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Madzharova E, Sabino F, Kalogeropoulos K, Francavilla C, Auf dem Keller U. Substrate O-glycosylation actively regulates extracellular proteolysis. Protein Sci 2024; 33:e5128. [PMID: 39074261 DOI: 10.1002/pro.5128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 05/30/2024] [Accepted: 07/14/2024] [Indexed: 07/31/2024]
Abstract
Extracellular proteolysis critically regulates cellular and tissue responses and is often dysregulated in human diseases. The crosstalk between proteolytic processing and other major post-translational modifications (PTMs) is emerging as an important regulatory mechanism to modulate protease activity and maintain cellular and tissue homeostasis. Here, we focus on matrix metalloproteinase (MMP)-mediated cleavages and N-acetylgalactosamine (GalNAc)-type of O-glycosylation, two major PTMs of proteins in the extracellular space. We investigated the influence of truncated O-glycan trees, also referred to as Tn antigen, following the inactivation of C1GALT1-specific chaperone 1 (COSMC) on the general and MMP9-specific proteolytic processing in MDA-MB-231 breast cancer cells. Quantitative assessment of the proteome and N-terminome using terminal amine isotopic labelling of substrates (TAILS) technology revealed enhanced proteolysis by MMP9 within the extracellular proteomes of MDA-MB-231 cells expressing Tn antigen. In addition, we detected substantial modifications in the proteome and discovered novel ectodomain shedding events regulated by the truncation of O-glycans. These results highlight the critical role of mature O-glycosylation in fine-tuning proteolytic processing and proteome homeostasis by modulating protein susceptibility to proteolytic degradation. These data suggest a complex interplay between proteolysis and O-GalNAc glycosylation, possibly affecting cancer phenotypes.
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Affiliation(s)
- Elizabeta Madzharova
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Fabio Sabino
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | | | - Chiara Francavilla
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Ulrich Auf dem Keller
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
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2
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Parghane RV, Basu S. False-Positive 68Ga-DOTATATE PET/CT Findings in Hereditary Hypophosphatemia-Osteomalacia Mimicking Culprit Lesions of Tumor-Induced Osteomalacia. J Nucl Med Technol 2023; 51:73-74. [PMID: 35197273 DOI: 10.2967/jnmt.121.263776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/28/2022] [Accepted: 01/28/2022] [Indexed: 11/16/2022] Open
Abstract
68Ga-DOTATATE PET/CT is an important imaging modality for detection of culprit lesions of tumor-induced osteomalacia in clinically symptomatic patients with hypophosphatemia-osteomalacia. Somatostatin receptor expression may at times be observed in inflammatory or granulomatous conditions and in fractures or degenerative bone disease, leading to false-positive scan findings. We present a rare case of hereditary hypophosphatemia-osteomalacia that showed increased false-positive uptake (for possible tumor-induced osteomalacia lesions) in an inflammatory condition of the maxillary sinus and a fracture of the tibia on somatostatin receptor-based 68Ga-DOTATATE PET/CT.
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Affiliation(s)
- Rahul V Parghane
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, and Homi Bhabha National Institute, Mumbai, India
| | - Sandip Basu
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, and Homi Bhabha National Institute, Mumbai, India
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Saad HKM, Abd Rahman AA, Ab Ghani AS, Taib WRW, Ismail I, Johan MF, Al-Wajeeh AS, Al-Jamal HAN. Activation of STAT and SMAD Signaling Induces Hepcidin Re-Expression as a Therapeutic Target for β-Thalassemia Patients. Biomedicines 2022; 10:biomedicines10010189. [PMID: 35052868 PMCID: PMC8773737 DOI: 10.3390/biomedicines10010189] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 01/27/2023] Open
Abstract
Iron homeostasis is regulated by hepcidin, a hepatic hormone that controls dietary iron absorption and plasma iron concentration. Hepcidin binds to the only known iron export protein, ferroportin (FPN), which regulates its expression. The major factors that implicate hepcidin regulation include iron stores, hypoxia, inflammation, and erythropoiesis. When erythropoietic activity is suppressed, hepcidin expression is hampered, leading to deficiency, thus causing an iron overload in iron-loading anemia, such as β-thalassemia. Iron overload is the principal cause of mortality and morbidity in β-thalassemia patients with or without blood transfusion dependence. In the case of thalassemia major, the primary cause of iron overload is blood transfusion. In contrast, iron overload is attributed to hepcidin deficiency and hyperabsorption of dietary iron in non-transfusion thalassemia. Beta-thalassemia patients showed marked hepcidin suppression, anemia, iron overload, and ineffective erythropoiesis (IE). Recent molecular research has prompted the discovery of new diagnostic markers and therapeutic targets for several diseases, including β-thalassemia. In this review, signal transducers and activators of transcription (STAT) and SMAD (structurally similar to the small mothers against decapentaplegic in Drosophila) pathways and their effects on hepcidin expression have been discussed as a therapeutic target for β-thalassemia patients. Therefore, re-expression of hepcidin could be a therapeutic target in the management of thalassemia patients. Data from 65 relevant published experimental articles on hepcidin and β-thalassemia between January 2016 and May 2021 were retrieved by using PubMed and Google Scholar search engines. Published articles in any language other than English, review articles, books, or book chapters were excluded.
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Affiliation(s)
- Hanan Kamel M. Saad
- School of Biomedicine, Faculty of Health Sciences, Universiti Sultan Zainal Abidin, Kuala Nerus 21300, Terengganu, Malaysia; (H.K.M.S.); (W.R.W.T.); (I.I.)
| | - Alawiyah Awang Abd Rahman
- Pathology Department, Hospital Sultanah Nur Zahirah, Kuala Terengganu 20400, Terengganu, Malaysia; (A.A.A.R.); (A.S.A.G.)
| | - Azly Sumanty Ab Ghani
- Pathology Department, Hospital Sultanah Nur Zahirah, Kuala Terengganu 20400, Terengganu, Malaysia; (A.A.A.R.); (A.S.A.G.)
| | - Wan Rohani Wan Taib
- School of Biomedicine, Faculty of Health Sciences, Universiti Sultan Zainal Abidin, Kuala Nerus 21300, Terengganu, Malaysia; (H.K.M.S.); (W.R.W.T.); (I.I.)
| | - Imilia Ismail
- School of Biomedicine, Faculty of Health Sciences, Universiti Sultan Zainal Abidin, Kuala Nerus 21300, Terengganu, Malaysia; (H.K.M.S.); (W.R.W.T.); (I.I.)
| | - Muhammad Farid Johan
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelatan, Malaysia;
| | | | - Hamid Ali Nagi Al-Jamal
- School of Biomedicine, Faculty of Health Sciences, Universiti Sultan Zainal Abidin, Kuala Nerus 21300, Terengganu, Malaysia; (H.K.M.S.); (W.R.W.T.); (I.I.)
- Correspondence: ; Tel.: +60-1747-29012
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Merz LM, Buerger F, Ziegelasch N, Zenker M, Wieland I, Lipek T, Wallborn T, Terliesner N, Prenzel F, Siekmeyer M, Dittrich K. A Case Report: First Long-Term Treatment With Burosumab in a Patient With Cutaneous-Skeletal Hypophosphatemia Syndrome. Front Endocrinol (Lausanne) 2022; 13:866831. [PMID: 35600592 PMCID: PMC9120998 DOI: 10.3389/fendo.2022.866831] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 03/18/2022] [Indexed: 11/28/2022] Open
Abstract
Epidermal nevus syndromes encompass a highly heterogeneous group of systemic disorders, characterized by epidermal nevi, and a spectrum of neuromuscular, ocular, and bone abnormalities. Cutaneous-skeletal hypophosphatemia syndrome (CSHS) constitutes a specific sub-entity in which elevated levels of fibroblast growth factor-23 cause hypophosphatemic rickets that are, to date, not amenable to causal therapy. Here, we report the first long-term follow-up of causal treatment with burosumab in a 3-year-old female patient with CSHS. 4 weeks after initiation of burosumab treatment, serum phosphate normalized to age-appropriate levels. Furthermore, long-term follow-up of 42 months revealed significant improvement of linear growth and gross physical functions, including respiratory insufficiency. Radiographic rickets severity as well as subjective bone pain were strongly reduced, and no side effects were observed over the course of treatment. In summary, we, here, report about a successful treatment of hypophosphatemic rickets in CSHS with burosumab over the time course of 42 months. In our patient, burosumab showed convincing efficacy and safety profile, without any loss of effect or increase of dose.
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Affiliation(s)
- Lea Maria Merz
- Department of Pediatric Nephrology and Pulmonology, University Hospital Leipzig, Leipzig, Germany
- *Correspondence: Lea Maria Merz,
| | - Florian Buerger
- Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Niels Ziegelasch
- Department of Pediatric Nephrology and Pulmonology, University Hospital Leipzig, Leipzig, Germany
| | - Martin Zenker
- Faculty of Medicine, University Hospital Magdeburg, Magdeburg, Germany
| | - Ilse Wieland
- Faculty of Medicine, University Hospital Magdeburg, Magdeburg, Germany
| | - Tobias Lipek
- Department of Pediatric Nephrology and Pulmonology, University Hospital Leipzig, Leipzig, Germany
| | - Tillmann Wallborn
- Department of Pediatric Nephrology, St. Georg Hospital, Leipzig, Germany
| | - Nicolas Terliesner
- Department of Pediatric Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Freerk Prenzel
- Department of Pediatric Nephrology and Pulmonology, University Hospital Leipzig, Leipzig, Germany
| | - Manuela Siekmeyer
- Department of Pediatric Nephrology and Pulmonology, University Hospital Leipzig, Leipzig, Germany
| | - Katalin Dittrich
- Department of Pediatric Nephrology and Pulmonology, University Hospital Leipzig, Leipzig, Germany
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Cao B, Liu M, Luo Q, Wang Q, Liu M, Liang X, Wu D, Li W, Su C, Chen J, Gong C. The Effect of BMI, Age, Gender, and Pubertal Stage on Bone Turnover Markers in Chinese Children and Adolescents. Front Endocrinol (Lausanne) 2022; 13:880418. [PMID: 35769079 PMCID: PMC9234688 DOI: 10.3389/fendo.2022.880418] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/22/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES To ascertain the associations of serum bone turnover markers (BTMs) levels with body mass index (BMI) in Chinese children and adolescents, and whether the influence of BMI, age, pubertal stage on BTMs varied by gender. METHODS A total of 500 students (180 controls and 320 children and adolescents with overweight/obesity) aged 9-14 years were randomly selected from the Chinese National Survey on Students Constitution and Health Cohort. Serum levels of BTMs, including bone formation marker bone alkaline phosphatase (BAP), collagen type 1 C-terminal propeptide (CICP), and bone resorption markers C-terminal telopeptide of type-I collagen (CTX) were determined by commercial enzyme-linked immunosorbent assay kits. The associations among BMI, age, gender, pubertal stage, and BTMs were analyzed. RESULTS Serum levels of CICP and CTX in overweight/obese children and adolescents were lower than those in controls (p<0.05). Moreover, after subgroup analysis stratified by gender, the decreased serum CICP and CTX levels in overweight/obese children and adolescents were observed only in boys (p<0.05). After adjustment of age and pubertal stage, there was a negative correlation between serum BAP and BMI in both boys and girls (p<0.05). However, the correlations between serum CICP, CTX levels, and BMI were significant in boys but not in girls. Serum BAP and CICP levels were independently correlated with BMI, age, gender, and pubertal stage, while CTX levels were independently correlated with BMI, age, and gender (p<0.05). BAP, CICP, and CTX levels showed a clear age, gender, and pubertal stage dependence with significantly higher values in boys (p<0.05). CONCLUSIONS Our findings support the associations between serum BTMs levels and BMI in Chinese children and adolescents, and suggest age, gender, and pubertal stage differences in this relationship that warrant future studies.
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Affiliation(s)
- Bingyan Cao
- Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Meijuan Liu
- Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Qipeng Luo
- Department of Pain Medicine, Peking University Third Hospital, Beijing, China
| | - Qiao Wang
- Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Min Liu
- Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Xuejun Liang
- Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Di Wu
- Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Wenjing Li
- Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Chang Su
- Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Jiajia Chen
- Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Chunxiu Gong
- Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
- *Correspondence: Chunxiu Gong,
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Meshkini F, Soltani S, Clark CCT, Tam V, Meyre D, Toupchian O, Saraf-Bank S, Abdollahi S. The effect of vitamin D supplementation on serum levels of fibroblast growth factor- 23: A systematic review and meta-analysis of randomized controlled trials. J Steroid Biochem Mol Biol 2022; 215:106012. [PMID: 34710560 DOI: 10.1016/j.jsbmb.2021.106012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 09/18/2021] [Accepted: 10/21/2021] [Indexed: 12/29/2022]
Abstract
Previous studies of the effect of vtamin D on serum levels of fibroblast growth factor- 23 (FGF-23) have yeilded an inconsistent findings. This systematic review and meta-analysis of randomized controlled trials (RCTs) sought to investigate the effect of vitamin D supplementation on serum levels of FGF-23. PubMed, Scopus, ISI Web of Science, and the Cochrane Library were searched, from database inception to November 2020, for RCTs that evaluated the effects of native or active vitamin D supplementation on serum levels of FGF-23 in adults. Weighted mean difference (WMD) were calculated and random effects meta-analysis was used to estimate the overall effects. Twenty-seven trials were included in the meta-analysis. Supplementation with native vitamin D (23 studies, n = 2247 participants; weighted mean difference [WMD] = 0.5 pg/mL, 95 % CI: -0.52 to 1.51, P = 0.33; I2 = 29.9 %), and active vitamin D (5 studies, n = 342 participants, WMD = 29.45 pg/mL, 95 % CI: -3.9 to 62.81, P = 0.08; I2 = 99.3%) had no significant effects on serum FGF-23 concentration. In subgroup analyses, supplementation with ergocalciferol (3 studies, n = 205 participants; WMD = 18.27 pg/mL, 95 % CI: 5.36-31.17, P = 0.006), and daily dosing regimens (9 studies, n = 1374 participants; WMD = 0.41 pg/mL, 95 % CI: 0.22 to 0.59, P < 0.001) increased serum FGF-23 levels compared to control. Overall, our findings revealed no significan effect of vitamin D supplementation on serum FGF-23 concentration. However, further high quality, large-scale studies are needed to better elucidate this relationship.
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Affiliation(s)
- Fatemeh Meshkini
- Department of Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; Student Research Committee, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Sepideh Soltani
- Yazd Cardiovascular Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Cain C T Clark
- Centre for Intelligent Healthcare, Coventry University, Coventry, CV1 5FB, UK
| | - Vivian Tam
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
| | - David Meyre
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
| | - Omid Toupchian
- Department of Nutrition, School of Public Health, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Sahar Saraf-Bank
- Food Security Research Center, Department of Community Nutrition, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shima Abdollahi
- Department of Nutrition, School of Public Health, North Khorasan University of Medical Sciences, Bojnurd, Iran.
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Sum M, Hoda ST, Rapp T, Zan E. Tumor-Induced Osteomalacia Localized and Excised After Pregnancy. AACE Clin Case Rep 2021; 7:363-366. [PMID: 34765732 PMCID: PMC8573288 DOI: 10.1016/j.aace.2021.06.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 06/11/2021] [Accepted: 06/13/2021] [Indexed: 11/29/2022] Open
Abstract
Objective Tumor-induced osteomalacia (TIO) is a rare osteomalacia characterized by paraneoplastic secretion of fibroblast growth factor 23. Concomitant occurrence of TIO during pregnancy is rarer still. Our objective was to report a young patient with debilitating fractures diagnosed with TIO who became pregnant and subsequently had her tumor localized by gallium-68 (Ga-68) DOTATATE positron emission tomography/magnetic resonance imaging (PET/MRI). Case Report A 28 year-old woman with a 2-year history of stress fractures was found to have the following: (1) alkaline phosphatase level, 220 (reference range, 30-95) U/L; (2) phosphorus level, 2.1 (2.5-5.0) mg/dL; (3) 1,25-dihydroxyvitamin D3 level, <8 (18-72) pg/mL; (4) 24-hour urine phosphorus level, 0.5 (0.3-1.3) g; and (5) fibroblast growth factor 23 levels, 1241 (reference range, <180) RU/mL. The patient became pregnant, and at term, a cesarean delivery was performed. Ga-68 DOTATATE PET/MRI showed a 9-mm intracortical mass in the right fibular head and right femoral and bilateral calcaneal stress fractures. The fibular lesion was resected; pathology showed a 1.5-cm lesion with positive fibroblast growth factor receptor 1 staining. Discussion This patient with TIO had an uneventful pregnancy and delivery. TIO is typically caused by benign mesenchymal tumors. Ga-68 DOTATATE PET/computed tomography has been used for localizing tumors causing TIO, yet MRI has superior contrast resolution over computed tomography. Therefore, it is not surprising that Ga-68 PET/MRI successfully localized this patient’s tumor to the intracortical space of the fibular head and distinguished it from insufficiency fractures. Conclusion To our knowledge, this is the first report of phosphate treatment in a pregnant patient with TIO and the first report of a tumor-inducing TIO being localized by Ga-68 DOTATATE PET/MRI.
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Key Words
- 1,25[OH]2D3, 1,25-dihydroxyvitamin D3
- ALP, alkaline phosphatase
- DOTATATE
- FGF23, fibroblast growth factor 23
- Ga-68, gallium-68
- MRI, magnetic resonance imaging
- PET, positron emission tomography
- PTH, parathyroid hormone
- SUV, standard uptake value
- TIO, tumor-induced osteomalacia
- TmP/GFR, tubular maximum reabsorption of phosphate per unit of glomerular filtration
- fibroblast growth factor 23
- hypophosphatemia
- iFGF23, intact fibroblast growth factor 23
- pregnancy
- renal phosphate wasting
- tumor-induced osteomalacia
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Affiliation(s)
- Melissa Sum
- Department of Medicine, NYU Langone Health, New York, New York
| | - Syed T Hoda
- Department of Pathology, NYU Langone Health, New York, New York
| | - Timothy Rapp
- Department of Orthopedic Surgery, NYU Langone Health, New York, New York
| | - Elcin Zan
- Department of Radiology, NYU Langone Health, New York, New York
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Zheng G, Kanduri SR, Canterbury JP, Nguyen T, Velez JCQ. A Case of Hypophosphatemia due to Oncogenic Osteomalacia in a Patient with Natural Killer T-Cell Lymphoma. Kidney Blood Press Res 2021; 46:647-651. [PMID: 34293749 DOI: 10.1159/000516390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 04/03/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Oncogenic osteomalacia (Onc-Ost) is a paraneoplastic phenomenon characterized by hypophosphatemia due to elevated fibroblast growth factor-23 (FGF-23). Onc-Ost has been previously reported in patients with germ line mesenchymal tumors and solid organ malignancies. This is the first report of aggressive natural killer (NK) T-cell lymphoma presenting as Onc-Ost. CASE DESCRIPTION A 33-year-old Vietnamese female with active hepatitis B and Mycobacterium avium complex, on ongoing therapy with tenofovir disoproxil, azithromycin, and ethambutol, presented with persistent fevers and developed refractory hypophosphatemia. Workup confirmed severe renal phosphate wasting. Tenofovir disoproxil was initially suspected; however, presence of isolated phosphaturia without Fanconi syndrome and persistence of hypophosphatemia despite discontinuation of medication led to clinical suspicion of Onc-Ost. Elevated FGF-23 warranted further workup, leading to a definitive diagnosis of clinically subtle NK T-cell lymphoma. Chemotherapy was initiated; however, patient continued to deteriorate clinically and expired. CONCLUSION Along with commonly reported germ line mesenchymal tumors and solid malignancies, NK T-cell lymphoma can also present as Onc-Ost. Timely detection of associated tumors and subsequent antitumor therapy would likely reverse hypophosphatemia and improve clinical outcomes.
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Affiliation(s)
- Guoliang Zheng
- Ochsner Clinical School/The University of Queensland, Brisbane, Queensland, Australia
| | - Swetha Rani Kanduri
- Department of Nephrology, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
| | - John P Canterbury
- Department of Nephrology, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
| | - Thuy Nguyen
- Ochsner Clinical School/The University of Queensland, Brisbane, Queensland, Australia
| | - Juan Carlos Q Velez
- Ochsner Clinical School/The University of Queensland, Brisbane, Queensland, Australia.,Department of Nephrology, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
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Bone loss in hepatitis B virus-infected patients can be associated with greater osteoclastic activity independently of the retroviral use. Sci Rep 2021; 11:10162. [PMID: 33986322 PMCID: PMC8119499 DOI: 10.1038/s41598-021-89486-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 04/20/2021] [Indexed: 01/04/2023] Open
Abstract
Nucleoside/nucleotide analogs such as tenofovir, have been used as long-term therapy for the treatment of hepatitis B and side effects such as the reduction in bone mineral density have been associated with their use. To determine the relationships between bone, hormonal, biochemical, and mineral parameters in patients with hepatitis B treated with nucleoside/nucleotide antiviral. A cross-sectional study was conducted with 81 adult patients with chronic hepatitis B infection. Dual-energy X-ray absorptiometry (DXA) was performed to assess bone mineral density. Biochemical analyses were performed for osteocalcin, deoxypyridinoline, parathyroid hormone, vitamin D, IGF-1, TSH, testosterone, estradiol, FSH, transaminases, urea, creatinine, calcium, serum and urinary phosphorus, magnesium, and FGF-23, body composition was performed by DXA. Participants, both gender, were divided according to the use of antiretrovirals: Group1: 27 inactive virus carriers without medication; Group2: 27 patients using tenofovir; and Group3: 27 patients using lamivudine or entecavir. DXA readings diagnosed osteopenia in the lumbar spine for 7.4% of individuals in Group1, 15% in Group2, and 3.7% in Group3. For all groups, we observed normal values in bone formation markers, osteocalcin levels as well as parathyroid hormone, insulin growth factor 1, and FGF-23. In all groups, we found increased levels of urinary deoxypyridinoline, a bone resorption marker. Increased levels in the bone resorption markers indicated a high resorptive activity of bone tissue. These data suggested high resorption activity of bone tissue in hepatitis B virus-infected patients independent of the use of antiretrovirals.
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Wang H, Zheng X, Zhang Y, Huang J, Zhou W, Li X, Tian H, Wang B, Xing D, Fu W, Chen T, Wang X, Zhang X, Wu A. The endocrine role of bone: Novel functions of bone-derived cytokines. Biochem Pharmacol 2020; 183:114308. [PMID: 33137323 DOI: 10.1016/j.bcp.2020.114308] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/18/2020] [Accepted: 10/27/2020] [Indexed: 02/08/2023]
Abstract
Bone-derived cytokines refer to various proteins and peptides that are released from the skeleton and can distribute in organisms to regulate homeostasis by targeting many organs, such as the pancreas, brain, testicles, and kidneys. In addition to providing support and movement, many studies have disclosed the novel endocrine function of bone, and bone can modulate glucose and energy metabolism as well as phosphate metabolism by versatile bone-derived cytokines. However, this specific exoskeletonfunction of bone-derived cytokines in the regulation of homeostasis and the pathological response caused by skeletal dysfunction are still not very clear, and elucidation of the above mechanisms is of great significance for understanding the pathological processes of metabolic disorders and in the search for novel therapeutic measures for maintaining organ stability and physical fitness.
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Affiliation(s)
- Hui Wang
- Department of Orthopaedics, Zhejiang Provincial Key Laboratory of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xuanqi Zheng
- Department of Orthopaedics, Zhejiang Provincial Key Laboratory of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yan Zhang
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Jinfeng Huang
- Department of Orthopaedics, Zhejiang Provincial Key Laboratory of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wenxian Zhou
- Department of Orthopaedics, Zhejiang Provincial Key Laboratory of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xunlin Li
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, PR China
| | - Haijun Tian
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, PR China
| | - Bin Wang
- Department of Sports Medicine and Adult Reconstruction Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210009, China
| | - Dan Xing
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing 100044, China
| | - Weili Fu
- Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu, China
| | - Tao Chen
- Department of Orthopaedics, Zhejiang Provincial Key Laboratory of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiangyang Wang
- Department of Orthopaedics, Zhejiang Provincial Key Laboratory of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaolei Zhang
- Department of Orthopaedics, Zhejiang Provincial Key Laboratory of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Aimin Wu
- Department of Orthopaedics, Zhejiang Provincial Key Laboratory of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
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11
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Saki F, Kassaee SR, Salehifar A, Omrani GHR. Interaction between serum FGF-23 and PTH in renal phosphate excretion, a case-control study in hypoparathyroid patients. BMC Nephrol 2020; 21:176. [PMID: 32398014 PMCID: PMC7218502 DOI: 10.1186/s12882-020-01826-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Accepted: 04/22/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND phosphate homeostasis is mediated through complex counter regulatory feed-back balance between parathyroid hormone, FGF-23 and 1,25(OH)2D. Both parathyroid hormone and FGF-23 regulate proximal tubular phosphate excretion through signaling on sodium- phosphate cotransporters IIa and IIc. However, the interaction between these hormones on phosphate excretion is not clearly understood. We performed the present study to evaluate whether the existence of sufficient parathyroid hormone is necessary for full phosphaturic function of FGF-23 or not. METHODS In this case-control study, 19 patients with hypoparathyroidism and their age- and gender-matched normal population were enrolled. Serum calcium, phosphate, alkaline phosphatase,parathyroid hormone, FGF-23, 25(OH)D, 1,25(OH)2D and Fractional excretion of phosphorous were assessed and compared between the two groups, using SPSS software. RESULTS The mean serum calcium and parathyroid hormone level was significantly lower in hypoparathyroid patients in comparison with the control group (P < 0.001 and P < 0.001, respectively). We found high serum level of phosphate and FGF-23 in hypoparathyroid patients compared to the control group (P < 0.001 and P < 0.001, respectively). However, there was no significant difference in Fractional excretion of phosphorous or 1,25OH2D level between the two groups. There was a positive correlation between serum FGF-23 and Fractional excretion of phosphorous just in the normal individuals (P < 0.001, r = 0.79). CONCLUSIONS Although the FGF-23 is a main regulator of urinary phosphate excretion but the existence of sufficient parathyroid hormone is necessary for the full phosphaturic effect of FGF-23.
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Affiliation(s)
- Forough Saki
- Shiraz Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, P.O. Box: 71345-1744, Shiraz, Iran
| | - Seyed Reza Kassaee
- Shiraz Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, P.O. Box: 71345-1744, Shiraz, Iran
| | - Azita Salehifar
- Shiraz Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, P.O. Box: 71345-1744, Shiraz, Iran
| | - Gholam Hossein Ranjbar Omrani
- Shiraz Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, P.O. Box: 71345-1744, Shiraz, Iran.
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12
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Dessordi R, Santana RDC, Navarro AM. Influence of antiretroviral therapy on bone metabolism of patients with chronic hepatitis B: a review. Rev Soc Bras Med Trop 2019; 52:e20180441. [PMID: 31596347 DOI: 10.1590/0037-8682-0441-2018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 08/21/2019] [Indexed: 11/21/2022] Open
Abstract
Hepatitis B is a major public health problem worldwide and associated with significant mortality. To prevent or delay the deleterious effects of chronic infection by the hepatitis B virus, patients should be carefully followed, and antiviral therapy indicated according to specific recommendations. Currently, available drugs inhibit viral replication and slow or stop the progression of inflammation and fibrosis of the liver. However, the drugs for oral use in the treatment of hepatitis B, jointly referred to as nucleoside/nucleotide analogs, are indicated for prolonged use and have potential side effects. The reduction in bone mineral density was associated with the use of tenofovir, already evaluated in patients infected with HIV because the drug is also part of the therapeutic arsenal for this viral infection. There are few studies on the effects of tenofovir in patients with mono hepatitis B. Therefore, this literature review proposes to examine how hepatitis B acts in the body and the mechanisms by which antiretroviral drugs (especially tenofovir) can affect bone metabolism.
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Affiliation(s)
- Renata Dessordi
- Universidade Estadual Paulista "Júlio de Mesquita Filho", Programa de Pós-Graduação Stricto Sensu em Alimentos e Nutrição, São Paulo, SP, Brasil.,Universidade Estadual Paulista, Faculdade de Ciências Farmacêuticas do Estado de São Paulo, Departamento de Alimentos e Nutrição, São Paulo, SP, Brasil
| | - Rodrigo de Carvalho Santana
- Universidade de São Paulo, Escola de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Ribeirão Preto, SP, Brasil
| | - Anderson Marliere Navarro
- Universidade Estadual Paulista, Faculdade de Ciências Farmacêuticas do Estado de São Paulo, Departamento de Alimentos e Nutrição, São Paulo, SP, Brasil.,Universidade de São Paulo, Escola de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Ribeirão Preto, SP, Brasil
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13
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Tumor-induced osteomalacia – Current imaging modalities and a systematic approach for tumor localization. Clin Imaging 2019; 56:114-123. [DOI: 10.1016/j.clinimag.2019.04.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 03/27/2019] [Accepted: 04/15/2019] [Indexed: 11/20/2022]
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14
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Sen A, Stark H. Role of cytochrome P450 polymorphisms and functions in development of ulcerative colitis. World J Gastroenterol 2019; 25:2846-2862. [PMID: 31249444 PMCID: PMC6589734 DOI: 10.3748/wjg.v25.i23.2846] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 04/26/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
Cytochromes P450s (CYPs) are terminal enzymes in CYP dependent monooxygenases, which constitute a superfamily of enzymes catalysing the metabolism of both endogenous and exogenous substances. One of their main tasks is to facilitate the excretion of these substances and eliminate their toxicities in most phase 1 reactions. Endogenous substrates of CYPs include steroids, bile acids, eicosanoids, cholesterol, vitamin D and neurotransmitters. About 80% of currently used drugs and environmental chemicals comprise exogenous substrates for CYPs. Genetic polymorphisms of CYPs may affect the enzyme functions and have been reported to be associated with various diseases and adverse drug reactions among different populations. In this review, we discuss the role of some critical CYP isoforms (CYP1A1, CYP2D6, CYP2J2, CYP2R1, CYP3A5, CYP3A7, CYP4F3, CYP24A1, CYP26B1 and CYP27B1) in the pathogenesis or aetiology of ulcerative colitis concerning gene polymorphisms. In addition, their significance in metabolism concerning ulcerative colitis in patients is also discussed showing a clear underestimation in genetic studies performed so far.
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Affiliation(s)
- Alaattin Sen
- Department of Molecular Biology and Genetics, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri 38080, Turkey
- Biology Department, Faculty of Arts and Sciences, Pamukkale University, Denizli 20070, Turkey
| | - Holger Stark
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Duesseldorf 40225, Germany
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15
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Rigante M, Loperfido A, Paludetti G. Oncogenic Osteomalacia with Elevated Fibroblast Growth Factor 23: A Rare Case of Paranasal Sinus Tumor Onset. Cureus 2019; 11:e4919. [PMID: 31423395 PMCID: PMC6692094 DOI: 10.7759/cureus.4919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Tumor-induced osteomalacia, also known as oncogenic osteomalacia, is a rare, acquired paraneoplastic disease characterized by hypophosphatemia and renal phosphate wasting. We report on the case of a 52-year-old-man admitted to our hospital for bone and muscular pains and difficulty in walking. He underwent a computed tomography (CT) scan of the legs that documented fractures in the right tibia, femur, and fifth metatarsus. Laboratory findings showed hypophosphatemia and elevated levels of parathyroid hormone (PTH). The first diagnosis was osteomalacia, treated with calcium and vitamin D, without any benefit. So he underwent a whole body CT scan, showing a small expansive lesion occupying the left frontal sinus. Furthermore, we found high serum levels of fibroblast growth factor 23 (FGF23) using the enzyme-linked immune sorbent assay (ELISA) assay. The patient underwent endoscopic surgical resection of the frontal tumor with complete clinical remission and the histopathological diagnosis of an ossifying fibromyxoid tumor. This is a rare case of oncogenic osteomalacia due to a paranasal sinus tumor. The main symptoms are not associated with nasal sinus involvement but with over-expressed FGF23. To conclude, physicians should never underestimate the chance of paraneoplastic syndrome in the head and neck district, even if such an occurrence is uncommon in this location. The clinical symptoms may be aspecific and not related to nose problems, making the differential diagnosis very difficult.
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Affiliation(s)
- Mario Rigante
- Otolaryngology Institute-Department of Head and Neck, Fondazione Policlinico Universitario A. Gemelli Irccs Università Cattolica Del Sacro Cuore, Rome, ITA
| | - Antonella Loperfido
- Otolaryngology Institute-Department of Head and Neck, Fondazione Policlinico Universitario A. Gemelli Irccs Università Cattolica Del Sacro Cuore, Rome, ITA
| | - Gaetano Paludetti
- Otolaryngology Institute-Department of Head and Neck, Fondazione Policlinico Universitario A. Gemelli Irccs Università Cattolica Del Sacro Cuore, Rome, ITA
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16
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Tumour-induced osteomalacia: A case report of craniofacial localization. OTOLARYNGOLOGY CASE REPORTS 2019. [DOI: 10.1016/j.xocr.2019.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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17
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Vlot MC, den Heijer M, de Jongh RT, Vervloet MG, Lems WF, de Jonge R, Obermayer-Pietsch B, Heijboer AC. Clinical utility of bone markers in various diseases. Bone 2018; 114:215-225. [PMID: 29920402 DOI: 10.1016/j.bone.2018.06.011] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 06/13/2018] [Accepted: 06/15/2018] [Indexed: 12/13/2022]
Abstract
Measurements of bone markers (BMs) in peripheral blood or urine are a pivotal part of bone research within modern clinical medicine. In recent years the use of BMs increased substantially as they can be useful either to diagnose bone (related) disease and to follow its natural history, but also to monitor the effects of interventions. However, the use of BMs is still complicated mainly due to (pre)analytical variability of these substances, limited accessibility of assays, variable cut-off values in different countries and laboratories and heterogeneous results with regard to clinical implications of measuring BMs in several studies. This review will provide the clinician with a practical guide, based on current evidence, in which circumstances to test which bone markers for optimal diagnostic purposes, in order to improve patient care in different areas of bone diseases including Paget's disease, primary osteoporosis, tumor induced osteomalacia, hypophosphatemic rickets, van Buchem disease, chronic kidney disease, rheumatoid arthritis, neoplasma/multiple myeloma, type 2 diabetes mellitus and primary hyperparathyroidism. The clinician should consider fasting state, recent fractures, aging, menopausal status, concomitant liver and kidney disease when ordering and interpreting BM measurements as these factors might result in misleading BM concentrations. We found that BMs are clearly useful in the current diagnosis of tumor induced osteomalacia, van Buchem disease, Paget's disease and hypophosphatemic rickets. In addition, BMs are useful to monitor disease activity in chronic kidney disease, Paget's disease and are useful to monitor treatment adherence in osteoporosis.
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Affiliation(s)
- M C Vlot
- Department of Clinical Chemistry, Endocrine Laboratory, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; Department of Internal Medicine, Endocrinology, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands
| | - M den Heijer
- Department of Internal Medicine, Endocrinology, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands
| | - R T de Jongh
- Department of Internal Medicine, Endocrinology, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands
| | - M G Vervloet
- Department Nephrology, Amsterdam Cardiovascular Sciences (ACS) VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands
| | - W F Lems
- Department of Rheumatology, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands
| | - R de Jonge
- Department of Clinical Chemistry, Endocrine Laboratory, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, the Netherlands
| | - B Obermayer-Pietsch
- Department of Internal Medicine, Endocrinology and Diabetology, Medical University of Graz, Graz 8036, Austria
| | - A C Heijboer
- Department of Clinical Chemistry, Endocrine Laboratory, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
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18
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Misgar RA, Sahu D, Sehgal A, Malik SA, Mohsin M, Wani AI, Bashir MI, Masoodi SR. Tumor-Induced Osteomalacia due to Hitherto Undiagnosed Subcutaneous Phosphaturic Mesenchymal Tumor. AACE Clin Case Rep 2018. [DOI: 10.4158/accr-2017-0048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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19
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Jones G, Kottler ML, Schlingmann KP. Genetic Diseases of Vitamin D Metabolizing Enzymes. Endocrinol Metab Clin North Am 2017; 46:1095-1117. [PMID: 29080636 DOI: 10.1016/j.ecl.2017.07.011] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Vitamin D metabolism involves 3 highly specific cytochrome P450 (CYP) enzymes (25-hydroxylase, 1α-hydroxylase, and 24-hydroxylase) involved in the activation of vitamin D3 to the hormonal form, 1,25-(OH)2D3, and the inactivation of 1,25-(OH)2D3 to biliary excretory products. Mutations of the activating enzymes CYP2R1 and CYP27B1 cause lack of normal 1,25-(OH)2D3 synthesis and result in rickets whereas mutations of the inactivating enzyme CYP24A1 cause build-up of excess 1,25-(OH)2D3 and result in hypercalcemia, nephrolithiasis, and nephrocalcinosis. This article reviews the literature for 3 clinical conditions. Symptoms, diagnosis, treatment, and management of vitamin D-dependent rickets and idiopathic infantile hypercalcemia are discussed.
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Affiliation(s)
- Glenville Jones
- Department of Biomedical and Molecular Sciences, Queen's University, Room 650, Botterell Hall, Kingston, ON K7L 3N6, Canada.
| | - Marie Laure Kottler
- Department of Genetics, University de Basse-Normandie, National Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism, Caen University Hospital, Avenue de la Côte de Nacre, 14033 Caen, France; Team 7450 BIOTARGEN, Caen-Normandy University, Esplanade de la Paix, 14032 Caen, France
| | - Karl Peter Schlingmann
- Department of General Pediatrics, University Children's Hospital, Waldeyerstr. 22, D-48149 Muenster, Germany
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20
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Fakhar M, Rashid S. Targeted inhibition of Klotho binding to fibroblast growth factor 23 prevents hypophosphetemia. J Mol Graph Model 2017; 75:9-19. [PMID: 28501532 DOI: 10.1016/j.jmgm.2017.04.024] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Revised: 04/13/2017] [Accepted: 04/18/2017] [Indexed: 02/08/2023]
Abstract
Klotho is a transmembrane protein which plays significant role in the pathogenesis of phosphate ion (Pi)-related disorders. Pi accumulation in human kidney tissues results in the major metabolic disorders due to malfunctioning of Klotho-FGFR1-FGF23 trimeric complex. The potential role of Klotho in Pi metabolism was elaborated through modeling and interaction analysis of glycosyl hydrolase (GS1 and GS2) domains with Fibroblast growth factor 23 (FGF23). In order to inhibit the association of Klotho and FGF23, binding patterns of three reported hits (N-(2-chlorophenyl)-1H-indole-3-carboxamide, N-[2-(1-cyclohexen-1-yl)ethyl]-6,7,8,9-tetrahydropyrido[1,2-e]purin-4-amine and 2-(1-propyl)amino-11-chlorothiazolo[5,4-a]acridine) were evaluated through molecular docking analysis. These inhibitors effectively targeted both GS1 and GS2 domains of Klotho at the similar sites required for FGF23 binding. To further characterize the comparative binding profile of these compounds, molecular dynamics simulation assays were performed. Taken together, current study emphasizes that Klotho may be anticipated as a target molecule in familial hypophosphatemic rickets and mentioned compounds may prove to be effective therapeutic targets against hypophosphetemia induced disorders.
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Affiliation(s)
- Muhammad Fakhar
- National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan
| | - Sajid Rashid
- National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.
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21
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Harjes LM, Parker VJ, Dembek K, Young GS, Giovaninni LH, Kogika MM, Chew DJ, Toribio RE. Fibroblast Growth Factor-23 Concentration in Dogs with Chronic Kidney Disease. J Vet Intern Med 2017; 31:784-790. [PMID: 28419560 PMCID: PMC5435078 DOI: 10.1111/jvim.14707] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 12/29/2016] [Accepted: 02/27/2017] [Indexed: 02/06/2023] Open
Abstract
Background Chronic kidney disease (CKD) is associated with hyperphosphatemia, decreased vitamin D metabolite concentrations, and hyperparathyroidism. This syndrome is known as CKD‐mineral bone disorder (CKD‐MBD). Recently, it has been shown that an increase in fibroblast growth factor‐23 (FGF‐23) concentration is an early biomarker of CKD in people. It is an independent risk factor for both progression of renal disease and survival time in humans and cats with CKD. Information about FGF‐23 in healthy dogs and those with CKD is lacking. Objectives To measure FGF‐23 concentration in dogs with different stages of CKD and determine its association with factors involved in CKD‐MBD, including serum phosphorus and parathyroid hormone (PTH) concentrations. A secondary aim was to validate an ELISA for measurement of plasma FGF‐23 concentration in dogs. Animals Thirty‐two client‐owned dogs with naturally occurring CKD and 10 healthy control dogs. Methods Prospective cross‐sectional study. An FGF‐23 ELISA was used to measure plasma FGF‐23 concentration in dogs and their association with serum creatinine, phosphorus, calcium, and PTH concentrations. Results Plasma FGF‐23 concentrations increased with severity of CKD and were significantly different between IRIS stages 1 and 2 versus stages 3 and 4 (P < .0001). Increases in FGF‐23 concentrations were more frequent than hyperparathyroidism or hyperphosphatemia in this cohort. Serum creatinine and phosphorus concentrations were the strongest independent predictors of FGF‐23 concentration. Conclusions and clinical importance Plasma FGF‐23 concentrations increase in dogs with CKD as disease progresses. Plasma FGF‐23 concentrations appear to be useful for further study of the pathophysiology of CKD‐MBD in dogs.
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Affiliation(s)
- L M Harjes
- Veterinary Clinical Sciences, The Ohio State University, Columbus, OH
| | - V J Parker
- Veterinary Clinical Sciences, The Ohio State University, Columbus, OH
| | - K Dembek
- Veterinary Clinical Sciences, The Ohio State University, Columbus, OH
| | - G S Young
- Center for Biostatistics, The Ohio State University, Columbus, OH
| | - L H Giovaninni
- School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, SP, Brazil
| | - M M Kogika
- School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, SP, Brazil
| | - D J Chew
- Veterinary Clinical Sciences, The Ohio State University, Columbus, OH
| | - R E Toribio
- Veterinary Clinical Sciences, The Ohio State University, Columbus, OH
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22
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Saeedi R, Mojebi-Mogharar A, Sandhu SK, Dubland JA, Ford JA, Yousefi M, Pudek M, Holmes DT, Erb SR, Peter Kwan WC, Kendler DL, Yoshida EM. Lamivudine, Entecavir, or Tenofovir Treatment of Hepatitis B Infection: Effects on Calcium, Phosphate, FGF23 and Indicators of Bone Metabolism. Ann Hepatol 2017; 16:207-214. [DOI: 10.5604/16652681.1231580] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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23
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Hyperphosphatemia and hs-CRP Initiate the Coronary Artery Calcification in Peritoneal Dialysis Patients. BIOMED RESEARCH INTERNATIONAL 2017; 2017:2520510. [PMID: 28321403 PMCID: PMC5340948 DOI: 10.1155/2017/2520510] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 01/11/2017] [Accepted: 01/29/2017] [Indexed: 12/21/2022]
Abstract
Background. Coronary artery calcification (CAC) contributes to high risk of cardiocerebrovascular diseases in dialysis patients. However, the risk factors for CAC initiation in peritoneal dialysis (PD) patients are not known clearly. Methods. Adult patients with baseline CaCS = 0 and who were followed up for at least 3 years or until the conversion from absent to any measurable CAC detected were included in this observational cohort study. Binary logistic regression was performed to identify the risk factors for CAC initiation in PD patients. Results. 70 patients recruited to our study were split into a noninitiation group (n = 37) and an initiation group (n = 33) according to the conversion of any measurable CAC during their follow-up or not. In univariate analysis, systolic blood pressure, serum phosphorus, fibrinogen, hs-CRP, serum creatinine, and triglycerides were positively associated with the initiation of CAC, while the high density lipoprotein and nPCR did the opposite function. Multivariate analysis revealed that hyperphosphatemia and hs-CRP were the independent risk factors for CAC initiation after adjustments. Conclusions. Hyperphosphatemia and hs-CRP were the independent risk factors for CAC initiation in PD patients. These results suggested potential clinical strategies to prevent the initiation of CAC in PD patients.
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Brannon PM, Weaver CM, Anderson CA, Donovan SM, Murphy SP, Yaktine AL. Scanning for new evidence to prioritize updates to the Dietary Reference Intakes: case studies for thiamin and phosphorus. Am J Clin Nutr 2016; 104:1366-1377. [PMID: 27733406 DOI: 10.3945/ajcn.115.128256] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 08/22/2016] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Dietary Reference Intakes (DRIs) are fundamental to inform national nutrition policy. However, a regular systematic review of the 51 nutrients that have DRIs has limited feasibility, and many DRIs have not been reviewed in >15 y. OBJECTIVE To address this issue, individuals (nutrient review group) who were members of the Food and Nutrition Board developed a streamlined, evidence-based methodology that could be used to identify nutrients potentially in need of a systematic review. DESIGN The proposed methodology, termed an evidence scan, comprises several steps. First, an analytic framework is developed to identify markers of associations between intake of a nutrient and a corresponding clinical outcome. Next, the framework is used to direct the identification of keywords for a scan of published research that is potentially relevant to intake requirements or upper intake levels for a nutrient. Last, a panel of content experts selects the abstracts that are likely to be relevant and reviews the full publications. The results may be used to determine whether a revision of the nutrient's DRI is an immediate priority but would not supplant a comprehensive systematic evidence review. RESULTS To illustrate the process, 2 nutrients were selected as case studies: thiamin and phosphorus (DRIs were last set in 1998 and 1997, respectively). Using the evidence scan for thiamin, we identified 70 potentially relevant abstracts, of which 9 full publications were reviewed. For phosphorus, 127 potentially relevant abstracts were identified, and 29 full publications were reviewed. CONCLUSIONS From the review of these 2 nutrients, the nutrient review group concluded that there was insufficient new evidence to assign a high priority to a comprehensive systematic review for either thiamin or phosphorus. Evidence scanning is an efficient method of identifying DRI nutrients that are most in need of either a new or an updated systematic review.
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Affiliation(s)
- Patsy M Brannon
- Division of Nutritional Science, Cornell University, Ithaca, NY
| | - Connie M Weaver
- Department of Nutrition Science, Purdue University, West Lafayette, IN
| | - Cheryl Am Anderson
- Division of Preventive Medicine, School of Medicine, University of California San Diego, San Diego, CA
| | - Sharon M Donovan
- Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL
| | - Suzanne P Murphy
- University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI; and
| | - Ann L Yaktine
- Food and Nutrition Board, The National Academies of Sciences, Engineering, and Medicine, Washington, DC
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25
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Abstract
Laboratory analyses of biochemical markers for bone and mineral metabolism can play a key role in the assessment of patients with osteoporosis. They may help to assess bone turnover in the diagnostic work-up and aid decision-making as well as selection of pharmaceutical therapy options. Recent publications on therapy response have shown that biochemical markers of bone turnover are valuable tools for the evaluation of therapy success in individual osteoporosis patients and the assessment of bone mineral density gain during therapy.
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Affiliation(s)
- B Obermayer-Pietsch
- Klinische Abteilung für Endokrinologie und Diabetologie, Univiversitätsklinik für Innere Medizin, Auenbruggerplatz 15, 8036, Graz, Österreich.
| | - V Schwetz
- Klinische Abteilung für Endokrinologie und Diabetologie, Univiversitätsklinik für Innere Medizin, Auenbruggerplatz 15, 8036, Graz, Österreich
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26
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Tumour-induced osteomalacia: a literature review and a case report. World J Surg Oncol 2016; 14:4. [PMID: 26744291 PMCID: PMC4705745 DOI: 10.1186/s12957-015-0763-7] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 12/30/2015] [Indexed: 12/24/2022] Open
Abstract
Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterised by severe hypophosphataemia and osteomalacia, with renal phosphate wasting that occurs in association with tumour. The epidemiology likewise aetiology is not known. The clinical presentation of TIO includes bone fractures, bone and muscular pains, and sometimes height and weight loss. TIO may be associated with mesenchymal tumours which may be benign or malignant in rare cases. Mesenchymal tumour itself may be related to fibroblast growth factor 23 (FGF23), which is responsible for hypophosphataemia and phosphaturia occurring in this paraneoplastic syndrome. Hypophosphataemia, phosphaturia and elevated alkaline phosphatase are the main laboratory readings that may lead to more precise investigations and better diagnosis. Finding the tumour can be a major diagnostic challenge and may involve total body magnetic resonance imaging, computed tomography and scintigraphy using radiolabelled somatostatin analogue. The treatment of choice for TIO is resection of a tumour with a wide margin to insure complete tumour removal, as recurrences of these tumours have been reported. We provide here an overview on the current available TIO case reports and review the best practices that may lead to earlier recognition of TIO and the subsequent treatment thereof, even though biochemical background and the long-term prognosis of the disease are not well understood. This review also includes a 4-year-long history of a patient that featured muscular pains, weakness and multiple stress fractures localised in the hips and vertebra with subsequent recovery after tumour resection. Because the occurrence of such a condition is rare, it may take years to correctly diagnose the disease, as is reported in this case report.
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Bhagatwala J, Zhu H, Parikh SJ, Guo DH, Kotak I, Huang Y, Havens R, Pham M, Afari E, Kim S, Cutler C, Pollock NK, Dong Y, Raed A, Dong Y. Dose and time responses of vitamin D biomarkers to monthly vitamin D3 supplementation in overweight/obese African Americans with suboptimal vitamin d status: a placebo controlled randomized clinical trial. BMC OBESITY 2015. [PMID: 26217542 PMCID: PMC4511449 DOI: 10.1186/s40608-015-0056-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background A critical need exists to better understand the physiological sequel of vitamin D supplementation in obese individuals and African Americans. The aim was to comprehensively evaluate dose- and time-responses of a panel of vitamin D biomarkers to vitamin D supplements in this population. Methods We conducted a 16-week randomized, double-blinded, and placebo-controlled clinical trial. Seventy overweight/obese African Americans (age 13–45 years, 84 % females) with 25-hydroxyvitamin D [25(OH)D] concentrations ≤20 ng/mL were randomly assigned to receive a supervised monthly oral vitamin D3 of 18,000 IU (~600 IU/day, n = 17), 60,000 IU (~2000 IU/day, n = 18), 120,000 IU (~4000 IU/day, n = 18), or placebo (n = 17). Results There were significant dose- and time-responses of circulating 25(OH)D, 1,25-dihydroxyvitamin D [1,25(OH)2D], and intact parathyroid hormone (iPTH), but not fibroblast growth factor-23 (FGF-23), phosphorus and urine calcium to the vitamin D supplements. The mean 25(OH)D concentrations in the 2000 IU and 4000 IU groups reached ≥30 ng/mL as early as 8-weeks and remained at similar level at 16-weeks. The increase of 25(OH)D was significantly higher in the 4000 IU group than all the other groups at 8-weeks. The increase of 1,25(OH)2D was significantly higher in the 2000 IU and 4000 IU groups than the placebo at 8-weeks. Only the 4000 IU compared to the placebo significantly reduced iPTH at 8- and 16-weeks. Conclusions Our RCT, for the first time, comprehensively evaluated time- and dose- responses of vitamin D supplementation in overweight/obese African Americans with suboptimal vitamin D status. Circulating 25(OH)D, 1,25(OH)2D, and iPTH, but not FGF-23, phosphorus and urine calcium, respond to vitamin D supplementation in a time- and dose–response manner. By monthly dosing, 2000 IU appears to be sufficient in achieving a 25(OH)D level of 30 ng/mL in this population. However, importantly, 4000 IU, rather than 2000 IU, seems to suppress iPTH. If replicated, these data might be informative in optimizing vitamin D status and providing individualized dosing recommendation in overweight/obese African Americans. Trial registration ClinicalTrials.gov number: NCT01583621, Registered on April 3, 2012.
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Affiliation(s)
- Jigar Bhagatwala
- Georgia Prevention Institute, Medical College of Georgia, Georgia Regents University, Building HS-1640, Augusta, 30912-3715 GA USA ; Department of Internal Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA USA
| | - Haidong Zhu
- Georgia Prevention Institute, Medical College of Georgia, Georgia Regents University, Building HS-1640, Augusta, 30912-3715 GA USA
| | - Samip J Parikh
- Georgia Prevention Institute, Medical College of Georgia, Georgia Regents University, Building HS-1640, Augusta, 30912-3715 GA USA ; Department of Internal Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA USA
| | - De-Huang Guo
- Georgia Prevention Institute, Medical College of Georgia, Georgia Regents University, Building HS-1640, Augusta, 30912-3715 GA USA
| | - Ishita Kotak
- Georgia Prevention Institute, Medical College of Georgia, Georgia Regents University, Building HS-1640, Augusta, 30912-3715 GA USA
| | - Ying Huang
- Georgia Prevention Institute, Medical College of Georgia, Georgia Regents University, Building HS-1640, Augusta, 30912-3715 GA USA
| | - Robyn Havens
- Georgia Prevention Institute, Medical College of Georgia, Georgia Regents University, Building HS-1640, Augusta, 30912-3715 GA USA ; College of Nursing, Georgia Regents University, Augusta, GA USA
| | - Michael Pham
- Georgia Prevention Institute, Medical College of Georgia, Georgia Regents University, Building HS-1640, Augusta, 30912-3715 GA USA
| | - Eric Afari
- Georgia Prevention Institute, Medical College of Georgia, Georgia Regents University, Building HS-1640, Augusta, 30912-3715 GA USA
| | - Susan Kim
- Georgia Prevention Institute, Medical College of Georgia, Georgia Regents University, Building HS-1640, Augusta, 30912-3715 GA USA
| | | | - Norman K Pollock
- Georgia Prevention Institute, Medical College of Georgia, Georgia Regents University, Building HS-1640, Augusta, 30912-3715 GA USA
| | - Yutong Dong
- Georgia Prevention Institute, Medical College of Georgia, Georgia Regents University, Building HS-1640, Augusta, 30912-3715 GA USA
| | - Anas Raed
- Georgia Prevention Institute, Medical College of Georgia, Georgia Regents University, Building HS-1640, Augusta, 30912-3715 GA USA ; Department of Internal Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA USA
| | - Yanbin Dong
- Georgia Prevention Institute, Medical College of Georgia, Georgia Regents University, Building HS-1640, Augusta, 30912-3715 GA USA
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Ho CL. Ga68-DOTA Peptide PET/CT to Detect Occult Mesenchymal Tumor-Inducing Osteomalacia: A Case Series of Three Patients. Nucl Med Mol Imaging 2015; 49:231-6. [PMID: 26279697 DOI: 10.1007/s13139-015-0328-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 02/14/2015] [Accepted: 02/17/2015] [Indexed: 10/23/2022] Open
Abstract
Tumor-induced osteomalacia (TIO) is a rare disease that manifests with paraneoplasic syndrome and overproduction of fibroblast growth factor 23 (FGF23), leading to renal phosphate wasting and hyperphosphaturia, eventually leading to acquired hypophosphatemic osteomalacia. Diagnosis of this disease is often challenging because of the small size of the lesion, which can be localized in bone or soft tissue anywhere in the body. Detecting these occult mesenchymal tumors (OMT) is of great importance as they are potentially curable after tumor resection. The purpose of this case series is to provide some insight into the diagnosis and localization of OMT associated with osteomalacia, particularly using functional imaging with Ga68-DOTA peptide PET/CT scans.
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Affiliation(s)
- Chi Long Ho
- Department of Diagnostic Radiology, Singapore General Hospital, 4 Outram Road, Singapore, 169608 Singapore
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Gkentzi D, Efthymiadou A, Kritikou D, Chrysis D. Fibroblast growth factor 23 and Klotho serum levels in healthy children. Bone 2014; 66:8-14. [PMID: 24880094 DOI: 10.1016/j.bone.2014.05.012] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Revised: 05/13/2014] [Accepted: 05/22/2014] [Indexed: 12/18/2022]
Abstract
Data for fibroblast growth factor 23 (FGF23) and particularly for Klotho in healthy children are limited. We aimed to investigate the relationship between FGF23 and Klotho with age and TmP/GFR and to evaluate parameters that might affect FGF23 and Klotho. In 159 healthy children (82 boys) with a mean±SD age of 8.78±3.47years we measured FGF23 (intact FGF23/iFGF23 and C-terminal FGF23/cFGF23) and soluble aKlotho serum levels by ELISA. Mean±SD value for cFGF23, was 51.14±12.79 RU/ml whereas median (range) values for iFGF23 and Klotho were 35 (8.8, 120) pg/ml and 1945 (372, 5866) pg/ml respectively. Neither FGF23 nor Klotho were significantly associated with age. Pubertal children had higher Klotho than prepubertal (p<0.05), and girls had higher levels of cFGF23 (p<0.05) and Klotho (p<0.001) than boys. Serum phosphate and TmP/GFR were positively associated with cFGF23 (p<0.01 and p<0.001), iFGF23 (p<0.05 and p<0.001) and Klotho (p<0.05 and p<0.01). Klotho was positively correlated with IGF-I (p<0.0001) and 1,25 (OH)2 vitamin D (p<0.05). In this study we provide data on cFGF23, iFGF23, and Klotho measured simultaneously in healthy children. The positive association of serum phosphate and TmP/GFR with FGF23 and Klotho suggests that they have a counterregulatory effect on phosphate homeostasis. The strong association of Klotho with IGF-I could indicate a role of Klotho in linear growth through phosphate regulation, but further studies are required.
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Affiliation(s)
- Despoina Gkentzi
- Department of Pediatrics, Medical School, University of Patras, Rio, Greece.
| | - Alexandra Efthymiadou
- Pediatric Endocrine Unit, Department of Pediatrics, Medical School, University of Patras, Rio, Greece
| | - Dimitra Kritikou
- Pediatric Endocrine Unit, Department of Pediatrics, Medical School, University of Patras, Rio, Greece
| | - Dionisios Chrysis
- Pediatric Endocrine Unit, Department of Pediatrics, Medical School, University of Patras, Rio, Greece
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Saeedi R, Jiang SY, Holmes DT, Kendler DL. Fibroblast growth factor 23 is elevated in tenofovir-related hypophosphatemia. Calcif Tissue Int 2014; 94:665-8. [PMID: 24706031 DOI: 10.1007/s00223-014-9854-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 03/18/2014] [Indexed: 12/15/2022]
Abstract
In human immunodeficiency virus (HIV)-infected patients, tenofovir disoproxil fumarate (TDF) may cause hypophosphatemia leading to osteomalacia due to renal phosphate wasting. Fibroblast growth factor 23 (FGF23) may play a role in this setting. We present an HIV-infected patient with TDF-induced profound hypophosphatemia, Fanconi syndrome, osteomalacia, and bilateral hip fracture. Routine serum biochemistry was assessed by standard methods. The plasma FGF23 concentration was measured at Mayo Laboratories (Scottsdale, AZ, USA). Bone mineral density (BMD) was measured using a Hologic Discovery densitometer. At presentation, the patient's plasma C-terminal FGF23 was 2,760 reference units (RU)/mL (15 times upper limit of normal; reference interval [RI] ≤ 180 RU/mL), serum phosphate was 0.58 (RI 0.8-1.6 mmol/L), and TmPO4/GFR was 95%. DXA at the lumbar spine showed a Z score of -4.0. Vitamin D3 and oral phosphate were administered, and TDF was discontinued. After 4 months off TDF, lumbar spine BMD significantly increased by 12% (Z score -3.5); by 6 months the plasma C-terminal FGF23 declined to 1.8 times the upper limit of normal, and both urine and serum phosphate levels normalized. By its marked elevation and subsequent near normalization, FGF23 may be responsible for a component of the phosphate wasting syndrome in these patients. The time course of resolution was 6 months. As expected, with calcium, vitamin D, and phosphate management, BMD significantly improved with resolution of osteomalacia. Clinicians should be aware of this side effect of TDF and the time course of its resolution.
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Affiliation(s)
- Ramesh Saeedi
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
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Malignant phosphaturic mesenchymal tumor of the pelvis: A report of two cases. Oncol Lett 2014; 8:67-71. [PMID: 24959220 PMCID: PMC4063565 DOI: 10.3892/ol.2014.2081] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 04/04/2014] [Indexed: 11/17/2022] Open
Abstract
Tumor-induced osteomalacia (TIO) is a rare acquired form of hypophosphatemia commonly associated with phosphaturic mesenchymal tumors (PMTs) located in the bone or soft tissue. Resection of the tumor can cure osteomalacia. Fibroblast growth factor 23 has been identified as a major pathophysiological factor responsible for phosphaturia. The majority of PMTs are benign, and malignant PMTs are uncommon. Even in rare cases, the malignant transformation of PMTs is extremely uncommon. The current study presents two cases in which the patients succumbed to malignant PMTs that developed in the pelvis. The first patient was a 35-year-old female with a malignant PMT occurring as a synchronous double cancer associated with papillary thyroid carcinoma. Diagnosis was difficult, as the multiple uptake on positron emission tomography with 18F-fluorodeoxyglucose presented as pseudofractures mimicking the metastases of thyroid carcinoma. The patient succumbed to rapidly progressive lung metastases. The second patient presented with a pelvic tumor that had developed over 26 years. The patient was diagnosed with a benign PMT by open biopsy and a complete resection was performed. However, two years later, the tumor recurred and lung metastases were observed. The patient ultimately succumbed to respiratory failure due to relapsing lung metastases and disseminated intravascular coagulation. These two cases demonstrate the potential lethality of malignant PMTs and the malignant transformation of benign PMTs. Therefore, TIO patients must be followed up even if diagnosed with a benign tumor. Although TIO is an extremely rare disease, the possibility of malignant PMTs must be recognized.
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Mattoo RL. The Roles of Fibroblast Growth Factor (FGF)-23, α-Klotho and Furin Protease in Calcium and Phosphate Homeostasis : A Mini-Review. Indian J Clin Biochem 2014; 29:8-12. [PMID: 24478543 PMCID: PMC3903929 DOI: 10.1007/s12291-013-0324-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Accepted: 03/28/2013] [Indexed: 01/01/2023]
Abstract
The roles of calcitonin, parathormone and calcitriol in the regulation of plasma calcium and phosphate are well-established. However, in autosomal-dominant hypophosphatemic rickety patients, studies have revealed normal plasma levels of calcium, associated with normal thyroid and parathyroid functions, but decreased levels of phosphate and calcitriol despite adequate reserves of vitamin D. Also, in tumoral calcinosis, persistent hyperphosphatemia with increased levels of 1,25(OH)2D3 have been observed. These studies indicate the involvement of factors other than the ones already known. The first decade of this century/millennium has led to the discovery of the involvement of fibroblast growth factor-23, furin protease and α-klotho in the homeostasis of calcium and phosphate, which is the subject of this mini-review.
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Affiliation(s)
- Roshan L. Mattoo
- />JDA Plot # 19, New Rehari, Jammu (Tawi), 180005 J&K India
- />Adesh University, NH-7 Barnala Road, Bathinda, 151101 Punjab India
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de Brito Galvao JF, Nagode LA, Schenck PA, Chew DJ. Calcitriol, calcidiol, parathyroid hormone, and fibroblast growth factor-23 interactions in chronic kidney disease. J Vet Emerg Crit Care (San Antonio) 2013; 23:134-62. [PMID: 23566108 PMCID: PMC3677418 DOI: 10.1111/vec.12036] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Accepted: 02/05/2013] [Indexed: 12/13/2022]
Abstract
Objective To review the inter-relationships between calcium, phosphorus, parathyroid hormone (PTH), parent and activated vitamin D metabolites (vitamin D, 25(OH)-vitamin D, 1,25(OH)2-vitamin D, 24,25(OH)2-vitamin D), and fibroblast growth factor-23 (FGF-23) during chronic kidney disease (CKD) in dogs and cats. Data Sources Human and veterinary literature. Human Data Synthesis Beneficial effects of calcitriol treatment during CKD have traditionally been attributed to regulation of PTH but new perspectives emphasize direct renoprotective actions independent of PTH and calcium. It is now apparent that calcitriol exerts an important effect on renal tubular reclamation of filtered 25(OH)-vitamin D, which may be important in maintaining adequate circulating 25(OH)-vitamin D. This in turn may be vital for important pleiotropic actions in peripheral tissues through autocrine/paracrine mechanisms that impact the health of those local tissues. Veterinary Data Synthesis Limited information is available reporting the benefit of calcitriol treatment in dogs and cats with CKD. Conclusions A survival benefit has been shown for dogs with CKD treated with calcitriol compared to placebo. The concentrations of circulating 25(OH)-vitamin D have recently been shown to be low in people and dogs with CKD and are related to survival in people with CKD. Combination therapy for people with CKD using both parental and activated vitamin D compounds is common in human nephrology and there is a developing emphasis using combination treatment with activated vitamin D and renin-angiotensin-aldosterone-system (RAAS) inhibitors.
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Abstract
The vitamin D signal transduction system involves a series of cytochrome P450-containing sterol hydroxylases to generate and degrade the active hormone, 1α,25-dihydroxyvitamin D3, which serves as a ligand for the vitamin D receptor-mediated transcriptional gene expression described in companion articles in this review series. This review updates our current knowledge of the specific anabolic cytochrome P450s involved in 25- and 1α-hydroxylation, as well as the catabolic cytochrome P450 involved in 24- and 23-hydroxylation steps, which are believed to initiate inactivation of the vitamin D molecule. We focus on the biochemical properties of these enzymes; key residues in their active sites derived from crystal structures and mutagenesis studies; the physiological roles of these enzymes as determined by animal knockout studies and human genetic diseases; and the regulation of these different cytochrome P450s by extracellular ions and peptide modulators. We highlight the importance of these cytochrome P450s in the pathogenesis of kidney disease, metabolic bone disease, and hyperproliferative diseases, such as psoriasis and cancer; as well as explore potential future developments in the field.
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Affiliation(s)
- Glenville Jones
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
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Hu FK, Yuan F, Jiang CY, Lv DW, Mao BB, Zhang Q, Yuan ZQ, Wang Y. Tumor-induced osteomalacia with elevated fibroblast growth factor 23: a case of phosphaturic mesenchymal tumor mixed with connective tissue variants and review of the literature. CHINESE JOURNAL OF CANCER 2013; 30:794-804. [PMID: 22035861 PMCID: PMC4013303 DOI: 10.5732/cjc.011.10013] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia (OOM), is a rare acquired Paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recent evidence shows that tumor-overexpressed fibroblast growth factor 23 (FGF23) is responsible for the hypophosphatemia and osteomalacia. The tumors associated with TIO are usually phosphaturic mesenchymal tumor mixed connective tissue variants (PMTMCT). Surgical removal of the responsible tumors is clinically essential for the treatment of TIO. However, identifying the responsible tumors is often difficult. Here, we report a case of a TIO patient with elevated serum FGF23 levels suffering from bone pain and hypophosphatemia for more than three years. A tumor was finally located in first metacarpal bone by octreotide scintigraphy and she was cured by surgery. After complete excision of the tumor, serum FGF23 levels rapidly decreased, dropping to 54.7% of the preoperative level one hour after surgery and eventually to a little below normal. The patient's serum phosphate level rapidly improved and returned to normal level in four days. Accordingly, her clinical symptoms were greatly improved within one month after surgery. There was no sign of tumor recurrence during an 18-month period of follow-up. According to pathology, the tumor was originally diagnosed as “glomangioma” based upon a biopsy sample, “proliferative giant cell tumor of tendon sheath” based upon sections of tumor, and finally diagnosed as PMTMCT by consultation one year after surgery. In conclusion, although an extremely rare disease, clinicians and pathologists should be aware of the existence of TIO and PMTMCT, respectively.
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Affiliation(s)
- Fang-Ke Hu
- Orthopedic Department, Chinese PLA General Hospital, Beijing 100853, P. R. China
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Wang M, You L, Li H, Lin Y, Zhang Z, Hao C, Chen J. Association of circulating fibroblast growth factor-23 with renal phosphate excretion among hemodialysis patients with residual renal function. Clin J Am Soc Nephrol 2013; 8:116-25. [PMID: 23085728 PMCID: PMC3531650 DOI: 10.2215/cjn.00230112] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2012] [Accepted: 09/20/2012] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES High serum levels of fibroblast growth factor-23 (FGF-23) are associated with mortality in patients with ESRD, but whether it still acts as a phosphaturic factor is unknown. This study aimed to explore the role of circulating FGF-23 on urinary phosphate excretion and phosphate balance in maintenance hemodialysis (MHD) patients with residual renal function (RRF). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS There were 134 MHD patients enrolled in this cross-sectional study from June to July 2010. Demographics, laboratory data, and excretion capacity of phosphate were recorded. Multivariable linear regression was used to analyze the relationship of serum phosphate and the tubular reabsorption rate of phosphate with other factors. RESULTS The median age of the patients was 61.0 years and 47.8% were male. Thirty percent of the patients had high urinary output (>200 ml/d) accompanied by lower serum levels of phosphate, calcium, intact parathyroid hormone, and FGF-23 compared with those with low urine output (≤200 ml/d). The independent predictors of serum phosphate were normalized protein nitrogen appearance, intact parathyroid hormone, and FGF-23 in the low urine output group and female sex and GFR in the high urine output group. The tubular reabsorption rate of phosphate decreased to 50% of the normal level in patients with RRF. Elevated circulating FGF-23 was significantly associated with lower tubular phosphate reabsorption after adjusting for GFR. CONCLUSIONS RRF is associated with significant capacity to excrete phosphate in MHD patients and high levels of serum FGF-23 may promote phosphate excretion by remnant nephrons.
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Affiliation(s)
| | - Li You
- Divisions of Nephrology and
| | | | - Yong Lin
- Clinical Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhijie Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Fudan University, Shanghai, China; and
- Key Laboratory of Public Health Safety, Ministry of Education, Shanghai, China
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Abstract
Phosphate is one of the most abundant minerals in the body, and its serum levels are regulated by a complex set of processes occurring in the intestine, skeleton, and kidneys. The currently known main regulators of phosphate homeostasis include parathyroid hormone (PTH), calcitriol, and a number of peptides collectively known as the "phosphatonins" of which fibroblast growth factor-23 (FGF-23) has been best defined. Maintenance of extracellular and intracellular phosphate levels within a narrow range is important for many biological processes, including energy metabolism, cell signaling, regulation of protein synthesis, skeletal development, and bone integrity. The presence of adequate amounts of phosphate is critical for the process of apoptosis of mature chondrocytes in the growth plate. Without the presence of this mineral in high enough quantities, chondrocytes will not go into apoptosis, and the normal physiological chain of events that includes invasion of blood vessels and the generation of new bone will be blocked, resulting in rickets and delayed growth. In the rest of the skeleton, hypophosphatemia will result in osteomalacia due to an insufficient formation of hydroxyapatite. This review will address phosphate metabolism and its role in bone health.
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Glade MJ. Vitamin D: health panacea or false prophet? Nutrition 2012; 29:37-41. [PMID: 23085014 DOI: 10.1016/j.nut.2012.05.010] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Revised: 05/09/2012] [Accepted: 05/11/2012] [Indexed: 12/23/2022]
Abstract
Vitamin D deficiency, diagnosed when the serum 25-hydroxyvitamin D (25-OHD(3)) concentration is less than 20 ng/mL, has joined vitamin A deficiency as two of the most common nutrition-responsive medical conditions worldwide. There have been more scientific articles published about vitamin D in the 21st century than about any other vitamin, reflecting the massive expansion of the field of vitamin D research. Adequate vitamin D status has been linked to decreased risks of developing specific cancers, including cancers of the esophagus, stomach, colon, rectum, gallbladder, pancreas, lung, breast, uterus, ovary, prostate, urinary bladder, kidney, skin, thyroid, and hematopoietic system (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma); bacterial infections; rheumatoid arthritis; Crohn's disease; periodontal disease; multiple sclerosis; asthma; type 2 diabetes; cardiovascular disease; stroke; peripheral artery disease; hypertension; chronic kidney disease; muscle weakness; cognitive impairment; Alzheimer's disease; clinical depression; and premature death. On the other hand, inadequate vitamin D status during human pregnancy may be associated with increased risk for the development of type 1 diabetes in the offspring. However, this point of view may be excessively optimistic. There also is evidence that despite the current heavy reliance on serum 25-OHD(3) concentration for the diagnosis of an individual's vitamin D status, local tissue vitamin D intoxication may be present in individuals with much lower serum 25-OHD(3) concentrations than are currently appreciated. Only rarely are the symptoms of local tissue vitamin D intoxication associated with vitamin D status or intake. An individual's serum 25-OHD(3) concentration may appear to be "low" for reasons totally independent of sunlight exposure or vitamin D intake. Serum 25-OHD(3) concentration is only poorly responsive to increases in vitamin D intake, and the prolonged routine consumption of thousands of international units of vitamin D may interfere with the regulation of phosphate homeostasis by fibroblast growth factor-23 (FGF23) and the Klotho gene product, with consequences that are detrimental to human health. In light of these counterbalancing observations, curbing excessive enthusiasm for universally increasing vitamin D intake recommendations may be in order.
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Linear nevus sebaceous syndrome with hypophosphatemic rickets with elevated FGF-23. Pediatr Nephrol 2012; 27:861-3. [PMID: 22205508 DOI: 10.1007/s00467-011-2086-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2011] [Revised: 11/24/2011] [Accepted: 11/24/2011] [Indexed: 10/14/2022]
Abstract
BACKGROUND Linear nevus sebaceous syndrome (LNSS) is a rare congenital neuroectodermal disorder characterized by involvement of the skeleton and central nervous system. CASE We report the case of a 5-year-old girl who had LNSS with hypophosphatemic rickets and multiple fractures of her extremities. Biochemical tests revealed a high serum level of fibroblast growth factor-23 (FGF-23) but normal levels of immunoglobulin E (IgE) and parathormone (PTH). FGF-23 mRNA expression in the skin lesions of our patient's skin was found to be below the limit of detection in all samples tested by quantitative-PCR analysis. CONCLUSIONS It is possible that an as-yet unidentified substance increases FGF-23 expression LNS lesions.
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Moreira Guimarães Penido MG, de Sousa Tavares M. Bone disease in pediatric idiopathic hypercalciuria. World J Nephrol 2012; 1:54-62. [PMID: 24175242 PMCID: PMC3782196 DOI: 10.5527/wjn.v1.i2.54] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2011] [Revised: 11/11/2011] [Accepted: 02/10/2012] [Indexed: 02/06/2023] Open
Abstract
Idiopathic hypercalciuria (IH) is the leading metabolic risk factor for urolithiasis and affects all age groups without gender or race predominance. IH has a high morbidity with or without lithiasis and reduced bone mineral density (BMD), as described previously in pediatric patients as well as in adults. The pathogenesis of IH is complex and not completely understood, given that urinary excretion of calcium is the end result of an interplay between three organs (gut, bone and kidney), which is further orchestrated by hormones, such as 1,25 dihydroxyvitamin D, parathyroid hormone, calcitonin and fosfatonins (i.e., fibroblast growth-factor-23). Usually, a primary defect in one organ induces compensatory mechanisms in the remaining two organs, such as increased absorption of calcium in the gut secondary to a primary renal loss. Thus, IH is a systemic abnormality of calcium homeostasis with changes in cellular transport of this ion in intestines, kidneys and bones. Reduced BMD has been demonstrated in pediatric patients diagnosed with IH. However, the precise mechanisms of bone loss or failure of adequate bone mass gain are still unknown. The largest accumulation of bone mass occurs during childhood and adolescence, peaking at the end of the second decade of life. This accumulation should occur without interference to achieve the peak of optimal bone mass. Any interference may be a risk factor for the reduction of bone mass with increased risk of fractures in adulthood. This review will address the pathogenesis of IH and its consequence in bone mass.
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Affiliation(s)
- Maria Goretti Moreira Guimarães Penido
- Maria Goretti Moreira Guimarães Penido, Marcelo de Sousa Tavares, Department of Pediatrics, Pediatric Nephrology Unit, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Belo Horizonte, CEP 30130100, Minas Gerais, Brazil
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Ramon I, Kleynen P, Valsamis J, Body JJ, Karmali R. Hypophosphatemia related to paraneoplastic Cushing syndrome in prostate cancer: cure after bilateral adrenalectomy. Calcif Tissue Int 2011; 89:442-5. [PMID: 21910004 DOI: 10.1007/s00223-011-9527-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2011] [Accepted: 08/09/2011] [Indexed: 10/17/2022]
Abstract
We report the case of a 71-year-old man with progressive metastatic prostate cancer in whom simultaneous occurrence of paraneoplastic Cushing syndrome (CS) and tumor-induced osteomalacia (TIO) initially was suspected. However, the evolution of biochemical markers of phosphate metabolism during disease course and after bilateral adrenalectomy argued against the diagnosis of TIO. Despite the persistence of progressive prostate cancer, CS and hypophosphatemia resolved in parallel after bilateral adrenalectomy. Thus, these data suggest that paraneoplastic CS per se was involved in the pathogenesis of hypophosphatemia. Calcitriol and intact fibroblast growth factor 23 (FGF23) levels were within the reference range at onset, which is inappropriate in the setting of severe hypophosphatemia. All parameters of phosphate metabolism normalized after resolution of hypercortisolism. Based on the known suppressive effect of glucocorticoids (GCs) on bone remodeling and the inverse relationship between bone turnover rate and circulating FGF23 levels, we postulate that GCs interfere indirectly with phosphate homeostasis by inducing inappropriate FGF23 production and release. This mechanism could further aggravate the hypophosphatemia resulting from GC-induced inhibition of intestinal phosphate absorption. Studies directed at the identification of the molecular pathways in bone mediating the interference of GCs with phosphate metabolism are warranted.
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Affiliation(s)
- Isolde Ramon
- Department of Internal Medicine-Endocrinology, University Hospital Brugmann, Free University of Brussels, Belgium.
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Jones G, Prosser DE, Kaufmann M. 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D. Arch Biochem Biophys 2011; 523:9-18. [PMID: 22100522 DOI: 10.1016/j.abb.2011.11.003] [Citation(s) in RCA: 339] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Revised: 10/19/2011] [Accepted: 11/01/2011] [Indexed: 01/08/2023]
Abstract
CYP24A1 is the cytochrome P450 component of the 25-hydroxyvitamin D(3)-24-hydroxylase enzyme that catalyzes the conversion of 25-hydroxyvitamin D(3) (25-OH-D(3)) and 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) into 24-hydroxylated products, which constitute the degradation of the vitamin D molecule. This review focuses on recent data in the CYP24A1 field, including biochemical, physiological and clinical developments. Notable among these are: the first crystal structure for rat CYP24A1; mutagenesis studies which change the regioselectivity of the enzyme; and the finding that natural inactivating mutations of CYP24A1 cause the genetic disease idiopathic infantile hypercalcemia (IIH). The review also discusses the emerging correlation between rising serum phosphate/FGF-23 levels and increased CYP24A1 expression in chronic kidney disease, which in turn underlies accelerated degradation of both serum 25-OH-D(3) and 1,25-(OH)(2)D(3) in this condition. This review concludes by evaluating the potential clinical utility of blocking this enzyme with CYP24A1 inhibitors in various disease states.
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Affiliation(s)
- Glenville Jones
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada K7L 3N6.
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Abstract
PURPOSE OF REVIEW Patients with chronic renal disease have elevated serum phosphate levels, elevated fibroblast-like growth factor 23 (FGF-23), and declining vitamin D status. These changes are related and may be responsible for elevated 25-hydroxyvitamin D-24-hydroxylase (CYP24A1) and dysfunctional vitamin D metabolism. This review focuses on the biochemistry and pathophysiology of CYP24A1 and the utility of blocking this enzyme with CYP24A1 inhibitors in chronic kidney disease (CKD) patients. RECENT FINDINGS CYP24A1 is the cytochrome P450 enzyme that catalyzes the conversion of 25-hydroxyvitamin D3 (25-OHD3) and its hormonal form, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], into 24-hydroxylated products targeted for excretion. The CYP24A1-null phenotype is consistent with the catabolic role of CYP24A1. A number of polymorphisms of CYP24A1 have recently been identified. New data from the uremic rat and humans suggest that dysfunctional vitamin D metabolism is due to changes in CYP24A1 expression caused by phosphate and FGF-23 elevations. SUMMARY Changes in serum phosphate and FGF-23 levels in the CKD patient increase CYP24A1 expression resulting in decreased vitamin D status. Vitamin D deficiency may exacerbate defective calcium and phosphate homeostasis causing renal osteodystrophy and contribute to the other complications of renal disease. These findings argue for increased focus on correcting vitamin D deficiency in CKD patients by blocking CYP24A1 activity.
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Affiliation(s)
- Martin Petkovich
- Division of Cancer Biology and Genetics, Cancer Research Institute, Department of Biochemistry, Queen's University, Kingston, Ontario, Canada.
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Liu P, Chen L, Bai X, Karaplis A, Miao D, Gu N. Impairment of spatial learning and memory in transgenic mice overexpressing human fibroblast growth factor-23. Brain Res 2011; 1412:9-17. [PMID: 21824606 DOI: 10.1016/j.brainres.2011.07.028] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2011] [Revised: 07/01/2011] [Accepted: 07/12/2011] [Indexed: 12/17/2022]
Abstract
Fibroblast growth factor-23 (FGF-23) is a potent circulating phosphaturic factor associated with renal phosphate wasting. Effects of FGF-23 on skeleton, phosphate homeostasis, and cardiovascular system have been investigated; however, the effect of FGF-23 on the central nervous system (CNS) is unknown. To assess whether FGF-23 influences the function and structure of the CNS and whether the effect of FGF-23 on the CNS is mediated by FGF receptors directly or by hypophosphatemia indirectly, FGF-23 transgenic mice and their wild-type littermates were fed a normal diet or a high-phosphate diet containing a normal diet plus 1.25% phosphate in drinking water from weaning for 5weeks and the phenotypes of the CNS were compared between FGF-23 transgenic mice and their wild-type littermates on the same diet. At the end of this time period, transgenic animals on the normal diet showed impaired spatial learning and memory. Furthermore, these mice exhibited the impairment of long-term potentiation in hippocampal CA1 region, and the reduction of hippocampal adenosine-triphosphate content and of choline acetyltransferase-positive neurons in basal forebrain, possibly as pathogenetic factors contributing to the cognitive deficit. The central nervous phenotypes of transgenic mice were rescued following improved hypophosphatemia by the high-phosphate diet intake. This study demonstrates that FGF-23 overexpression can result in abnormalities in the CNS mediated by the secondary severe hypophosphatemia.
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Affiliation(s)
- Peidang Liu
- Department of Toxicology, School of Public Health, Southeast University, Nanjing 210009, PR China
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Sliem H, Tawfik G, Moustafa F, Zaki H. Relationship of associated secondary hyperparathyroidism to serum fibroblast growth factor-23 in end stage renal disease: a case-control study. Indian J Endocrinol Metab 2011; 15:105-109. [PMID: 21731867 PMCID: PMC3124995 DOI: 10.4103/2230-8210.81939] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
INTRODUCTION Secondary hyperparathyroidism (SHPT) is an insidious disease that develops early in the course of chronic kidney disease (CKD) and increases in severity as the glomerular filtration rate deteriorates. Recent studies have identified fibroblast growth factor-23 (FGF23) as a new protein with phosphaturic activity. It is mainly secreted by osteoblasts and is now considered the most important factor for regulation of phosphorus homeostasis. It is not yet proven if there is any direct relation between parathyroid hormone (PTH) and FGF23. The present study aims to evaluate the relation between serum FGF23, phosphorus, and PTH in end-stage renal disease in patients with SHPT on regular hemodialysis. MATERIALS AND METHODS Forty-six consecutive CKD adult patients (case group) and 20 healthy adults (control group) were included in the study. All patients had SHPT and were on regular hemodialysis. Both groups were subjected to full medical history, clinical examination and biochemical studies. Serum phosphorus, calcium, ferritin, hemoglobin level, blood urea, creatinine, PTH, and FGF23 were analyzed. RESULTS Levels of FGF23 were significantly higher in the case group in comparison with those in the control group, viz., 4-fold, and positively correlated with PTH. Phosphorus levels in the case group were significantly high in spite of the increasing levels of FGF23. Both PTH and FGF23 were positively correlated with phosphorus and negatively with hemoglobin levels. CONCLUSION SHPT and FGF23 may have a partial role in the development of anemia in patients with CKD. FGF23 could be a central factor in the pathogenesis of SHPT. Its role in controlling hyperphosphatemia in CKD is vague.
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Affiliation(s)
- Hamdy Sliem
- Department of Internal Medicine, Suez Canal University, Ismailia, Egypt.
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Abstract
OBJECTIVE To report a case of primary hyperphosphatemic tumoral calcinosis (TC) and its long-term 10-year follow-up. PATIENT The patient was an 18-year-old male, who had been diagnosed with TC at the age of 8 years. In spite of nine surgeries for tumoral resection and medical treatments (i.e., aluminum hydroxide, non-steroidal anti-inflammatory agents) the lesions continued to progress. Physical examination showed calcified masses on shoulders, hip, elbows and right foot. PTH, calcitonin, 25(OH) vitamin D, 1,25(OH)2 vitamin D, renal and liver function, electrolytes, alkaline phosphatase, calcium and magnesium were normal. Serum phosphorus was elevated. FGF-23 (C-terminal): 1960 RU/mL (<180) Radiological and histological studies were compatible with TC. CONCLUSION This long-term follow-up illustrates the morbidity and difficulty in treating these patients due to the progressive and recurrent nature of the calcified masses, for which there is no effective treatment as yet. The discovery of FGF-23 as the factor responsible for the hyperphosphatemic type of TC paves the way for forthcoming therapies.
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Affiliation(s)
- Crésio Alves
- Pediatric Endocrinology Unit, Hospital Universitario Professor Edgard Santos, Faculty of Medicine, Federal University of Bahia, Brazil.
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Crenshaw TD, Rortvedt LA, Hassen Z. Triennial Growth Symposium: a novel pathway for vitamin D-mediated phosphate homeostasis: implications for skeleton growth and mineralization. J Anim Sci 2010; 89:1957-64. [PMID: 21097685 DOI: 10.2527/jas.2010-3411] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Systemic factors that ultimately affect skeletal growth involve interrelationships among Ca, parathyroid hormone (PTH), and conversion of 25-OH vitamin D(3) to the active hormone, 1α,25-(OH)(2)D(3). These interrelationships, with a focus on mechanisms that affect Ca homeostasis, are referred to as the Ca, PTH, and vitamin D axis. Relatively little research has focused on these interrelationships and P homeostasis. In the past decade, discovery of a previously unrecognized hormone involved in a pathway for P homeostasis offers opportunities to improve P efficiency without compromising skeletal growth and animal well-being. The objective of this review was to summarize pivotal research discoveries that led to the current understanding of the roles of fibroblast growth factor 23 (FGF23) in P homeostasis that are independent from the well-described pathways involved with Ca homeostasis. The novel pathways are referred to as the FGF23, P, and vitamin D axis. The peptide, FGF23, directly affects P homeostasis via action on renal target tissues to regulate Na-P transport proteins and renal 25(OH)D(3)-1α hydroxylase activity. Identification of bone as the primary site for FGF23 production ascribes an endocrine gland function to bone. Within 9 h after a single injection of recombinant FGF23, mice displayed hypophosphatemia and urinary P wasting. In contrast, FGF23 knockout mice displayed hyperphosphatemia and renal P conservation. These responses were independent of PTH. Applications of the FGF23, P, and vitamin D axis in dietary strategies for animal agriculture need to be explored. Development of dietary inputs to balance both Ca and P homeostasis are needed to improve skeletal growth and nutrient efficiency.
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Affiliation(s)
- T D Crenshaw
- Department of Animal Sciences, University of Wisconsin, Madison, 53706-1284, USA.
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Uzum AK, Salman S, Telci A, Boztepe H, Tanakol R, Alagol F, Ozbey NC. Effects of vitamin D replacement therapy on serum FGF23 concentrations in vitamin D-deficient women in short term. Eur J Endocrinol 2010; 163:825-31. [PMID: 20732956 DOI: 10.1530/eje-10-0591] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
OBJECTIVE Fibroblast growth factor 23 (FGF23), a phosphatonin, inhibits renal phosphate reabsorption and suppresses 1-α hydroxylase activity. Calcitriol stimulates FGF23 synthesis in bone. We aimed to determine the effect of vitamin D replacement therapy on serum FGF23 concentrations in vitamin D-deficient women and to compare the FGF23 concentrations of vitamin D-deficient patients with healthy subjects and patients with genetically determined hypophosphatemic rachitis. DESIGN AND METHODS The study group was composed of vitamin D-deficient females (n=18, mean age 29.1 ± 9.9 years), vitamin D-sufficient healthy females (control group; n=19, mean age 28.5 ± 5.2 years), and patients with genetically determined hypophosphatemic rachitis (n=13, mean age 26.5 ± 15.1 years). The groups were compared for serum FGF23, 1,25-dihydroxyvitamin D3 (1,25(OH)2D), calcium, phosphate, bone turnover markers, intact parathyroid hormone (PTH), and urinary excretion of calcium and phosphate. The vitamin D-deficient group was re-evaluated after a standard treatment regimen. RESULTS Serum FGF23 concentrations were significantly lower in vitamin D-deficient patients than in vitamin D-sufficient women and hypophosphatemic rachitis group. Serum FGF23 and phosphate concentrations further decreased significantly during replacement of vitamin D (P<0.05). A significant negative correlation was evident between FGF23 and PTH before vitamin D replacement in the patients (r=-0.469, P<0.05). CONCLUSION Decreased FGF23 concentrations, which further decline during vitamin D replacement therapy, may have favorable action on bone mineralization by counterregulatory effect on phosphate homeostasis. Lower 1,25(OH)2D concentrations at baseline and hypophosphatemia during treatment may have dominating effects on FGF23 concentrations in vitamin D deficiency, leading to decreased FGF23 concentrations at baseline and during replacement therapy.
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Affiliation(s)
- Ayse Kubat Uzum
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Istanbul Faculty of Medicine, University of Istanbul, Istanbul 34390, Turkey.
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Affiliation(s)
- Marcello Tonelli
- Department of Medicine, University of Alberta, Edmonton, Canada.
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Escher N, Ernst G, Melle C, Berndt A, Clement JH, Junker K, Friedrich K, Guntinas-Lichius O, von Eggeling F. Comparative proteomic analysis of normal and tumor stromal cells by tissue on chip based mass spectrometry (toc-MS). Diagn Pathol 2010; 5:10. [PMID: 20205871 PMCID: PMC2826342 DOI: 10.1186/1746-1596-5-10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2009] [Accepted: 01/28/2010] [Indexed: 01/20/2023] Open
Abstract
In carcinoma tissues, genetic and metabolic changes not only occur at the tumor cell level, but also in the surrounding stroma. This carcinoma-reactive stromal tissue is heterogeneous and consists e.g. of non-epithelial cells such as fibroblasts or fibrocytes, inflammatory cells and vasculature-related cells, which promote carcinoma growth and progression of carcinomas. Nevertheless, there is just little knowledge about the proteomic changes from normal connective tissue to tumor stroma. In the present study, we acquired and analysed specific protein patterns of small stromal sections surrounding head and neck cell complexes in comparison to normal subepithelial connective tissue. To gain defined stromal areas we used laser-based tissue microdissection. Because these stromal areas are limited in size we established the highly sensitive 'tissue on chip based mass spectrometry' (toc-MS). Therefore, the dissected areas were directly transferred to chromatographic arrays and the proteomic profiles were subsequently analysed with mass spectrometry. At least 100 cells were needed for an adequate spectrum. The locating of differentially expressed proteins enables a precise separation of normal and tumor stroma. The newly described toc-MS technology allows an initial insight into proteomic differences between small numbers of exactly defined cells from normal and tumor stroma.
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Affiliation(s)
- Niko Escher
- Core Unit Chip Application, Institute of Human Genetics, University Hospital Jena, Jena, Germany
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