{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:39:07Z","timestamp":1787161147078,"version":"build-2736575974"},"reference-count":35,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF)","award":["2022R1F1A1076563"],"award-info":[{"award-number":["2022R1F1A1076563"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Oral cellular aging plays a critical role in the pathogenesis of chronic periodontitis and alveolar bone resorption. Although activating transcription factor 3 (ATF3) has been implicated as a senescence-associated factor, its specific role in periodontal ligament cell (PDLC) senescence remains unclear. Human PDLCs were exposed to lipopolysaccharide (LPS, 1 \u03bcg\/mL) and nicotine (5 mM) for 3 days to induce senescence. ATF3 expression was silenced using siRNA. The expression of senescence-associated secretory phenotype (SASP) factors (IFN\u03b3, IL6, IL8, TNF\u03b1, and IL1\u03b2) and the secretion of nitric oxide (NO) and prostaglandin E2 (PGE2) were assessed by RT-PCR and immunoassay. Conditioned media (CM) from these cells were applied to mouse bone marrow macrophages (BMMs) to evaluate osteoclast differentiation and bone resorption. In addition, key signaling pathways, including STAT3, ERK, NF-\u03baB (p65), and AP-1, were investigated by Western blotting and immunofluorescence. ATF3 knockdown markedly reduced the LPS\/nicotine-induced expression of SASP factors and decreased NO and PGE2 levels. CM from ATF3-silenced PDLCs markedly inhibited osteoclast differentiation, as evidenced by reduced tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and diminished bone resorption. Moreover, ATF3 inhibition led to a decreased RANKL\/OPG ratio and attenuated the phosphorylation of STAT3 and ERK, along with the reduced nuclear translocation of p65 and AP-1 components. These findings suggest that ATF3 plays a critical role in mediating cellular senescence and osteoclastogenesis in PDLCs. Targeting ATF3 may represent a novel therapeutic strategy for managing age-related oral diseases, such as chronic periodontitis.<\/jats:p>","DOI":"10.3390\/ijms26104959","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T13:59:43Z","timestamp":1747835983000},"page":"4959","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Activating Transcription Factor 3 (ATF3) Regulates Cellular Senescence and Osteoclastogenesis via STAT3\/ERK and p65\/AP-1 Pathways in Human Periodontal Ligament Cells"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3927-6656","authenticated-orcid":false,"given":"Won-Jung","family":"Bae","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Dentistry, Dankook University, Cheonan 31116, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2635-6876","authenticated-orcid":false,"given":"Sang-Im","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Dental Hygiene, College of Health Science, Dankook University, Cheonan 31116, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1038\/nm.4000","article-title":"Cellular senescence in aging and age-related disease: From mechanisms to therapy","volume":"21","author":"Childs","year":"2015","journal-title":"Nat. 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