{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T16:45:07Z","timestamp":1788885907457,"version":"build-2803163510"},"reference-count":36,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T00:00:00Z","timestamp":1725926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Georg E. and Marianne Kosing-Stiftung","award":["T0503\/37590\/2021\/sm"],"award-info":[{"award-number":["T0503\/37590\/2021\/sm"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Our study investigates the impact of FGF23 overexpression on SaOS-2 cells to elucidate its role in cellular stress and morphology, contributing to the understanding of skeletal pathologies like X-linked hypophosphatemia (XLH). Using transmission electron microscopy and protein analysis (Western blot), we analyzed the rough endoplasmic reticulum (rER) and mitochondria in SaOS-2 cells with FGF23 overexpression compared to controls. We found significant morphological changes, including enlarged and elongated rER and mitochondria, with increased contact zones, suggesting enhanced interaction and adaptation to elevated protein synthesis and secretion demands. Additionally, we observed higher apoptosis rates of the cells after 24\u201372 h in vitro and upregulated proteins associated with ER stress and apoptosis, such as CHOP, XBP1 (spliced and unspliced), GRP94, eIF2\u03b1, and BAX. These findings indicate a robust activation of the unfolded protein response (UPR) and apoptotic pathways due to FGF23 overexpression. Our results highlight the critical role of ER and mitochondrial interactions in cellular stress responses and provide new insights into the mechanistic link between FGF23 signaling and cellular homeostasis. In conclusion, our study underscores the importance of analyzing UPR-related pathways in the development of therapeutic strategies for skeletal and systemic diseases and contributes to a broader understanding of diseases like XLH.<\/jats:p>","DOI":"10.3390\/cells13181515","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T07:33:25Z","timestamp":1725953605000},"page":"1515","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["FGF23 and Cell Stress in SaOS-2 Cells\u2014A Model Reflecting X-Linked Hypophosphatemia Dynamics"],"prefix":"10.3390","volume":"13","author":[{"given":"Lisanne","family":"Brueck","sequence":"first","affiliation":[{"name":"Department of Cytology, Institute of Anatomy, Ruhr-University Bochum, D-44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sascha","family":"Roocke","sequence":"additional","affiliation":[{"name":"The Medical Proteome Center, Ruhr-University Bochum, D-44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9717-4485","authenticated-orcid":false,"given":"Veronika","family":"Matschke","sequence":"additional","affiliation":[{"name":"Department of Cytology, Institute of Anatomy, Ruhr-University Bochum, D-44801 Bochum, Germany"},{"name":"International Graduate School of Neuroscience (IGSN), Ruhr-University Bochum, D-44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Richter-Unruh","sequence":"additional","affiliation":[{"name":"Clinic for Children and Adolescents, Pediatric Endocrinology, St. Josefs-Hospital, D-44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3313-8845","authenticated-orcid":false,"given":"Katrin","family":"Marcus-Alic","sequence":"additional","affiliation":[{"name":"The Medical Proteome Center, Ruhr-University Bochum, D-44801 Bochum, Germany"},{"name":"International Graduate School of Neuroscience (IGSN), Ruhr-University Bochum, D-44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7983-0143","authenticated-orcid":false,"given":"Carsten","family":"Theiss","sequence":"additional","affiliation":[{"name":"Department of Cytology, Institute of Anatomy, Ruhr-University Bochum, D-44801 Bochum, Germany"},{"name":"International Graduate School of Neuroscience (IGSN), Ruhr-University Bochum, D-44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Stahlke","sequence":"additional","affiliation":[{"name":"Department of Cytology, Institute of Anatomy, Ruhr-University Bochum, D-44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1007\/s00198-006-0172-4","article-title":"An estimate of the worldwide prevalence and disability associated with osteoporotic fractures","volume":"17","author":"Johnell","year":"2006","journal-title":"Osteoporos. Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/s41574-022-00662-x","article-title":"Interdisciplinary management of FGF23-related phosphate wasting syndromes: A Consensus Statement on the evaluation, diagnosis and care of patients with X-linked hypophosphataemia","volume":"18","author":"Trombetti","year":"2022","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1681\/ASN.2007010068","article-title":"How Fibroblast Growth Factor 23 Works","volume":"18","author":"Liu","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2021\/8821292","article-title":"FGF23: A Review of Its Role in Mineral Metabolism and Renal and Cardiovascular Disease","volume":"2021","author":"Kurpas","year":"2021","journal-title":"Dis. Markers"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e10190","DOI":"10.1002\/jbm4.10190","article-title":"FGF23, Hypophosphatemia, and Emerging Treatments","volume":"3","author":"Imel","year":"2019","journal-title":"JBMR Plus"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/s41581-019-0152-5","article-title":"Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia","volume":"15","author":"Haffner","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1530\/EC-19-0481","article-title":"Increased prevalence of overweight and obesity in children with X-linked hypophosphatemia","volume":"9","author":"Zhukouskaya","year":"2020","journal-title":"Endocr. Connect."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Di Conza, G., and Ho, P.-C. (2020). ER Stress Responses: An Emerging Modulator for Innate Immunity. Cells, 9.","DOI":"10.3390\/cells9030695"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.molcel.2017.06.017","article-title":"The Unfolded Protein Response and Cell Fate Control","volume":"69","author":"Hetz","year":"2018","journal-title":"Mol. Cell."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1146\/annurev-pathol-012513-104649","article-title":"The Role of Endoplasmic Reticulum Stress in Human Pathology","volume":"10","author":"Oakes","year":"2015","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Oslowski, C.M., and Urano, F. (2011). Measuring ER Stress and the Unfolded Protein Response Using Mammalian Tissue Culture System. Methods in Enzymology, Elsevier.","DOI":"10.1016\/B978-0-12-385114-7.00004-0"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Meyer, B.A., and Doroudgar, S. (2020). ER Stress-Induced Secretion of Proteins and Their Extracellular Functions in the Heart. Cells, 9.","DOI":"10.3390\/cells9092066"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3983","DOI":"10.1016\/j.apsb.2021.05.018","article-title":"A small molecule UPR modulator for diabetes identified by high throughput screening","volume":"11","author":"Marrocco","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.bbamcr.2011.10.013","article-title":"GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum","volume":"1823","author":"Marzec","year":"2012","journal-title":"Biochim. Et Biophys. Acta (BBA)\u2014Mol. Cell Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Shimizu, M., and Sato, R. (2022). Endocrine Fibroblast Growth Factors in Relation to Stress Signaling. Cells, 11.","DOI":"10.3390\/cells11030505"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.tox.2017.07.019","article-title":"Mitochondrial fusion, fission, and mitochondrial toxicity","volume":"391","author":"Meyer","year":"2017","journal-title":"Toxicol"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kumar, V., and Maity, S. (2021). ER Stress-Sensor Proteins and ER-Mitochondrial Crosstalk\u2014Signaling Beyond (ER) Stress Response. Biomolecules, 11.","DOI":"10.3390\/biom11020173"},{"key":"ref_18","first-page":"3743","article-title":"Characterization of osteosarcoma cell lines MG-63, Saos-2 and U-2 OS in comparison to human osteoblasts","volume":"24","author":"Pautke","year":"2004","journal-title":"Anticancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1111\/j.1476-5829.2011.00310.x","article-title":"The effect of Zhangfei on the unfolded protein response and growth of cells derived from canine and human osteosarcomas","volume":"11","author":"Bergeron","year":"2012","journal-title":"Vet. Comp. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"923","DOI":"10.17305\/bb.2024.10181","article-title":"Comprehensive in vitro and in ovo assessment of cytotoxicity: Unraveling the impact of sodium fluoride, xylitol, and their synergistic associations in dental products","volume":"24","author":"Chioibas","year":"2024","journal-title":"Biomol. Biomed."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1083\/jcb.200604016","article-title":"Structural and functional features and significance of the physical linkage between ER and mitochondria","volume":"174","author":"Renken","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7282","DOI":"10.18632\/aging.204238","article-title":"Impact of cytotoxic agents or apoptosis stimulants on \u03b1klotho in MDCK, NRK-52E and HK2 kidney cells","volume":"14","author":"Wolf","year":"2022","journal-title":"Aging"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hunt, E.G., Andrews, A.M., Larsen, S.R., and Thaxton, J.E. (2022). The ER-Mitochondria Interface as a Dynamic Hub for T Cell Efficacy in Solid Tumors. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.867341"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"R\u00fchmkorf, A., and Harbauer, A.B. (2023). Role of Mitochondria\u2013ER Contact Sites in Mitophagy. Biomolecules, 13.","DOI":"10.3390\/biom13081198"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6900","DOI":"10.1038\/s41467-023-42521-x","article-title":"DIAPH1-MFN2 interaction regulates mitochondria-SR\/ER contact and modulates ischemic\/hypoxic stress","volume":"14","author":"Yepuri","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1002\/biof.12","article-title":"Endocrine fibroblast growth factors as regulators of metabolic homeostasis","volume":"35","author":"Kurosu","year":"2009","journal-title":"BioFactors"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.tips.2021.11.011","article-title":"ER stress in obesity pathogenesis and management","volume":"43","author":"Ajoolabady","year":"2022","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"101169","DOI":"10.1016\/j.molmet.2021.101169","article-title":"A guide to understanding endoplasmic reticulum stress in metabolic disorders","volume":"47","author":"Lemmer","year":"2021","journal-title":"Mol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.clnu.2016.12.010","article-title":"Associations of serum fibroblast growth factor 23 levels with obesity and visceral fat accumulation","volume":"37","author":"Hu","year":"2018","journal-title":"Clin. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"110620","DOI":"10.1016\/j.diabres.2023.110620","article-title":"The relationship between FGF23 and body composition according to albuminuria stage in type 1 diabetes","volume":"198","author":"Parente","year":"2023","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Park, S.-M., Kang, T.-I., and So, J.-S. (2021). Roles of XBP1s in Transcriptional Regulation of Target Genes. Biomed, 9.","DOI":"10.3390\/biomedicines9070791"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.semcdb.2010.03.004","article-title":"GRP94 in ER quality control and stress responses","volume":"21","author":"Eletto","year":"2010","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.15252\/embr.201642195","article-title":"The integrated stress response","volume":"17","author":"Koryga","year":"2016","journal-title":"EMBO Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/0092-8674(93)90509-O","article-title":"Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death","volume":"74","author":"Oltval","year":"1993","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.bbamcr.2011.01.021","article-title":"Mitochondrial outer membrane permeabilization during apoptosis: The role of mitochondrial fission","volume":"1813","author":"Landes","year":"2011","journal-title":"Biochim. Et Biophys. Acta (BBA)\u2014Mol. Cell Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/18\/1515\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:53:02Z","timestamp":1760111582000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/18\/1515"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,10]]},"references-count":36,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["cells13181515"],"URL":"https:\/\/doi.org\/10.3390\/cells13181515","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,10]]}}}