Excess Fibroblast Growth Factor 23 in Alcoholic Osteomalacia is Derived from the Bone

Overview

Journal JBMR Plus

Publisher Oxford University Press

Date 2025 Feb 18

PMID 39963340

Authors

Naoko Hidaka

Yuko Oyama

Minae Koga

Naoki Kondo

Yoichi Yasunaga

Taketoshi Shimakura

Noriaki Yamamoto

Hideaki E Takahashi

Yoichi Iwafuchi

So Watanabe

Soichiro Kimura

Yoshitomo Hoshino

Hajime Kato

Yuka Kinoshita

Hiroshi Kobayashi

Takeyuki Tanaka

Tetsuo Ushiku

Masaomi Nangaku

Sakae Tanaka

Noriko Makita

Taku Saito

Nobuaki Ito

Affiliations

Soon will be listed here.

Abstract

Excess fibroblast growth factor 23 (FGF23), a mature osteocyte-derived phosphaturic hormone, causes chronic hypophosphatemic osteomalacia in adults. This rare condition was recently reported in 2 alcoholic patients, with marked improvement upon cessation of alcohol consumption, suggesting a link between alcohol and FGF23-related hypophosphatemia within the highly limited cases. This study aimed to investigate whether the source of excess FGF23 in alcohol-induced FGF23-related hypophosphatemic osteomalacia is the bone or the other organs. To achieve this goal, an immunohistochemical approach for the bone obtained from a patient was employed. Initial attempts at quantifying FGF23 in the bone using conventional immunohistochemistry (IHC) faced issues in quantifiability and sensitivity for low FGF23 expression levels. Therefore, next-generation IHC with phosphor-integrated dots (PIDs) was applied, which enabled the quantification of FGF23 expression in the bone across a broad range. Preliminary analyses using IHC with PIDs on normal bone samples ( = 12) provided a reference level (154.5 PID particles per cell). IHC with PIDs quantified suppressed physiological FGF23 expression in the bone samples from 3 patients with tumor-induced osteomalacia, where FGF23 is oversecreted from a tumor (13.6 PID particles per cell). Subsequently, bone samples obtained from a 70-yr-old male with alcohol-induced FGF23-related hypophosphatemic osteomalacia were analyzed, showing a higher number of PID particles per cell (199.4 PID particles per cell) than the reference level. This study suggests that orthotopic, bone-derived FGF23 is implicated in alcohol-induced FGF23-related hypophosphatemic osteomalacia. Furthermore, the study also demonstrated that highly sensitive IHC with PIDs could aid in the differential diagnosis of FGF23-related hypophosphatemia of unknown origin. Specifically, a bone sample with a low number of PID particles per cell indicates an excess ectopic secretion of FGF23; a bone sample with a normal to high number of PID particles per cell indicates an excess orthotopic secretion of FGF23.

References

Ito N, Hidaka N, Kato H . The pathophysiology of hypophosphatemia. Best Pract Res Clin Endocrinol Metab. 2023; 38(2):101851. DOI: 10.1016/j.beem.2023.101851. View

Quintero-Platt G, Gonzalez-Reimers E, Rodriguez-Gaspar M, Martin-Gonzalez C, Perez-Hernandez O, Romero-Acevedo L . Alpha Klotho and Fibroblast Growth Factor-23 Among Alcoholics. Alcohol Alcohol. 2017; 52(5):542-549. DOI: 10.1093/alcalc/agx041. View

Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K . Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology. 2002; 143(8):3179-82. DOI: 10.1210/endo.143.8.8795. View

Maurel D, Boisseau N, Benhamou C, Jaffre C . Alcohol and bone: review of dose effects and mechanisms. Osteoporos Int. 2011; 23(1):1-16. DOI: 10.1007/s00198-011-1787-7. View

Kato H, Koga M, Kinoshita Y, Hidaka N, Hoshino Y, Takashi Y . Utility of Multimodality Approach Including Systemic FGF23 Venous Sampling in Localizing Phosphaturic Mesenchymal Tumors. J Endocr Soc. 2022; 7(2):bvac181. PMC: 9757682. DOI: 10.1210/jendso/bvac181. View

Tajima S, Takashi Y, Ito N, Fukumoto S, Fukuyama M . ERG and FLI1 are useful immunohistochemical markers in phosphaturic mesenchymal tumors. Med Mol Morphol. 2015; 49(4):203-209. DOI: 10.1007/s00795-015-0115-2. View

Hidaka N, Koga M, Kimura S, Hoshino Y, Kato H, Kinoshita Y . Clinical Challenges in Diagnosis, Tumor Localization and Treatment of Tumor-Induced Osteomalacia: Outcome of a Retrospective Surveillance. J Bone Miner Res. 2022; 37(8):1479-1488. DOI: 10.1002/jbmr.4620. View

Ito N, Kubota T, Kitanaka S, Fujiwara I, Adachi M, Takeuchi Y . Clinical performance of a novel chemiluminescent enzyme immunoassay for FGF23. J Bone Miner Metab. 2021; 39(6):1066-1075. DOI: 10.1007/s00774-021-01250-1. View

Wasserman H, Ikomi C, Hafberg E, Miethke A, Bove K, Backeljauw P . Two Case Reports of FGF23-Induced Hypophosphatemia in Childhood Biliary Atresia. Pediatrics. 2016; 138(2). DOI: 10.1542/peds.2015-4453. View

10.

Kato H, Hidaka N, Koga M, Ogawa N, Takahashi S, Miyazaki H . Performance evaluation of the new chemiluminescent intact FGF23 assay relative to the existing assay system. J Bone Miner Metab. 2021; 40(1):101-108. DOI: 10.1007/s00774-021-01258-7. View

11.

Ashrafzadeh-Kian S, Ito N, Srivastava T, Garg U, Kato H, Algeciras-Schimnich A . The effect of burosumab on intact and C-terminal FGF23 measurements. Clin Endocrinol (Oxf). 2022; 99(2):152-157. DOI: 10.1111/cen.14832. View

12.

Laroia S, Vellore Srinivasan S, Yadav K, Rastogi A, Kumar S, Kumar G . Performance of shear wave elastography: A single centre pilot study of mixed etiology liver disease patients with normal BMI. Australas J Ultrasound Med. 2021; 24(3):120-136. PMC: 8409442. DOI: 10.1002/ajum.12244. View

13.

Pathak J, Bakker A, Luyten F, Verschueren P, Lems W, Klein-Nulend J . Systemic Inflammation Affects Human Osteocyte-Specific Protein and Cytokine Expression. Calcif Tissue Int. 2016; 98(6):596-608. DOI: 10.1007/s00223-016-0116-8. View

14.

Hidaka N, Kato H, Koga M, Katsura M, Oyama Y, Kinoshita Y . Induction of FGF23-related hypophosphatemic osteomalacia by alcohol consumption. Bone Rep. 2021; 15:101144. PMC: 8640868. DOI: 10.1016/j.bonr.2021.101144. View

15.

Guo Z, Tada H, Kitamura N, Hamada Y, Miyashita M, Harada-Shoji N . Automated Quantification of Extranuclear ERα using Phosphor-integrated Dots for Predicting Endocrine Therapy Resistance in HR/HER2 Breast Cancer. Cancers (Basel). 2019; 11(4). PMC: 6520781. DOI: 10.3390/cancers11040526. View

16.

Ramos P, Larson B, Ashrafzadeh-Kian S, Ito N, Kato H, Bornhorst J . Intact Fibroblast Growth Factor 23 Concentrations in Hypophosphatemic Disorders. Endocr Pract. 2023; 29(3):193-198. DOI: 10.1016/j.eprac.2023.01.003. View

17.

Imel E, Peacock M, Gray A, Padgett L, Hui S, Econs M . Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab. 2011; 96(11):3541-9. PMC: 3205884. DOI: 10.1210/jc.2011-1239. View

18.

Frishberg Y, Ito N, Rinat C, Yamazaki Y, Feinstein S, Urakawa I . Hyperostosis-hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23. J Bone Miner Res. 2006; 22(2):235-42. DOI: 10.1359/jbmr.061105. View

19.

Shimizu Y, Tada Y, Yamauchi M, Okamoto T, Suzuki H, Ito N . Hypophosphatemia induced by intravenous administration of saccharated ferric oxide: another form of FGF23-related hypophosphatemia. Bone. 2009; 45(4):814-6. DOI: 10.1016/j.bone.2009.06.017. View

20.

Gonda K, Watanabe M, Tada H, Miyashita M, Takahashi-Aoyama Y, Kamei T . Quantitative diagnostic imaging of cancer tissues by using phosphor-integrated dots with ultra-high brightness. Sci Rep. 2017; 7(1):7509. PMC: 5548777. DOI: 10.1038/s41598-017-06534-z. View