_CR1","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1038\/nature01661","volume":"423","author":"GS Firestein","year":"2003","unstructured":"Firestein, G. 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