{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T20:01:32Z","timestamp":1793995292419,"version":"4.8.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T00:00:00Z","timestamp":1675382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 81972072 No. 81800982"],"award-info":[{"award-number":["No. 81972072 No. 81800982"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Diabetes-associated periodontitis (DPD) is an inflammatory and destructive disease of periodontal tissues in the diabetic population. The disease is manifested as more severe periodontal destruction and is more difficult to treat when compared with periodontitis (PD). Eldecalcitol (ELD) is a novel active vitamin D3 analog; however, little clinical evidence is available on its role on improving PD and DPD, and its specific mechanisms remain unclear. In this study, we evaluated the preventative effects of ELD toward PD and DPD and explored its underlying molecular mechanisms.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Experimental PD and DPD mouse models were established by ligation combined with lipopolysaccharide (LPS) from <jats:italic>Porphyromonas gingivalis<\/jats:italic> injection in C57BL\/6J and C57BLKS\/J Iar- + Leprdb\/+Leprdb (db\/db) mice, respectively. Simultaneously, ELD (0.25\u00a0\u03bcg\/kg) was orally administered to mice <jats:italic>via<\/jats:italic> an intragastric method. Micro-computed tomography (CT), hematoxylin-eosin (HE) staining, immunohistochemistry (IHC), and tartrate-resistant acid phosphatase (TRAP) staining were used to evaluate alveolar bone alterations <jats:italic>in vivo<\/jats:italic>. Flow cytometry, immunofluorescence, and real-time polymerase chain reaction (qRT-PCR) were also used to examine gene expression and probe systemic and local changes in Treg and Th17 cell numbers. Additionally, western blotting and immunofluorescence staining were used to examine changes in STAT3\/STAT5 signaling.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Micro-CT and HE staining showed that the DPD group had higher alveolar bone loss when compared with the PD group. After applying ELD, alveolar bone loss decreased significantly in both PD and DPD groups, and particularly evident in the DPD group. IHC and TRAP staining also showed that ELD promoted osteoblast activity while inhibiting the number of osteoclasts, and after ELD treatment, the receptor activator of nuclear factor-\u03baB ligand (RANKL) to osteoprotegerin (OPG) ratio decreased. More importantly, this decreasing trend was more obvious in the DPD group. Flow cytometry and qRT-PCR also showed that the systemic Th17\/Treg imbalance in PD and DPD groups was partially resolved when animals were supplemented with ELD, while immunofluorescence staining and qRT-PCR data showed the Th17\/Treg imbalance was partially resolved in the alveolar bone of both ELD supplemented groups. Western blotting and immunofluorescence staining showed increased p-STAT5 and decreased p-STAT3 levels after ELD application.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> ELD exerted preventative effects toward PD and DPD by partially rectifying Th17\/Treg cell imbalance <jats:italic>via<\/jats:italic> STAT3\/STAT5 signaling. More importantly, given the severity of DPD, we found ELD was more advantageous in preventing DPD.<\/jats:p>","DOI":"10.3389\/fbioe.2023.1070117","type":"journal-article","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T13:18:42Z","timestamp":1675430322000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":28,"title":["Eldecalcitol effectively prevents alveolar bone loss by partially improving Th17\/Treg cell balance in diabetes-associated periodontitis"],"prefix":"10.3389","volume":"11","author":[{"given":"Ruihan","family":"Gao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujun","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junzhe","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongrui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minqi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"395","DOI":"10.22074\/cellj.2015.1","article-title":"STATs: An old story, yet mesmerizing","volume":"17","author":"Abroun","year":"2015","journal-title":"Cell J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/j.coph.2010.04.001","article-title":"Vitamin D: Modulator of the immune system","volume":"10","author":"Baeke","year":"2010","journal-title":"Curr. Opin. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"178","DOI":"10.3390\/biomedicines10010178","article-title":"Novel insight into the mechanisms of the bidirectional relationship between diabetes and periodontitis","volume":"10","author":"Barutta","year":"2022","journal-title":"Biomedicines"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1111\/odi.13884","article-title":"Innate and adaptive immunity of periodontal disease. From etiology to alveolar bone loss","volume":"28","author":"Becerra-Ruiz","year":"2022","journal-title":"Oral Dis."},{"key":"B5","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1111\/prd.12153","article-title":"The periodontal pocket: Pathogenesis, histopathology and consequences","volume":"76","author":"Bosshardt","year":"2018","journal-title":"Periodontol. 2000"},{"key":"B6","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1002\/jper.20-0055","article-title":"Boldine inhibits the alveolar bone resorption during ligature-induced periodontitis by modulating the Th17\/Treg imbalance","volume":"92","author":"Cafferata","year":"2021","journal-title":"J. Periodontol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"272","DOI":"10.3390\/medicina56060272","article-title":"Periodontitis, low-grade inflammation and systemic health: A scoping review","volume":"56","author":"Cecoro","year":"2020","journal-title":"Med. Kaunas."},{"key":"B8","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/j.bone.2011.05.022","article-title":"Eldecalcitol, a second-generation vitamin D analog, drives bone minimodeling and reduces osteoclastic number in trabecular bone of ovariectomized rats","volume":"49","author":"de Freitas","year":"2011","journal-title":"Bone"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1038\/mi.2015.136","article-title":"Characterization of the human immune cell network at the gingival barrier","volume":"9","author":"Dutzan","year":"2016","journal-title":"Mucosal Immunol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.cyto.2013.07.022","article-title":"IL-17 family: Cytokines, receptors and signaling","volume":"64","author":"Gu","year":"2013","journal-title":"Cytokine"},{"key":"B11","doi-asserted-by":"publisher","first-page":"53","DOI":"10.2334\/josnusd.17-0357","article-title":"Vitamin D reduces the serum levels of inflammatory cytokines in rat models of periodontitis and chronic obstructive pulmonary disease","volume":"61","author":"Han","year":"2019","journal-title":"J. Oral Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s10735-016-9705-0","article-title":"Histochemical examination of systemic administration of eldecalcitol combined with guided bone regeneration for bone defect restoration in rats","volume":"48","author":"Han","year":"2017","journal-title":"J. Mol. Histol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e0199856","DOI":"10.1371\/journal.pone.0199856","article-title":"Eldecalcitol is more effective in promoting osteogenesis than alfacalcidol in Cyp27b1-knockout mice","volume":"13","author":"Hirota","year":"2018","journal-title":"PLoS One"},{"key":"B14","doi-asserted-by":"publisher","first-page":"4901","DOI":"10.2147\/dddt.s269223","article-title":"<p&gt;Eldecalcitol inhibits LPS-induced NLRP3 inflammasome-dependent pyroptosis in human gingival fibroblasts by activating the Nrf2\/HO-1 signaling pathway<\/p&gt;","volume":"14","author":"Huang","year":"2020","journal-title":"Drug Des. Devel Ther."},{"key":"B15","doi-asserted-by":"publisher","first-page":"3591","DOI":"10.1111\/jcmm.17399","article-title":"Osteoimmunology: The correlation between osteoclasts and the Th17\/Treg balance in osteoporosis","volume":"26","author":"Huang","year":"2022","journal-title":"J. Cell Mol. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/s11914-020-00559-6","article-title":"The interrelationship between diabetes, IL-17 and bone loss","volume":"18","author":"Huang","year":"2020","journal-title":"Curr. Osteoporos. Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e13112","DOI":"10.1111\/aji.13112","article-title":"The role and mechanism of vitamin D-mediated regulation of Treg\/Th17 balance in recurrent pregnancy loss","volume":"81","author":"Ji","year":"2019","journal-title":"Am. J. Reprod. Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1007\/s00774-019-01009-9","article-title":"Eldecalcitol increases bone mineral density in Chinese osteoporotic patients without vitamin D or calcium supplementation","volume":"37","author":"Jiang","year":"2019","journal-title":"J. Bone Min. Metab."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/odi.14072","article-title":"Regulatory T cells showed characteristics of T helper-17(Th17) cells in mice periodontitis model","volume":"2021","author":"Kou","year":"2021","journal-title":"Oral Dis."},{"key":"B20","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1902\/jop.1996.67.5.472","article-title":"pH changes observed in the inflamed gingival crevice modulate human polymorphonuclear leukocyte activation in vitro","volume":"67","author":"Leblebicioglu","year":"1996","journal-title":"J. Periodontol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1007\/s00125-017-4269-4","article-title":"Diabetes, bone and glucose-lowering agents: Basic biology","volume":"60","author":"Lecka-Czernik","year":"2017","journal-title":"Diabetologia"},{"key":"B22","doi-asserted-by":"publisher","first-page":"730","DOI":"10.3390\/ijms19030730","article-title":"The balance of Th17 versus Treg cells in autoimmunity","volume":"19","author":"Lee","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"B23","first-page":"55","article-title":"Effect of type 2 diabetes mellitus and periodontitis on the Th1\/Th2 and Th17\/Treg paradigm","volume":"35","author":"Li","year":"2022","journal-title":"Am. J. Dent."},{"key":"B24","doi-asserted-by":"publisher","first-page":"327","DOI":"10.14670\/HH-28.327","article-title":"Histological examination on osteoblastic activities in the alveolar bone of transgenic mice with induced ablation of osteocytes","volume":"28","author":"Li","year":"2013","journal-title":"Histol. Histopathol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"691013","DOI":"10.3389\/fimmu.2021.691013","article-title":"Inflammasomes in alveolar bone loss","volume":"12","author":"Li","year":"2021","journal-title":"Front. Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1111\/odi.13268","article-title":"Acid sphingomyelinase deficiency exacerbates LPS-induced experimental periodontitis","volume":"26","author":"Li","year":"2020","journal-title":"Oral Dis."},{"key":"B27","doi-asserted-by":"publisher","first-page":"854439","DOI":"10.3389\/fendo.2022.854439","article-title":"Efficacy and safety of eldecalcitol for osteoporosis: A meta-analysis of randomized controlled trials","volume":"13","author":"Liu","year":"2022","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"329","DOI":"10.2337\/diacare.16.1.329","article-title":"Periodontal disease. The sixth complication of diabetes mellitus","volume":"16","author":"L\u00f6e","year":"1993","journal-title":"Diabetes Care"},{"key":"B29","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1186\/s13287-022-02800-8","article-title":"Exendin-4 and eldecalcitol synergistically promote osteogenic differentiation of bone marrow mesenchymal stem cells through M2 macrophages polarization via PI3K\/AKT pathway","volume":"13","author":"Lu","year":"2022","journal-title":"Stem Cell Res. Ther."},{"key":"B30","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1016\/j.job.2021.10.006","article-title":"Periodontitis and diabetes mellitus co-morbidity: A molecular dialogue","volume":"63","author":"Luong","year":"2021","journal-title":"J. Oral Biosci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1016\/j.bone.2011.07.011","article-title":"A new active vitamin D3 analog, eldecalcitol, prevents the risk of osteoporotic fractures-a randomized, active comparator, double-blind study","volume":"49","author":"Matsumoto","year":"2011","journal-title":"Bone"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1111\/odi.13097","article-title":"The influence of vitamin D supplementation on local and systemic inflammatory markers in periodontitis patients: A pilot study","volume":"25","author":"Meghil","year":"2019","journal-title":"Oral Dis."},{"key":"B33","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1038\/nrrheum.2018.17","article-title":"Proteinases and their receptors in inflammatory arthritis: An overview","volume":"14","author":"Oikonomopoulou","year":"2018","journal-title":"Nat. Rev. Rheumatol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1111\/jcpe.12803","article-title":"An update on the evidence for pathogenic mechanisms that may link periodontitis and diabetes","volume":"45","author":"Polak","year":"2018","journal-title":"J. Clin. Periodontol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"108917","DOI":"10.1016\/j.clim.2021.108917","article-title":"Immunomodulatory effect of vitamin D on the STATs and transcription factors of CD4+ T cell subsets in pregnant women with preeclampsia","volume":"234","author":"Ribeiro","year":"2022","journal-title":"Clin. Immunol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1007\/s11657-020-00842-0","article-title":"Plain vitamin D or active vitamin D in the treatment of osteoporosis: Where do we stand today?","volume":"15","author":"Ringe","year":"2020","journal-title":"Arch. Osteoporos."},{"key":"B37","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1007\/s00774-016-0779-2","article-title":"The safety and effectiveness profile of eldecalcitol in a prospective, post-marketing observational study in Japanese patients with osteoporosis: Interim report","volume":"35","author":"Saito","year":"2017","journal-title":"J. Bone Min. Metab."},{"key":"B38","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1186\/s40168-021-01097-8","article-title":"Novel insights into the genetically obese (ob\/ob) and diabetic (db\/db) mice: Two sides of the same coin","volume":"9","author":"Suriano","year":"2021","journal-title":"Microbiome"},{"key":"B39","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1007\/s11010-019-03561-4","article-title":"Role and mechanism of the Th17\/Treg cell balance in the development and progression of insulin resistance","volume":"459","author":"Tao","year":"2019","journal-title":"Mol. Cell Biochem."},{"key":"B40","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1111\/odi.12592","article-title":"PKR regulates LPS-induced osteoclast formation and bone destruction in vitro and in vivo","volume":"23","author":"Teramachi","year":"2017","journal-title":"Oral Dis."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2020\/6910312","article-title":"RANKL\/RANK\/OPG pathway: A mechanism involved in exercise-induced bone remodeling","volume":"2020","author":"Tobeiha","year":"2020","journal-title":"Biomed. Res. Int."},{"key":"B42","doi-asserted-by":"publisher","first-page":"S149","DOI":"10.1111\/jcpe.12945","article-title":"Staging and grading of periodontitis: Framework and proposal of a new classification and case definition","volume":"45","author":"Tonetti","year":"2018","journal-title":"J. Clin. Periodontol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s00774-020-01162-6","article-title":"Osteoclast differentiation by RANKL and OPG signaling pathways","volume":"39","author":"Udagawa","year":"2021","journal-title":"J. Bone Min. Metab."},{"key":"B44","doi-asserted-by":"publisher","first-page":"2957","DOI":"10.1016\/j.jmb.2019.05.016","article-title":"The structure of dental plaque microbial communities in the transition from health to dental caries and periodontal disease","volume":"431","author":"Valm","year":"2019","journal-title":"J. Mol. Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"108570","DOI":"10.1016\/j.steroids.2019.108570","article-title":"25-Hydroxyvitamin D(3) positively regulates periodontal inflammaging via SOCS3\/STAT signaling in diabetic mice","volume":"156","author":"Wang","year":"2020","journal-title":"Steroids"},{"key":"B46","doi-asserted-by":"publisher","first-page":"e149538","DOI":"10.1172\/JCI149538","article-title":"Fibroblast pathology in inflammatory diseases","volume":"131","author":"Wei","year":"2021","journal-title":"J. Clin. Invest"},{"key":"B47","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1111\/jre.12912","article-title":"Hyperglycemia modulates M1\/M2 macrophage polarization via reactive oxygen species overproduction in ligature-induced periodontitis","volume":"56","author":"Zhang","year":"2021","journal-title":"J. Periodontal Res."},{"key":"B48","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1186\/s12974-021-02298-6","article-title":"Diabetes mellitus exacerbates experimental autoimmune myasthenia gravis via modulating both adaptive and innate immunity","volume":"18","author":"Zhang","year":"2021","journal-title":"J. Neuroinflammation"},{"key":"B49","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.jep.2018.02.023","article-title":"Restoring Th17\/Treg balance via modulation of STAT3 and STAT5 activation contributes to the amelioration of chronic obstructive pulmonary disease by Bufei Yishen formula","volume":"217","author":"Zhao","year":"2018","journal-title":"J. Ethnopharmacol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1007\/s00592-021-01738-2","article-title":"Prevalence of periodontitis in people clinically diagnosed with diabetes mellitus: A meta-analysis of epidemiologic studies","volume":"58","author":"Zheng","year":"2021","journal-title":"Acta Diabetol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"20662","DOI":"10.1002\/jcp.28671","article-title":"Exosomal microRNA-155-5p from PDLSCs regulated Th17\/Treg balance by targeting sirtuin-1 in chronic periodontitis","volume":"234","author":"Zheng","year":"2019","journal-title":"J. Cell Physiol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2022\/3046777","article-title":"The effects of RBP4 and vitamin D on the proliferation and migration of vascular smooth muscle cells via the JAK2\/STAT3 signaling pathway","volume":"2022","author":"Zhou","year":"2022","journal-title":"Oxid. Med. Cell Longev."},{"key":"B53","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s12979-020-00202-z","article-title":"The correlation between the Th17\/Treg cell balance and bone health","volume":"17","author":"Zhu","year":"2020","journal-title":"Immun. Ageing"},{"key":"B54","doi-asserted-by":"publisher","first-page":"8011","DOI":"10.3390\/ijms21218011","article-title":"CD4 T helper cell subsets and related human immunological disorders","volume":"21","author":"Zhu","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B55","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1002\/jlb.3vmr0321-027rrr","article-title":"Phenotypes, roles, and modulation of regulatory lymphocytes in periodontitis and its associated systemic diseases","volume":"111","author":"Zou","year":"2022","journal-title":"J. Leukoc. Biol."}],"container-title":["Frontiers in Bioengineering and Biotechnology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2023.1070117\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T13:18:49Z","timestamp":1675430329000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2023.1070117\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,3]]},"references-count":55,"alternative-id":["10.3389\/fbioe.2023.1070117"],"URL":"https:\/\/doi.org\/10.3389\/fbioe.2023.1070117","relation":{},"ISSN":["2296-4185"],"issn-type":[{"value":"2296-4185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,3]]},"article-number":"1070117"}}