{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T09:05:28Z","timestamp":1791882328502,"version":"4.3.4"},"reference-count":37,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T00:00:00Z","timestamp":1767052800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T00:00:00Z","timestamp":1767052800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82470961"],"award-info":[{"award-number":["82470961"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170951"],"award-info":[{"award-number":["82170951"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81741106"],"award-info":[{"award-number":["81741106"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cell Proliferation"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Periapical periodontitis is one of the most common inflammatory bone destructive diseases. Epidemiological evidence suggests that hypoxia exposure, such as that resulting from high\u2010altitude exposure or sleep apnea syndrome, may be a significant risk factor that exacerbates the disease process. However, its specific role and the underlying molecular mechanisms remain unclear. In this study, we established a mouse model of periapical periodontitis under conditions of chronic hypoxia to evaluate its impact on pathological bone loss using micro\u2010computed tomography, histological staining, and serum cytokine analysis. Furthermore, we explored the potential molecular regulatory mechanisms using in\u00a0vitro osteoclast differentiation models, adeno\u2010associated virus\u2010mediated in\u00a0vivo gene knockdown, and cleavage under targets and tagmentation (CUT&amp;Tag) sequencing. Our study revealed that hypoxia exposure significantly aggravated alveolar bone resorption, osteoclast activation, and systemic inflammation in the mouse model of periapical periodontitis compared to normoxia. At the molecular level, hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1) showed a rapid but transient increase under hypoxia, whereas HIF\u20102\u03b1 displayed a progressive and sustained elevation throughout osteoclast differentiation. These dynamics indicate that HIF\u20102\u03b1 plays a more prominent role than HIF\u20101\u03b1 in mediating the hypoxia\u2010accelerated osteoclastogenic response. In\u00a0vivo, local knockdown of HIF\u20102\u03b1 in the periapical region markedly attenuated bone destruction exacerbated by hypoxia exposure. Further mechanistic investigation, combining CUT&amp;Tag sequencing and functional validation experiments, revealed that HIF\u20102\u03b1 mediates its pro\u2010osteoclastogenic function by directly binding to the promoter region of the calmodulin\u2010dependent protein kinase IV (\n                    <jats:italic>Camk4<\/jats:italic>\n                    ) gene and activating its transcription. This study unveils that hypoxia exposure, acting as a critical environmental risk factor, functions as a \u2018synergistic amplifier\u2019 to enhance pathological osteoclastic responses in periapical periodontitis through the HIF\u20102\u03b1\u2013CAMK4 regulatory axis. The findings deepen our understanding of periapical periodontitis and suggest that targeting HIF\u20102\u03b1 or downstream pathways may be an adjunctive therapeutic strategy for hypoxia\u2010associated inflammatory bone loss.\n                  <\/jats:p>","DOI":"10.1111\/cpr.70160","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T09:26:42Z","timestamp":1767086802000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hypoxia Exacerbates Periapical Periodontitis\u2010Associated Pathological Bone Loss via the Hypoxia\u2010Inducible Factor\u20102\u03b1\u2010Calmodulin\u2010Dependent Protein Kinase\n                    <scp>IV<\/scp>\n                    Axis"],"prefix":"10.1111","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2940-8777","authenticated-orcid":false,"given":"Kang","family":"Gao","sequence":"first","affiliation":[{"name":"Department of International Medical Center, Beijing Stomatological Hospital Capital Medical University  Beijing China"},{"name":"Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology Capital Medical University  Beijing China"},{"name":"Beijing Laboratory of Oral Health Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Xu","sequence":"additional","affiliation":[{"name":"Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology Capital Medical University  Beijing China"},{"name":"Beijing Laboratory of Oral Health Capital Medical University  Beijing China"},{"name":"Department of Dental Implant Center, Beijing Stomatological Hospital Capital Medical University  Beijing China"},{"name":"Laboratory for Clinical Medicine Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Du","sequence":"additional","affiliation":[{"name":"Department of International Medical Center, Beijing Stomatological Hospital Capital Medical University  Beijing China"},{"name":"Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology Capital Medical University  Beijing China"},{"name":"Beijing Laboratory of Oral Health Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of International Medical Center, Beijing Stomatological Hospital Capital Medical University  Beijing China"},{"name":"Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology Capital Medical University  Beijing China"},{"name":"Beijing Laboratory of Oral Health Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochen","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of International Medical Center, Beijing Stomatological Hospital Capital Medical University  Beijing China"},{"name":"Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology Capital Medical University  Beijing China"},{"name":"Beijing Laboratory of Oral Health Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of International Medical Center, Beijing Stomatological Hospital Capital Medical University  Beijing China"},{"name":"Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology Capital Medical University  Beijing China"},{"name":"Beijing Laboratory of Oral Health Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6711-3841","authenticated-orcid":false,"given":"Jia","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Beijing Advanced Innovation Center for Big Data\u2010Based Precision Medicine Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zha","sequence":"additional","affiliation":[{"name":"Laboratory for Clinical Medicine Capital Medical University  Beijing China"},{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianglong","family":"Han","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology Sichuan University  Chengdu China"},{"name":"Department of Orthodontics and Pediatric Dentistry, West China Hospital of Stomatology Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5839-7114","authenticated-orcid":false,"given":"Weihua","family":"Guo","sequence":"additional","affiliation":[{"name":"Yunnan Key Laboratory of Stomatology &amp; Department of Pediatric Dentistry, The Affiliated Stomatology Hospital Kunming Medical University  Kunming China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xicheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory for Clinical Medicine Capital Medical University  Beijing China"},{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of International Medical Center, Beijing Stomatological Hospital Capital Medical University  Beijing China"},{"name":"Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology Capital Medical University  Beijing China"},{"name":"Beijing Laboratory of Oral Health Capital Medical University  Beijing China"},{"name":"Laboratory for Clinical Medicine Capital Medical University  Beijing China"},{"name":"Laboratory for Oral and General Health Integration and Translation, Beijing Tiantan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.908859"},{"issue":"2","key":"e_1_2_11_3_1","first-page":"101","article-title":"Oral Health Status of Air Force Personnel on Plateau and on Plain","volume":"18","author":"She J.","year":"2016","journal-title":"Journal of Military Surgery of Southwest China"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.10.005"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2012.02.006"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201078003\u2010z"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.658893"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276\u2010021\u201000594\u2010y"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12903\u2010023\u201002712\u2010w"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2024.01.030"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.16156"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25158246"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13535"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.12182\/20250360101"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtemb.2025.127767"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tmaid.2025.102867"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.archoralbio.2024.105881"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms221810146"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.12778"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/iej.14125"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010025\u201092523\u20106"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003\u2010024\u201006581\u2010z"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells14090673"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-019-0054-y"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1515"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keac381"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01658"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276\u2010024\u201001157\u20107"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/odi.15031"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2015.05.009"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.01.002"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102591.2006.01099.x"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.14744\/eej.2020.42714"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00784\u2010019\u201003094\u20106"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/iej.13316"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joen.2023.07.005"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.identj.2025.100874"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.103"}],"container-title":["Cell Proliferation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cpr.70160","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cpr.70160","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cpr.70160","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T18:03:47Z","timestamp":1783447427000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cpr.70160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,30]]},"references-count":37,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1111\/cpr.70160"],"URL":"https:\/\/doi.org\/10.1111\/cpr.70160","archive":["Portico"],"relation":{},"ISSN":["0960-7722","1365-2184"],"issn-type":[{"value":"0960-7722","type":"print"},{"value":"1365-2184","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,30]]},"assertion":[{"value":"2025-10-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70160"}}