{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T18:56:17Z","timestamp":1768589777960,"version":"3.49.0"},"reference-count":75,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"crossref","award":["DE-025255 (XH)"],"award-info":[{"award-number":["DE-025255 (XH)"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"crossref","award":["DE-027851 (TK)"],"award-info":[{"award-number":["DE-027851 (TK)"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"crossref","award":["DE-028715 (TK)"],"award-info":[{"award-number":["DE-028715 (TK)"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"crossref","award":["DE029709-S2 (TK, EL-trainee)"],"award-info":[{"award-number":["DE029709-S2 (TK, EL-trainee)"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"crossref","award":["DE-032156 (XH)"],"award-info":[{"award-number":["DE-032156 (XH)"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"crossref","award":["DE-032907 (SS)"],"award-info":[{"award-number":["DE-032907 (SS)"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"crossref","award":["DE-034069 (SS)"],"award-info":[{"award-number":["DE-034069 (SS)"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"crossref","award":["DE-034154 (TK)"],"award-info":[{"award-number":["DE-034154 (TK)"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Science","doi-asserted-by":"crossref","award":["GM150469 (AH)"],"award-info":[{"award-number":["GM150469 (AH)"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Porphyromonas gingivalis (Pg), a keystone pathogen of chronic periodontitis, releases outer membrane vesicles (OMVs) that act as nanoscale vehicles to disseminate virulence factors within periodontal tissues and systemically beyond the oral cavity. Although Pg-OMVs are increasingly recognized as critical mediators of host\u2013pathogen interactions, their effects on the differentiation and function of monocyte\u2013macrophage\/osteoclast lineage cells remain unclear. Here, we examined the impact of Pg-OMVs on the differentiation of RAW264.7 monocyte\/macrophage-like cells into osteoclasts (OC) and\/or macrophages (M\u03a6) in the presence of receptor activator of nuclear factor-\u03baB ligand (RANKL). OMVs were isolated from Pg W83 and applied to RANKL-primed RAW264.7 cells using three distinct stimulation schedules: (1) simultaneous treatment with Pg-OMVs and RANKL at Day 0; (2) RANKL priming at Day 0 followed by Pg-OMV stimulation at Day 1; and (3) RANKL priming at Day 0 followed by Pg-OMV stimulation at Day 3. In all schedules, cells were cultured for 7 days from the initial RANKL exposure. Remarkably, simultaneous exposure to Pg-OMVs and RANKL (Schedule 1) markedly suppressed osteoclastogenesis (OC-genesis) while promoting M1 macrophage polarization. In contrast, delayed Pg-OMV stimulation of RANKL-primed cells (Schedules 2 and 3) significantly enhanced OC-genesis while reducing M1 polarization. These schedule-dependent effects were consistent with altered expression of osteoclastogenic markers, including dc-stamp, oc-stamp, nfatc1, and acp5. Importantly, a monoclonal antibody against OC-STAMP counteracted the Pg-OMV-induced upregulation of OC-genesis in Schedules 2 and 3. Furthermore, levels of Pg-OMV phagocytosis were inversely correlated with osteoclast formation. Finally, co-stimulation with RANKL and Pg-OMVs (Schedule 1) enhanced macrophage migratory capacity, whereas delayed stimulation with Pg-OMVs (Schedules 2 and 3) did not. Collectively, these findings indicate that Pg-OMVs exert stage-specific effects on the OC\/M\u03a6 lineage: stimulation at early stages of RANKL priming suppresses OC-genesis and promotes M1 polarization, whereas stimulation at later stages enhances OC-genesis without inducing M1 differentiation. Thus, Pg-OMVs may critically influence the fate of the OC\/M\u03a6 unit in periodontal lesions, contributing to disease progression and tissue destruction.<\/jats:p>","DOI":"10.3390\/ijms27020831","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T15:12:04Z","timestamp":1768403524000},"page":"831","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Porphyromonas gingivalis Vesicles Control Osteoclast\u2013Macrophage Lineage Fate"],"prefix":"10.3390","volume":"27","author":[{"given":"Elizabeth","family":"Leon","sequence":"first","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4904-3880","authenticated-orcid":false,"given":"Shin","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"},{"name":"Department of Periodontics and Endodontics, Division of Dentistry, Okayama University Hospital, Okayama 700-8525, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0478-9363","authenticated-orcid":false,"given":"Satoru","family":"Shindo","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Rita","family":"Pastore","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9422-9292","authenticated-orcid":false,"given":"Tomoki","family":"Kumagai","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5266-1041","authenticated-orcid":false,"given":"Alireza","family":"Heidari","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3168-7998","authenticated-orcid":false,"given":"Elaheh Dalir","family":"Abdolahinia","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoya","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takumi","family":"Memida","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Duran-Pinedo","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Frias-Lopez","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8357-1471","authenticated-orcid":false,"given":"Xiaozhe","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengyuan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoqin","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunniva","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3600-7461","authenticated-orcid":false,"given":"Jan","family":"Potempa","sequence":"additional","affiliation":[{"name":"Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville, Louisville, KY 40202, USA"},{"name":"Department of Microbiology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihisa","family":"Kawai","sequence":"additional","affiliation":[{"name":"Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1016\/S0140-6736(05)67728-8","article-title":"Periodontal diseases","volume":"366","author":"Pihlstrom","year":"2005","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"32291","DOI":"10.1074\/jbc.M114.602052","article-title":"Structure and mechanism of cysteine peptidase gingipain K (Kgp), a major virulence factor of Porphyromonas gingivalis in periodontitis","volume":"289","author":"Veillard","year":"2014","journal-title":"J. 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