{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T07:49:14Z","timestamp":1782460154440,"version":"3.54.5"},"reference-count":53,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Faculty of Medical Science, University of Kragujevac, Kragujevac, Serbia","award":["JP 07\/2025"],"award-info":[{"award-number":["JP 07\/2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Dentistry Journal"],"abstract":"<jats:p>Background\/Objectives: The objective of this study was to investigate the effects of local zoledronate treatment during periapical lesion development on inflammatory and bone remodeling responses in two immunologically distinct inbred rat strains, Dark Agouti (DA) and Albino Oxford (AO). Methods: Periapical lesions were induced in the mandibular first molars of AO and DA rats (n = 44) by pulp exposure. Animals were assigned to four groups: DA + zoledronate, DA + saline, AO + zoledronate, and AO + saline. Zoledronate (0.15 mg\/kg) or saline was locally administered on days 0, 7, 14, and 21 during lesion development. Animals were sacrificed on day 28. Mandibles were analyzed radiographically and histologically for lesion size, while osteogenic activity was assessed by osteocalcin immunohistochemistry. Gene expression was evaluated by qRT-PCR, and systemic oxidative stress parameters were analyzed spectrophotometrically. Statistical analysis included parametric or non-parametric tests according to data distribution, with significance set at p &lt; 0.05. Results: Zoledronate -treated AO rats exhibited smaller periapical lesions and higher radiographic grayscale density than DA rats (p &lt; 0.05). Histological analysis confirmed the radiographic findings and demonstrated smaller lesion areas in AO rats. Osteocalcin expression was significantly higher in AO rats (p &lt; 0.05), indicating increased osteogenic activity. At the molecular level, DA rats showed higher expression of TNF-\u03b1 and IL-1\u03b2, whereas AO rats exhibited higher expression of IL-10 and IL-4 (p &lt; 0.05). In addition, expression of osteoclastogenic factor RANKL was significantly lower in AO rats than in DA rats (p &lt; 0.05), while OPG expression showed a non-significant tendency toward higher levels in AO rats. Systemic redox analysis demonstrated lower NO2\u2212 and O2\u2212 levels in zoledronate-treated AO rats, whereas no significant differences were observed in the remaining oxidative stress parameters. Conclusions: Following local zoledronate treatment during lesion development, Th2-dominant AO rats exhibited reduced inflammatory responses and increased osteogenic activity compared with Th1-dominant DA rats. In contrast, DA rats primarily demonstrated attenuation of osteoclastogenic signaling without comparable osteogenic responses. These findings indicate that the biological effects of local zoledronate treatment in developing periapical lesions are influenced by the host immune phenotype.<\/jats:p>","DOI":"10.3390\/dj14070393","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:52:11Z","timestamp":1782453131000},"page":"393","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Local Zoledronate Administration Modulates Periapical Lesion Development in Immunologically Distinct Rat Strains"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1082-8114","authenticated-orcid":false,"given":"Tamara","family":"Milunovic","sequence":"first","affiliation":[{"name":"Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7970-4892","authenticated-orcid":false,"given":"Milos","family":"Papic","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjana V.","family":"Papi\u0107","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miona","family":"Vuletic","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Misic","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dejan","family":"Zdravkovic","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jovan","family":"Rakic","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ksenija","family":"Vucicevic","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5177-1521","authenticated-orcid":false,"given":"Marina Miletic","family":"Kovacevic","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milica","family":"Popovic","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Slobodanka","family":"Mitrovic","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6759-2720","authenticated-orcid":false,"given":"Biljana","family":"Ljujic","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzana","family":"Zivanovic","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1111\/iej.14125","article-title":"The immune landscape in apical periodontitis: From mechanism to therapy","volume":"57","author":"Wen","year":"2024","journal-title":"Int. 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