{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T16:05:49Z","timestamp":1787069149699,"version":"build-2736575974"},"reference-count":63,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,27]],"date-time":"2025-04-27T00:00:00Z","timestamp":1745712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science and Technology Project of Xiamen","award":["3502Z20224028"],"award-info":[{"award-number":["3502Z20224028"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Klotho, an anti-aging protein, has been extensively studied in systemic conditions such as chronic kidney disease and cardiovascular disorders. In recent years, its pivotal protective role and clinical significance in various oral and maxillofacial diseases have been increasingly demonstrated. It has been demonstrated that Klotho regulates oxidative stress, apoptosis, inflammation, and fibrosis via multiple molecular signaling pathways, including Nrf2, NF-\u03baB, PI3K\/Akt\/FoxO1, insulin\/IGF-1, FGF\/FGFR, and Wnt\/\u03b2-catenin. Consequently, these regulatory effects have been observed in conditions such as periodontitis, oral squamous cell carcinoma, malignant salivary gland tumors, oral submucous fibrosis, etc. Moreover, the decreased expression or dysfunctional activity of Klotho is frequently associated with the onset and progression of these diseases. This study provides a comprehensive review of the underlying mechanisms and recent advances in Klotho research within the realm of oral and maxillofacial diseases, offering novel perspectives for future basic and clinical investigations.<\/jats:p>","DOI":"10.3390\/biom15050624","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T08:28:11Z","timestamp":1746174491000},"page":"624","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Role of Klotho in Oral and Maxillofacial Diseases: Mechanisms and Research Progress"],"prefix":"10.3390","volume":"15","author":[{"given":"Shiqi","family":"Lin","sequence":"first","affiliation":[{"name":"School of Medicine, Xiamen University, Xiamen 361102, China"},{"name":"Department of Stomatology, Xiang\u2019an Hospital of Xiamen University, Xiamen 361102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bozhao","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medicine, Xiamen University, Xiamen 361102, China"},{"name":"Department of Stomatology, Xiang\u2019an Hospital of Xiamen University, Xiamen 361102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6141-9441","authenticated-orcid":false,"given":"Jian","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medicine, Xiamen University, Xiamen 361102, China"},{"name":"Department of Stomatology, Xiang\u2019an Hospital of Xiamen University, Xiamen 361102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Idrees, M., Kumar, V., Khan, A.M., Joo, M.-D., Lee, K.-W., Sohn, S.-H., and Kong, I.-K. (2023). Cycloastragenol Activation of Telomerase Improves \u03b2-Klotho Protein Level and Attenuates Age-Related Malfunctioning in Ovarian Tissues. Mech. Ageing Dev., 209.","DOI":"10.1016\/j.mad.2022.111756"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Niu, Q., Chen, H., Ou, Q., Yang, S., Peng, Y., Xie, Y., Yu, L., Cheng, Z., Cao, Y., and Wang, Y. (2023). Klotho Enhances Bone Regenerative Function of hPDLSCs via Modulating Immunoregulatory Function and Cell Autophagy. J. Orthop. Surg. Res., 18.","DOI":"10.1186\/s13018-023-03849-8"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ashour, A., Xue, M., Al-Motawa, M., Thornalley, P.J., and Rabbani, N. (2020). Glycolytic Overload-Driven Dysfunction of Periodontal Ligament Fibroblasts in High Glucose Concentration, Corrected by Glyoxalase 1 Inducer. BMJ Open Diabetes Res. Care, 8.","DOI":"10.1136\/bmjdrc-2020-001458"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Gupta, S., Ghosh, S., Gupta, S., and Sakhuja, P. (2017). Effect of Curcumin on the Expression of P53, Transforming Growth Factor-\u03b2, and Inducible Nitric Oxide Synthase in Oral Submucous Fibrosis: A Pilot Study. J. Investig. Clin. Dent., 8.","DOI":"10.1111\/jicd.12252"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Chang, M.-C., Chen, Y.-J., Chang, H.-H., Chan, C.-P., Yeh, C.-Y., Wang, Y.-L., Cheng, R.-H., Hahn, L.-J., and Jeng, J.-H. (2014). Areca Nut Components Affect COX-2, Cyclin B1\/cdc25C and Keratin Expression, PGE2 Production in Keratinocyte Is Related to Reactive Oxygen Species, CYP1A1, Src, EGFR and Ras Signaling. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0101959"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/36285","article-title":"Mutation of the Mouse Klotho Gene Leads to a Syndrome Resembling Ageing","volume":"390","author":"Matsumura","year":"1997","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Yuan, Q., Sato, T., Densmore, M., Saito, H., Sch\u00fcler, C., Erben, R.G., and Lanske, B. (2012). Deletion of PTH Rescues Skeletal Abnormalities and High Osteopontin Levels in Klotho\u2212\/\u2212 Mice. PLOS Genet., 8.","DOI":"10.1371\/journal.pgen.1002726"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/j.ajpath.2016.01.013","article-title":"Nuclear Factor Erythroid 2-Related Factor 2 Down-Regulation in Oral Neutrophils Is Associated with Periodontal Oxidative Damage and Severe Chronic Periodontitis","volume":"186","author":"Sima","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Gao, W., Guo, L., Yang, Y., Wang, Y., Xia, S., Gong, H., Zhang, B.-K., and Yan, M. (2022). Dissecting the Crosstalk Between Nrf2 and NF-\u03baB Response Pathways in Drug-Induced Toxicity. Front. Cell Dev. Biol, 9.","DOI":"10.3389\/fcell.2021.809952"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.reth.2021.07.003","article-title":"The Protective Mechanism of Klotho Gene-Modified Bone Marrow Mesenchymal Stem Cells on Acute Kidney Injury Induced by Rhabdomyolysis","volume":"18","author":"Ni","year":"2021","journal-title":"Regen. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.autrev.2011.04.034","article-title":"Immunosenescence and Rheumatoid Arthritis: Does Telomere Shortening Predict Impending Disease?","volume":"10","author":"Costenbader","year":"2011","journal-title":"Autoimmun. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1093\/gerona\/gly261","article-title":"Klotho Deficiency Accelerates Stem Cells Aging by Impairing Telomerase Activity","volume":"74","author":"Ullah","year":"2019","journal-title":"J. Gerontol. A"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Distefano, A., Orlando, L., Partsinevelos, K., Longhitano, L., Emma, R., Caruso, M., Vicario, N., Denaro, S., Sun, A., and Giordano, A. (2024). Comparative Evaluation of Cigarette Smoke and a Heated Tobacco Product on Microglial Toxicity, Oxidative Stress and Inflammatory Response. J. Transl. Med., 22.","DOI":"10.1186\/s12967-024-05688-5"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1093\/jb\/mvad001","article-title":"Klotho Protects Chromosomal DNA from Radiation-Induced Damage","volume":"173","author":"Nakayama","year":"2023","journal-title":"J. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gao, Q., Chen, F., Zhang, L., Wei, A., Wang, Y., Wu, Z., and Cao, W. (2022). Inhibition of DNA Methyltransferase Aberrations Reinstates Antioxidant Aging Suppressors and Ameliorates Renal Aging. Aging Cell, 21.","DOI":"10.1111\/acel.13526"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Chen, H., Huang, X., Fu, C., Wu, X., Peng, Y., Lin, X., and Wang, Y. (2019). Recombinant Klotho Protects Human Periodontal Ligament Stem Cells by Regulating Mitochondrial Function and the Antioxidant System during H2O2 -Induced Oxidative Stress. Oxidative Med. Cell. Longev., 2019.","DOI":"10.1155\/2019\/9261565"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.bbrc.2020.11.061","article-title":"Klotho Ameliorates Diabetic Nephropathy by Activating Nrf2 Signaling Pathway in Podocytes","volume":"534","author":"Xing","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1097\/MNH.0000000000000467","article-title":"FGF-23 and \u03b1-Klotho Co-Dependent and Independent Functions","volume":"28","author":"Quarles","year":"2019","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tem.2022.10.002","article-title":"Can Sodium-Glucose Cotransporter 2 Inhibitors \u2018Spin the Thread of Life\u2019?","volume":"34","author":"Maltese","year":"2023","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Typiak, M., and Piwkowska, A. (2021). Antiinflammatory Actions of Klotho: Implications for Therapy of Diabetic Nephropathy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020956"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Miao, J., Huang, J., Luo, C., Ye, H., Ling, X., Wu, Q., Shen, W., and Zhou, L. (2021). Klotho Retards Renal Fibrosis through Targeting Mitochondrial Dysfunction and Cellular Senescence in Renal Tubular Cells. Physiol. Rep., 9.","DOI":"10.14814\/phy2.14696"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Rao, Z., Landry, T., Li, P., Bunner, W., Laing, B.T., Yuan, Y., and Huang, H. (2019). Administration of Alpha Klotho Reduces Liver and Adipose Lipid Accumulation in Obese Mice. Heliyon, 5.","DOI":"10.1016\/j.heliyon.2019.e01494"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1126\/science.1112766","article-title":"Suppression of Aging in Mice by the Hormone Klotho","volume":"309","author":"Kurosu","year":"2005","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1111\/jcpe.13396","article-title":"The Prevalence and Severity of Periodontal Disease in Mainland China: Data from the Fourth National Oral Health Survey (2015\u20132016)","volume":"48","author":"Jiao","year":"2021","journal-title":"J. Clin. Periodontol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Villalobos, V., Garrido, M., Rryes, A., Fernandez, C., Diaz, C., Torres, V.A., Gonzalez, P.A., and Caceres, M. (2022). Aging Envisage Imbalance of the Periodontium: A Keystone in Oral Disease and Systemic Health. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1044334"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/prd.12342","article-title":"Periodontitis Is an Inflammatory Disease of Oxidative Stress: We Should Treat It That Way","volume":"84","author":"Sczepanik","year":"2020","journal-title":"Periodontology 2000"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"F791","DOI":"10.1152\/ajprenal.00462.2017","article-title":"Klotho Plays a Protective Role against Glomerular Hypertrophy in a Cell Cycle-Dependent Manner in Diabetic Nephropathy","volume":"315","author":"Oh","year":"2018","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_28","first-page":"428","article-title":"Photothermal Therapy with Regulated Nrf2\/NF-\u03baB Signaling Pathway for Treating Bacteria-Induced Periodontitis","volume":"9","author":"Tian","year":"2021","journal-title":"Bioact. Mater."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1111\/1440-1681.13547","article-title":"Klotho Inhibits H2O2-induced Oxidative Stress and Apoptosis in Periodontal Ligament Stem Cells by Regulating UCP2 Expression","volume":"48","author":"Zhu","year":"2021","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Tossetta, G., Fantone, S., Togni, L., Santarelli, A., Olivieri, F., Marzioni, D., and Rippo, M.R. (2024). Modulation of NRF2\/KEAP1 Signaling by Phytotherapeutics in Periodontitis. Antioxidants, 13.","DOI":"10.3390\/antiox13101270"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Schiavoni, V., Emanuelli, M., Milanese, G., Galosi, A.B., Pompei, V., Salvolini, E., and Campagna, R. (2024). Nrf2 Signaling in Renal Cell Carcinoma: A Potential Candidate for the Development of Novel Therapeutic Strategies. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252413239"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1111\/iej.13467","article-title":"The Global Prevalence of Apical Periodontitis: A Systematic Review and Meta-Analysis","volume":"54","author":"Michelon","year":"2021","journal-title":"Int. Endod. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1111\/odi.14703","article-title":"The Roles of Stress-induced Premature Senescence and Akt\/FOXO1 Signaling in Periapical Lesions","volume":"30","author":"Liu","year":"2024","journal-title":"Oral Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"R67","DOI":"10.1530\/JOE-17-0002","article-title":"FoxO Integration of Insulin Signaling with Glucose and Lipid Metabolism","volume":"233","author":"Lee","year":"2017","journal-title":"J. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Morii, K., Yamasaki, S., Doi, S., Irifuku, T., Sasaki, K., Doi, T., Nakashima, A., Arihiro, K., and Masaki, T. (2019). microRNA-200c Regulates KLOTHO Expression in Human Kidney Cells under Oxidative Stress. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0218468"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1038\/nrm2190","article-title":"Stressing the Role of FoxO Proteins in Lifespan and Disease","volume":"8","author":"Burgering","year":"2007","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/jdi.12410","article-title":"Periodontitis Aggravated Pancreatic \u0392-cell Dysfunction in Diabetic Mice through Interleukin-12 Regulation on Klotho","volume":"7","author":"Liu","year":"2016","journal-title":"J. Diabetes Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7899","DOI":"10.1074\/jbc.M008262200","article-title":"Induction of Nitric-Oxide Synthase and Activation of NF-kappaB by Interleukin-12 P40 in Microglial Cells","volume":"276","author":"Pahan","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3229","DOI":"10.3892\/mmr.2016.5601","article-title":"Curcumin Attenuates Cyclosporine A-induced Renal Fibrosis by Inhibiting Hypermethylation of the Klotho Promoter","volume":"14","author":"Hu","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"E359","DOI":"10.1002\/ijc.29210","article-title":"Cancer Incidence and Mortality Worldwide: Sources, Methods and Major Patterns in GLOBOCAN 2012","volume":"136","author":"Ferlay","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.oraloncology.2014.03.008","article-title":"Incidence and Survival Trends of Head and Neck Squamous Cell Carcinoma in the Netherlands between 1989 and 2011","volume":"50","author":"Braakhuis","year":"2014","journal-title":"Oral Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"vi7","DOI":"10.1093\/annonc\/mdi452","article-title":"Current Clinical Outcomes Demand New Treatment Options for SCCHN","volume":"16","author":"Lefebvre","year":"2005","journal-title":"Ann. Oncol."},{"key":"ref_43","first-page":"255","article-title":"Klotho gene expression and its methylation level are correlated with LC3 and NSUN2 gene expression in head and neck squamous cell carcinoma","volume":"49","author":"Hu","year":"2020","journal-title":"Acta Med. Univ. Sci. Technol. Huazhong"},{"key":"ref_44","unstructured":"Shang, Y. (2020). Klotho Induces Cells Apoptosis via Inhibition of the Wnt\/\u03b2-Cantenin Pathway in Human Tongue Squamous Cell Carcinoma Cells, Nanchang University."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1007\/s12253-013-9663-8","article-title":"Klotho Acts as a Tumor Suppressor in Cancers","volume":"19","author":"Xie","year":"2013","journal-title":"Pathol. Oncol. Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Chen, B., Wang, X., Zhao, W., and Wu, J. (2010). Klotho Inhibits Growth and Promotes Apoptosis in Human Lung Cancer Cell Line A549. J. Exp. Clin. Cancer Res., 29.","DOI":"10.1186\/1756-9966-29-99"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s00795-017-0156-9","article-title":"Immunohistochemical Evaluation of Klotho and DNA Methyltransferase 3a in Oral Squamous Cell Carcinomas","volume":"50","author":"Adhikari","year":"2017","journal-title":"Med. Mol. Morphol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1007\/s00784-018-2497-8","article-title":"Overexpression of Nicotinamide N-Methyltransferase in HSC-2 OSCC Cell Line: Effect on Apoptosis and Cell Proliferation","volume":"23","author":"Seta","year":"2019","journal-title":"Clin. Oral Investig."},{"key":"ref_49","first-page":"322","article-title":"Expression and significance of DDR1 in salivary gland mucoepidermoid carcinoma","volume":"25","author":"Wang","year":"2016","journal-title":"Shanghai J. Stomatol."},{"key":"ref_50","unstructured":"Ma, S., Zhang, L., Wang, Q., Zhang, F., Liu, B., Li, L., Wang, J., and An, F. (2017). Expression and Clinical Significance of Tumor-Associated Proteins in Salivary Gland Malignancies, The First Affiliated Hospital of Hebei North University."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1136\/jclinpath-2015-202929","article-title":"Klotho Expression in Cervical Cancer: Differential Expression in Adenocarcinoma and Squamous Cell Carcinoma","volume":"69","author":"Rubinek","year":"2016","journal-title":"J. Clin. Pathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"7094","DOI":"10.1038\/onc.2008.292","article-title":"Klotho: A Tumor Suppressor and a Modulator of the IGF-1 and FGF Pathways in Human Breast Cancer","volume":"27","author":"Wolf","year":"2008","journal-title":"Oncogene"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Ma, J., Li, Y., Mi, Y., Gong, Q., Zhang, P., Meng, B., Wang, J., Wang, J., and Fan, Y. (2024). Novel 3D Printed TPMS Scaffolds: Microstructure, Characteristics and Applications in Bone Regeneration. J. Tissue Eng., 15.","DOI":"10.1177\/20417314241263689"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s41392-022-00957-5","article-title":"Klotho in Osx+-Mesenchymal Progenitors Exerts Pro-Osteogenic and Anti-Inflammatory Effects during Mandibular Alveolar Bone Formation and Repair","volume":"7","author":"Fan","year":"2022","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"103","DOI":"10.17779\/KAOMP.2020.44.4.001","article-title":"Dysosteogenesis in the Mandibular Bone of SAMP1\/Klotho-Deficient Mice","volume":"44","author":"Yook","year":"2020","journal-title":"Korean J. Oral Maxillofac. Pathol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Ni, C., Bao, D., Yan, F., and Chen, B. (2023). Correlation between Serum \u03b1-Klotho Levels and Different Stages of Periodontitis. BMC Oral Health, 23.","DOI":"10.1186\/s12903-023-03099-4"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1002\/1873-3468.13613","article-title":"Soluble Klotho Regulates Bone Differentiation by Upregulating Expression of the Transcription Factor EGR-1","volume":"594","author":"Toan","year":"2020","journal-title":"FEBS Lett."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.kint.2017.02.014","article-title":"Klotho Expression in Osteocytes Regulates Bone Metabolism and Controls Bone Formation","volume":"92","author":"Komaba","year":"2017","journal-title":"Kidney Int."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/jbmr.2606","article-title":"FGF23 Regulates Bone Mineralization in a 1,25(OH)2 D3 and Klotho-Independent Manner","volume":"31","author":"Murali","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Portales-Castillo, I., and Simic, P. (2022). PTH, FGF-23, Klotho and Vitamin D as Regulators of Calcium and Phosphorus: Genetics, Epigenetics and Beyond. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.992666"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Chen, X., Wei, Y., Li, Z., Zhou, C., and Fan, Y. (2024). Distinct Role of Klotho in Long Bone and Craniofacial Bone: Skeletal Development, Repair and Regeneration. PeerJ, 12.","DOI":"10.7717\/peerj.18269"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Yu, T., Dou, C., Lu, Y., Duan, L., Tan, J., Li, J., Kang, F., Dong, S., Bai, Y., and Xu, J. (2021). Klotho Upregulates the Interaction between RANK and TRAF6 to Facilitate RANKL-Induced Osteoclastogenesis via the NF-\u03baB Signaling Pathway. Ann. Transl. Med., 9.","DOI":"10.21037\/atm-21-4332"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Franco, M.L., Beyerstedt, S., and Rangel, \u00c9.B. (2021). Klotho and Mesenchymal Stem Cells: A Review on Cell and Gene Therapy for Chronic Kidney Disease and Acute Kidney Disease. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14010011"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/5\/624\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:22:41Z","timestamp":1760030561000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/5\/624"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,27]]},"references-count":63,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["biom15050624"],"URL":"https:\/\/doi.org\/10.3390\/biom15050624","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,27]]}}}