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Lins PJB, Andrade NS, Caliento R, Sarmento DJS, Zambrana JRM, Costa C, Gallotini M. Alveolar bone healing patterns in chronic kidney failure and kidney transplant recipients: A pixel intensity and fractal analyses. SPECIAL CARE IN DENTISTRY 2025; 45:e13065. [PMID: 39323049 DOI: 10.1111/scd.13065] [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: 01/30/2024] [Revised: 08/30/2024] [Accepted: 09/11/2024] [Indexed: 09/27/2024]
Abstract
AIMS To assess and compare radiographically the alveolar bone after tooth extractions in individuals with chronic kidney failure undergoing hemodialysis (CKFh), those submitted to kidney transplantation (KT), and those without kidney disease (CG) by using fractal analysis (FA) and pixel intensity (PI). METHODS AND RESULTS Periapical radiographs of 48 CKFh individuals (87 extracted teeth), 12 KT individuals (26 extracted teeth and 29 control individuals [76 extracted teeth] were analyzed at 7 and 60 days after tooth extraction. Fractal dimension (FD) and PI were assessed to evaluate the alveolar trabecular bone structural complexity and mineral content. The difference in FD values between the 7th and 60th postoperative days in KT individuals (0.03 ± 0.08) was significantly lower compared to those of CKFh individuals (0.09 ± 0.10) and controls (0.15 ± 0.06). As for the difference in PI values, KT (4.55 ± 10.24) and CKFh groups (9.88 ± 15.90) showed significantly lower values compared to those of the control group (17.93 ± 11.86) in the same period. These results indicate a lower gain in the trabecular bone complexity and bone density in the alveolus of KT individuals compared to the other groups. CONCLUSIONS Overall mineral content and thickness of the bone in the plane of the x-ray beam were lower in KT and CKFh individuals compared to controls, reflecting the need for careful consideration in recommending rehabilitation with dental implants for these patients. Particular attention should be given to the potential challenges in oral rehabilitation of KT patients.
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Affiliation(s)
- Paula J B Lins
- Special Care Dentistry Center, Department of Stomatology, Dental School, University of Sao Paulo, Sao Paulo, Brazil
| | - Natalia S Andrade
- Department of Dentistry, Federal University of Sergipe, Sergipe, Brazil
| | - Rubens Caliento
- Special Care Dentistry Center, Department of Stomatology, Dental School, University of Sao Paulo, Sao Paulo, Brazil
| | | | - Jéssica R M Zambrana
- Department of Stomatology, Dental School, University of Sao Paulo, Sao Paulo, Brazil
| | - Claudio Costa
- Department of Stomatology, Dental School, University of Sao Paulo, Sao Paulo, Brazil
| | - Marina Gallotini
- Special Care Dentistry Center, Department of Stomatology, Dental School, University of Sao Paulo, Sao Paulo, Brazil
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Park MY, Tu CL, Perie L, Verma N, Serdan TDA, Shamsi F, Shapses S, Heffron S, Gamallo-Lana B, Mar AC, Alemán JO, Mueller E, Chang W, Sitara D. Targeted Deletion of Fibroblast Growth Factor 23 Rescues Metabolic Dysregulation of Diet-induced Obesity in Female Mice. Endocrinology 2024; 165:bqae141. [PMID: 39446375 PMCID: PMC11538792 DOI: 10.1210/endocr/bqae141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Indexed: 11/07/2024]
Abstract
Fibroblast growth factor 23 (FGF23) is a bone-secreted protein widely recognized as a critical regulator of skeletal and mineral metabolism. However, little is known about the nonskeletal production of FGF23 and its role in tissues other than bone. Growing evidence indicates that circulating FGF23 levels rise with a high-fat diet (HFD) and they are positively correlated with body mass index (BMI) in humans. In the present study, we show for the first time that increased circulating FGF23 levels in obese humans correlate with increased expression of adipose Fgf23 and both positively correlate with BMI. To understand the role of adipose-derived Fgf23, we generated adipocyte-specific Fgf23 knockout mice (AdipoqFgf23Δfl/Δfl) using the adiponectin-Cre driver, which targets mature white, beige, and brown adipocytes. Our data show that targeted ablation of Fgf23 in adipocytes prevents HFD-fed female mice from gaining body weight and fat mass while preserving lean mass but has no effect on male mice, indicating the presence of sexual dimorphism. These effects are observed in the absence of changes in food and energy intake. Adipose Fgf23 inactivation also prevents dyslipidemia, hyperglycemia, and hepatic steatosis in female mice. Moreover, these changes are associated with decreased respiratory exchange ratio and increased brown fat Ucp1 expression in knockout mice compared to HFD-fed control mice (Fgf23fl/fl). In conclusion, this is the first study highlighting that targeted inactivation of Fgf23 is a promising therapeutic strategy for weight loss and lean mass preservation in humans.
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Affiliation(s)
- Min Young Park
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA
| | - Chia-Ling Tu
- Endocrine Research Unit, Department of Medicine, San Francisco Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Luce Perie
- Holman Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Narendra Verma
- Holman Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | | | - Farnaz Shamsi
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA
| | - Sue Shapses
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901, USA
- Department of Medicine, Rutgers-RWJ Medical School, New Brunswick, NJ 08903, USA
| | - Sean Heffron
- Department of Medicine, Division of Cardiology, NYU Langone Health Cardiovascular Research Center, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Begona Gamallo-Lana
- Department of Neuroscience and Physiology, Neuroscience Institute, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Adam C Mar
- Department of Neuroscience and Physiology, Neuroscience Institute, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - José O Alemán
- Holman Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Elisabetta Mueller
- Holman Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Wenhan Chang
- Endocrine Research Unit, Department of Medicine, San Francisco Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Despina Sitara
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA
- Holman Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
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Martínez-Heredia L, Canelo-Moreno JM, García-Fontana B, Muñoz-Torres M. Non-Classical Effects of FGF23: Molecular and Clinical Features. Int J Mol Sci 2024; 25:4875. [PMID: 38732094 PMCID: PMC11084844 DOI: 10.3390/ijms25094875] [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: 04/08/2024] [Revised: 04/21/2024] [Accepted: 04/26/2024] [Indexed: 05/13/2024] Open
Abstract
This article reviews the role of fibroblast growth factor 23 (FGF23) protein in phosphate metabolism, highlighting its regulation of vitamin D, parathyroid hormone, and bone metabolism. Although it was traditionally thought that phosphate-calcium homeostasis was controlled exclusively by parathyroid hormone (PTH) and calcitriol, pathophysiological studies revealed the influence of FGF23. This protein, expressed mainly in bone, inhibits the renal reabsorption of phosphate and calcitriol formation, mediated by the α-klotho co-receptor. In addition to its role in phosphate metabolism, FGF23 exhibits pleiotropic effects in non-renal systems such as the cardiovascular, immune, and metabolic systems, including the regulation of gene expression and cardiac fibrosis. Although it has been proposed as a biomarker and therapeutic target, the inhibition of FGF23 poses challenges due to its potential side effects. However, the approval of drugs such as burosumab represents a milestone in the treatment of FGF23-related diseases.
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Affiliation(s)
- Luis Martínez-Heredia
- Instituto de Investigación Biosanitaria de Granada, 18014 Granada, Spain;
- Biomedical Research Network in Fragility and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | | | - Beatriz García-Fontana
- Instituto de Investigación Biosanitaria de Granada, 18014 Granada, Spain;
- Biomedical Research Network in Fragility and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, 18016 Granada, Spain
- Department of Cell Biology, University of Granada, 18016 Granada, Spain
| | - Manuel Muñoz-Torres
- Instituto de Investigación Biosanitaria de Granada, 18014 Granada, Spain;
- Biomedical Research Network in Fragility and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, 18016 Granada, Spain
- Department of Medicine, University of Granada, 18016 Granada, Spain
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Yang Z, Zarbl H, Guo GL. Circadian Regulation of Endocrine Fibroblast Growth Factors on Systemic Energy Metabolism. Mol Pharmacol 2024; 105:179-193. [PMID: 38238100 PMCID: PMC10877735 DOI: 10.1124/molpharm.123.000831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 01/05/2024] [Indexed: 02/17/2024] Open
Abstract
The circadian clock is an endogenous biochemical timing system that coordinates the physiology and behavior of organisms to earth's ∼24-hour circadian day/night cycle. The central circadian clock synchronized by environmental cues hierarchically entrains peripheral clocks throughout the body. The circadian system modulates a wide variety of metabolic signaling pathways to maintain whole-body metabolic homeostasis in mammals under changing environmental conditions. Endocrine fibroblast growth factors (FGFs), namely FGF15/19, FGF21, and FGF23, play an important role in regulating systemic metabolism of bile acids, lipids, glucose, proteins, and minerals. Recent evidence indicates that endocrine FGFs function as nutrient sensors that mediate multifactorial interactions between peripheral clocks and energy homeostasis by regulating the expression of metabolic enzymes and hormones. Circadian disruption induced by environmental stressors or genetic ablation is associated with metabolic dysfunction and diurnal disturbances in FGF signaling pathways that contribute to the pathogenesis of metabolic diseases. Time-restricted feeding strengthens the circadian pattern of metabolic signals to improve metabolic health and prevent against metabolic diseases. Chronotherapy, the strategic timing of medication administration to maximize beneficial effects and minimize toxic effects, can provide novel insights into linking biologic rhythms to drug metabolism and toxicity within the therapeutical regimens of diseases. Here we review the circadian regulation of endocrine FGF signaling in whole-body metabolism and the potential effect of circadian dysfunction on the pathogenesis and development of metabolic diseases. We also discuss the potential of chrononutrition and chronotherapy for informing the development of timing interventions with endocrine FGFs to optimize whole-body metabolism in humans. SIGNIFICANCE STATEMENT: The circadian timing system governs physiological, metabolic, and behavioral functions in living organisms. The endocrine fibroblast growth factor (FGF) family (FGF15/19, FGF21, and FGF23) plays an important role in regulating energy and mineral metabolism. Endocrine FGFs function as nutrient sensors that mediate multifactorial interactions between circadian clocks and metabolic homeostasis. Chronic disruption of circadian rhythms increases the risk of metabolic diseases. Chronological interventions such as chrononutrition and chronotherapy provide insights into linking biological rhythms to disease prevention and treatment.
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Affiliation(s)
- Zhenning Yang
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (Z.Y., G.L.G.), Environmental and Occupational Health Sciences Institute (Z.Y., H.Z., G.L.G.), Department of Environmental and Occupational Health Justice, School of Public Health (H.Z.), Rutgers Center for Lipid Research (G.L.G.), Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.)
| | - Helmut Zarbl
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (Z.Y., G.L.G.), Environmental and Occupational Health Sciences Institute (Z.Y., H.Z., G.L.G.), Department of Environmental and Occupational Health Justice, School of Public Health (H.Z.), Rutgers Center for Lipid Research (G.L.G.), Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.)
| | - Grace L Guo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (Z.Y., G.L.G.), Environmental and Occupational Health Sciences Institute (Z.Y., H.Z., G.L.G.), Department of Environmental and Occupational Health Justice, School of Public Health (H.Z.), Rutgers Center for Lipid Research (G.L.G.), Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.)
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Mouse Models of Mineral Bone Disorders Associated with Chronic Kidney Disease. Int J Mol Sci 2023; 24:ijms24065325. [PMID: 36982400 PMCID: PMC10048881 DOI: 10.3390/ijms24065325] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 02/27/2023] [Accepted: 03/03/2023] [Indexed: 03/14/2023] Open
Abstract
Patients with chronic kidney disease (CKD) inevitably develop mineral and bone disorders (CKD–MBD), which negatively impact their survival and quality of life. For a better understanding of underlying pathophysiology and identification of novel therapeutic approaches, mouse models are essential. CKD can be induced by surgical reduction of a functional kidney mass, by nephrotoxic compounds and by genetic engineering specifically interfering with kidney development. These models develop a large range of bone diseases, recapitulating different types of human CKD–MBD and associated sequelae, including vascular calcifications. Bones are usually studied by quantitative histomorphometry, immunohistochemistry and micro-CT, but alternative strategies have emerged, such as longitudinal in vivo osteoblast activity quantification by tracer scintigraphy. The results gained from the CKD–MBD mouse models are consistent with clinical observations and have provided significant knowledge on specific pathomechanisms, bone properties and potential novel therapeutic strategies. This review discusses available mouse models to study bone disease in CKD.
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Yuan D, Li J, Guo M, Yang Q, Huang J, Nie J, Li R, Li Q. Correlation study of FGF23/D-serine in maintenance hemodialysis patients with combined hearing impairment. PLoS One 2023; 18:e0280378. [PMID: 36649363 PMCID: PMC9844913 DOI: 10.1371/journal.pone.0280378] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 12/27/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Recent studies have reported an association between chronic renal failure and hearing impairment. Yet, the exact mechanism of action is still not fully understood. In this study, we investigated the expression of fibroblast growth factor 23 (FGF23) and D-serine in maintenance hemodialysis (MHD) patients with end-stage renal disease (ESRD) complicated with hearing impairment and further investigated the correlation between FGF23/D-serine and hearing impairment. METHODS A total of 90 subjects, including 30 MHD patients complicated with hearing impairment, 30 MHD patients with normal hearing, and 30 controls, were included in this case-control study. Relevant data were obtained by questionnaire survey, audiometric test, enzyme-linked immunosorbent assay (ELISA) to determine FGF23 level, and high-performance liquid chromatography to determine D-serine level. RESULTS MHD patients showed abnormally high expression of FGF23 and D-serine, where FGF23 and D-serine levels were significantly higher in the group with hearing impairment than in the group with normal hearing and normal controls (all P<0.01). Also, elevated FGF23 and D-serine were identified as risk factors for hearing impairment in ESRD, with ORs of 16.54 (95%CI, 2.75-99.55) and 15.22 (95%CI, 2.59-89.51), respectively. Further Person correlation analysis showed a moderate positive correlation between FGF23 and D-serine (r = 0.683, P<0.001). CONCLUSION This study provides potential biomarkers for the early detection of hearing impairment complicated by chronic renal failure, and the reduction of FGF23/D-serine may provide a potential target for the treatment of hearing impairment complicated by chronic renal failure.
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Affiliation(s)
- Dunlu Yuan
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jiaqing Li
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Min Guo
- Department of Otolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Qing Yang
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jingjing Huang
- Department of Medical Record, The Third People’s Hospital of Kunming, Kunming, China
| | - Jingwen Nie
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ruomei Li
- Department of Otolaryngology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Qing Li
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
- * E-mail:
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7
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Sirikul W, Siri-Angkul N, Chattipakorn N, Chattipakorn SC. Fibroblast Growth Factor 23 and Osteoporosis: Evidence from Bench to Bedside. Int J Mol Sci 2022; 23:ijms23052500. [PMID: 35269640 PMCID: PMC8909928 DOI: 10.3390/ijms23052500] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 02/18/2022] [Accepted: 02/21/2022] [Indexed: 02/05/2023] Open
Abstract
Osteoporosis is a chronic debilitating disease caused by imbalanced bone remodeling processes that impair the structural integrity of bone. Over the last ten years, the association between fibroblast growth factor 23 (FGF23) and osteoporosis has been studied in both pre-clinical and clinical investigations. FGF23 is a bone-derived endocrine factor that regulates mineral homeostasis via the fibroblast growth factor receptors (FGFRs)/αKlotho complex. These receptors are expressed in kidney and the parathyroid gland. Preclinical studies have supported the link between the local actions of FGF23 on the bone remodeling processes. In addition, clinical evidence regarding the effects of FGF23 on bone mass and fragility fractures suggest potential diagnostic and prognostic applications of FGF23 in clinical contexts, particularly in elderly and patients with chronic kidney disease. However, inconsistent findings exist and there are areas of uncertainty requiring exploration. This review comprehensively summarizes and discusses preclinical and clinical reports on the roles of FGF23 on osteoporosis, with an emphasis on the local action, as opposed to the systemic action, of FGF23 on the bone. Current gaps in knowledge and future research directions are also suggested to encourage further rigorous research in this important field.
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Affiliation(s)
- Wachiranun Sirikul
- Department of Community Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Natthaphat Siri-Angkul
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (N.S.-A.); (N.C.)
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Nipon Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (N.S.-A.); (N.C.)
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Siriporn C. Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (N.S.-A.); (N.C.)
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand
- Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
- Correspondence: ; Tel.: +66-53-944-451; Fax: +66-53-222-844
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8
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Navarro-García JA, González-Lafuente L, Fernández-Velasco M, Ruilope LM, Ruiz-Hurtado G. Fibroblast Growth Factor-23-Klotho Axis in Cardiorenal Syndrome: Mediators and Potential Therapeutic Targets. Front Physiol 2021; 12:775029. [PMID: 34867481 PMCID: PMC8634640 DOI: 10.3389/fphys.2021.775029] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 10/25/2021] [Indexed: 12/24/2022] Open
Abstract
Cardiorenal syndrome (CRS) is a complex disorder that refers to the category of acute or chronic kidney diseases that induce cardiovascular disease, and inversely, acute or chronic heart diseases that provoke kidney dysfunction. There is a close relationship between renal and cardiovascular disease, possibly due to the presence of common risk factors for both diseases. Thus, it is well known that renal diseases are associated with increased risk of developing cardiovascular disease, suffering cardiac events and even mortality, which is aggravated in those patients with end-stage renal disease or who are undergoing dialysis. Recent works have proposed mineral bone disorders (MBD) as the possible link between kidney dysfunction and the development of cardiovascular outcomes. Traditionally, increased serum phosphate levels have been proposed as one of the main factors responsible for cardiovascular damage in kidney patients. However, recent studies have focused on other MBD components such as the elevation of fibroblast growth factor (FGF)-23, a phosphaturic bone-derived hormone, and the decreased expression of the anti-aging factor Klotho in renal patients. It has been shown that increased FGF-23 levels induce cardiac hypertrophy and dysfunction and are associated with increased cardiovascular mortality in renal patients. Decreased Klotho expression occurs as renal function declines. Despite its expression being absent in myocardial tissue, several studies have demonstrated that this antiaging factor plays a cardioprotective role, especially under elevated FGF-23 levels. The present review aims to collect the recent knowledge about the FGF-23-Klotho axis in the connection between kidney and heart, focusing on their specific role as new therapeutic targets in CRS.
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Affiliation(s)
- José Alberto Navarro-García
- Cardiorenal Translational Laboratory, Institute of Research i + 12, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Laura González-Lafuente
- Cardiorenal Translational Laboratory, Institute of Research i + 12, Hospital Universitario 12 de Octubre, Madrid, Spain
| | | | - Luis M Ruilope
- Cardiorenal Translational Laboratory, Institute of Research i + 12, Hospital Universitario 12 de Octubre, Madrid, Spain.,CIBER-CV, Hospital Universitario 12 de Octubre, Madrid, Spain.,School of Doctoral Studies and Research, European University of Madrid, Madrid, Spain
| | - Gema Ruiz-Hurtado
- Cardiorenal Translational Laboratory, Institute of Research i + 12, Hospital Universitario 12 de Octubre, Madrid, Spain.,CIBER-CV, Hospital Universitario 12 de Octubre, Madrid, Spain
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9
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Weidner H, Baschant U, Lademann F, Ledesma Colunga MG, Balaian E, Hofbauer C, Misof BM, Roschger P, Blouin S, Richards WG, Platzbecker U, Hofbauer LC, Rauner M. Increased FGF-23 levels are linked to ineffective erythropoiesis and impaired bone mineralization in myelodysplastic syndromes. JCI Insight 2020; 5:137062. [PMID: 32759495 DOI: 10.1172/jci.insight.137062] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 06/25/2020] [Indexed: 12/26/2022] Open
Abstract
Myelodysplastic syndromes (MDS) are clonal malignant hematopoietic disorders in the elderly characterized by ineffective hematopoiesis. This is accompanied by an altered bone microenvironment, which contributes to MDS progression and higher bone fragility. The underlying mechanisms remain largely unexplored. Here, we show that myelodysplastic NUP98‑HOXD13 (NHD13) transgenic mice display an abnormally high number of osteoblasts, yet a higher fraction of nonmineralized bone, indicating delayed bone mineralization. This was accompanied by high fibroblast growth factor-23 (FGF-23) serum levels, a phosphaturic hormone that inhibits bone mineralization and erythropoiesis. While Fgf23 mRNA expression was low in bone, brain, and kidney of NHD13 mice, its expression was increased in erythroid precursors. Coculturing these precursors with WT osteoblasts induced osteoblast marker gene expression, which was inhibited by blocking FGF-23. Finally, antibody-based neutralization of FGF-23 in myelodysplastic NHD13 mice improved bone mineralization and bone microarchitecture, and it ameliorated anemia. Importantly, higher serum levels of FGF‑23 and an elevated amount of nonmineralized bone in patients with MDS validated the findings. C‑terminal FGF‑23 correlated negatively with hemoglobin levels and positively with the amount of nonmineralized bone. Thus, our study identifies FGF-23 as a link between altered bone structure and ineffective erythropoiesis in MDS with the prospects of a targeted therapeutic intervention.
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Affiliation(s)
- Heike Weidner
- Bone Lab Dresden, Department of Medicine III & Center for Healthy Aging, and
| | - Ulrike Baschant
- Bone Lab Dresden, Department of Medicine III & Center for Healthy Aging, and
| | - Franziska Lademann
- Bone Lab Dresden, Department of Medicine III & Center for Healthy Aging, and
| | | | - Ekaterina Balaian
- Department of Medicine I, Technische Universität Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christine Hofbauer
- Bone Lab Dresden, Department of Medicine III & Center for Healthy Aging, and.,Department of Orthopedics and Trauma Surgery, Technische Universität Dresden, Dresden, Germany
| | - Barbara M Misof
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEKG and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Paul Roschger
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEKG and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Stéphane Blouin
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEKG and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | | | - Uwe Platzbecker
- Department of Medicine I, Technische Universität Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Lorenz C Hofbauer
- Bone Lab Dresden, Department of Medicine III & Center for Healthy Aging, and.,German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martina Rauner
- Bone Lab Dresden, Department of Medicine III & Center for Healthy Aging, and
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10
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Abstract
PURPOSE OF REVIEW The molecular mechanisms of the bone disease associated with chronic kidney disease (CKD), called renal osteodystrophy (ROD), are poorly understood. New transcriptomics technologies may provide clinically relevant insights into the pathogenesis of ROD. This review summarizes current progress and limitations in the study and treatment of ROD, and in transcriptomics analyses of skeletal tissues. RECENT FINDINGS ROD is characterized by poor bone quality and strength leading to increased risk of fracture. Recent studies indicate permanent alterations in bone cell populations during ROD. Single-cell transcriptomics analyses, successful at identifying specialized cell subpopulations in bone, have not yet been performed in ROD. ROD is a widespread poorly understood bone disease with limited treatment options. Transcriptomics analyses of bone are needed to identify the bone cell subtypes and their role in the pathogenesis of ROD, and to develop adequate diagnosis and treatment strategies.
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Affiliation(s)
- Aline Martin
- Division of Nephrology and Hypertension, Center for Translational Metabolism and Health and Feinberg Cardiovascular and Renal Research Institute, Northwestern University, 320 East Superior Street, Chicago, IL, 60611, USA.
| | - Valentin David
- Division of Nephrology and Hypertension, Center for Translational Metabolism and Health and Feinberg Cardiovascular and Renal Research Institute, Northwestern University, 320 East Superior Street, Chicago, IL, 60611, USA.
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11
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Nephrectomy Does not Exacerbate Cancellous Bone loss in Thalassemic Mice. Sci Rep 2020; 10:7786. [PMID: 32385316 PMCID: PMC7210954 DOI: 10.1038/s41598-020-64681-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 04/20/2020] [Indexed: 11/20/2022] Open
Abstract
Patients with β-thalassemia have an increased risk of developing chronic kidney disease which is associated with osteoporosis and periodontitis. The purpose of this study was to evaluate mandibular and femoral bone change in heterozygous β-globin knockout (BKO) mice following 5/6 nephrectomy (Nx). Female and male BKO mouse blood smears demonstrated microcytic hypochromic anemia. Serum urea nitrogen, creatinine, calcium, and phosphorus levels were not changed in BKO mice. Nx increased the serum levels of urea nitrogen in both wild type (WT) and BKO mice and the level was much higher in BKO males. Serum level of creatinine was increased in Nx WT but not BKO mice. However, serum calcium and phosphorus levels were not altered. Nx induced comparable renal fibrosis in BKO mice and WT controls. Bone loss was observed in mandibular cancellous bone but not cortical bone of both male and female BKO mice. Nx decreased cancellous bone volume and cortical thickness in WT. Interestingly, BKO mice were resistant to Nx-induced cancellous bone loss. However, cortical thickness and cortical bone mineral density were reduced in Nx male BKO mice. Nx increased mRNA levels of type I collagen, Osx and Trap in WT but not BKO mice. Similarly, Nx reduced cancellous bone volume in femurs and increased osteoblast number and osteoclast number in WT not BKO mice. Serum FGF23 and erythropoietin levels were markedly increased in BKO mice. Nx decreased serum erythropoietin but not FGF23 levels. Since WT treated with erythropoietin exhibited a significant reduction in cancellous bone volume, it was possible that lower level of erythropoietin in Nx BKO mice prevented the Nx-induced cancellous bone loss.
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12
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Ren Z, Piepenburg AJ, Yang X, Cook ME. Effect of anti-fibroblast growth factor 23 antibody on phosphate and calcium metabolism in adenine gavaged laying hens. Poult Sci 2019; 98:4896-4900. [PMID: 31064011 DOI: 10.3382/ps/pez239] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 04/30/2019] [Indexed: 01/26/2023] Open
Abstract
Dietary factors such as adenine have been linked to phosphate-calcium metabolism disturbance and adverse productive outcomes. Anti-fibroblast growth factor 23 (FGF-23) antibody has been proposed to ameliorate adenine-induced abnormal FGF23/phosphate metabolism. This experiment was conducted to investigate the application of anti-FGF-23 antibody in adenine-gavaged laying hens. Single Comb White Leghorn laying hens with (n = 10) or without (control group, n = 10) systemic anti-FGF-23 antibody were orally gavaged with adenine (600 mg/hen/D) for 21 consecutive days. Adenine gavage increased (P ≤ 0.01) plasma phosphate and calcium levels and tended to increase (0.05 < P ≤ 0.1) plasma 1,25-dihydroxy-cholecalciferol [1,25(OH)2D3] level of hens without FGF-23 antibody. In hen with anti-FGF-23 antibody, adenine gavage increased (P ≤ 0.01) body weight and plasma calcium level and decreased (P ≤ 0.05) plasma FGF-23 level. Feed intake of hens in both treatments was suddenly decreased (control hens decreased from 111 to 55 g, P ≤ 0.01; anti-FGF-23 hens decreased from 96 to 46 g, P ≤ 0.01) 10 D after adenine gavage. Anti-FGF-23 antibody tended to increase (0.05 < P ≤ 0.1) plasma phosphorus level of hens before adenine gavage, interestingly, and decreased (P ≤ 0.01) plasma FGF-23 level and kidney index (% of body weight) of hens after adenine gavage. In conclusion, anti-FGF-23 antibody might be used (before or in the early stage) to delay the development of adenine-induced abnormal FGF23/phosphate metabolism. This is the first study to investigate the FGF-23 status in chickens suffering from dietary factors which may cause abnormal renal phosphate resorption.
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Affiliation(s)
- Zhouzheng Ren
- College of Animal Science and Technology, Northwest A&F University, 22 XiNong Road, Yangling, Shaanxi 712100, China.,Department of Animal Sciences, University of Wisconsin-Madison, 1675 Observatory Drive, Madison, WI 53706, USA
| | - Alexis J Piepenburg
- Department of Animal Sciences, University of Wisconsin-Madison, 1675 Observatory Drive, Madison, WI 53706, USA
| | - Xiaojun Yang
- College of Animal Science and Technology, Northwest A&F University, 22 XiNong Road, Yangling, Shaanxi 712100, China
| | - Mark E Cook
- Department of Animal Sciences, University of Wisconsin-Madison, 1675 Observatory Drive, Madison, WI 53706, USA
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13
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Ren Z, Bütz DE, Ramuta M, Zhang K, Zeng Q, Yang X, Yang X, Crenshaw TD, Cook ME. Effect of anti-fibroblast growth factor receptor 1 antibodies on phosphorus metabolism in laying hens and their progeny chicks. Poult Sci 2019; 98:5691-5699. [PMID: 31237331 DOI: 10.3382/ps/pez353] [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: 12/17/2018] [Accepted: 06/01/2019] [Indexed: 11/20/2022] Open
Abstract
Targeting fibroblast growth factor 23 (FGF-23) signaling pathway is of interest in controlling body phosphate metabolism. This study investigated the effect of anti-fibroblast growth factor receptor 1 (FGFR1, major FGF-23 receptor in the kidney) antibodies on phosphate metabolism. White Leghorn laying hens (65-wk-old) were vaccinated with either a FGFR1 peptide vaccine (five 8-amino-acid peptides were selected, CrZ-1:LPEDPRWE, CrZ-2:LDKDKPNR, CrZ-3:RRPPGMEY, CrZ-4:GSPYPGVP, and CrZ-5:RMDKPSNC) or adjuvant control. At peak antibody titer, hens were artificially inseminated. Chicks from control-vaccinated hens were fed either a non-phytate phosphorus (nPP) sufficient (nPP = 0.45%, positive control) or deficient (nPP = 0.20%, negative control) diet, while chicks from each of the FGFR1 peptide vaccinated hens were fed with the above nPP-deficient diet, for 14 D. When compared to control hens, plasma phosphate in CrZ-1, CrZ-2, CrZ-3, CrZ-4, and CrZ-5 vaccinated hens were decreased by 33, 30, 24, 20, and 26%, respectively (P < 0.05); egg weight in CrZ-2 and CrZ-5 vaccinated hens were increased by 6 and 7%, respectively (P < 0.05); egg production in CrZ-3, CrZ-4, and CrZ-5 vaccinated hens tended to decrease (P = 0.085; decreased by 14, 15, and 13%, respectively). When compared to positive control, chicks from all other groups had decreased body weight gain (BWG) and feed intake (FI) during 1 to 14 D, and had decreased plasma phosphate, tibiotarsus ash, and 24-h phosphorus excretion on day 14. When compared to negative control, BWG of CrZ-1, CrZ-2, CrZ-3, and CrZ-4 antibody chicks were decreased by 23, 28, 26, and 20%, respectively (P < 0.05); FI of CrZ-1, CrZ-2, and CrZ-3 antibody chicks were decreased by 15, 15, and 18%, respectively (P < 0.05); plasma phosphate of CrZ-5 antibody chicks were decreased by 26% (P < 0.05); plasma FGF-23 levels of CrZ-4 antibody chicks were increased by 18% (P < 0.05); tibiotarsus ash content of CrZ-2, CrZ-3, and CrZ-4 antibody chicks were decreased by 20, 20, and 21%, respectively (P < 0.05). In conclusion, anti-FGFR1 peptide antibodies decreased egg production of hens and growth performance of their progeny chicks probably by activating FGF-23 signaling and stimulating FGF-23 production.
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Affiliation(s)
- Zhouzheng Ren
- College of Animal Science and Technology, Northwest A&F University, 22 XiNong Road, Yangling, Shaanxi 712100, China
| | - Daniel E Bütz
- Department of Animal Sciences, University of Wisconsin-Madison, 1675 Observatory Drive, Madison, WI 53706
| | - Mitchell Ramuta
- Department of Animal Sciences, University of Wisconsin-Madison, 1675 Observatory Drive, Madison, WI 53706
| | - Keying Zhang
- Institute of Animal Nutrition, Sichuan Agricultural University, 211 Huimin Road, Chengdu, Sichuan 611130, China
| | - Qiufeng Zeng
- Institute of Animal Nutrition, Sichuan Agricultural University, 211 Huimin Road, Chengdu, Sichuan 611130, China
| | - Xin Yang
- College of Animal Science and Technology, Northwest A&F University, 22 XiNong Road, Yangling, Shaanxi 712100, China
| | - Xiaojun Yang
- College of Animal Science and Technology, Northwest A&F University, 22 XiNong Road, Yangling, Shaanxi 712100, China
| | - Thomas D Crenshaw
- Department of Animal Sciences, University of Wisconsin-Madison, 1675 Observatory Drive, Madison, WI 53706
| | - Mark E Cook
- Department of Animal Sciences, University of Wisconsin-Madison, 1675 Observatory Drive, Madison, WI 53706
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14
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Acipinar S, Karsiyaka Hendek M, Olgun E, Kisa U. Evaluation of FGF-23 and 25(OH)D 3 levels in peri-implant sulcus fluid in peri-implant health and diseases. Clin Implant Dent Relat Res 2019; 21:1106-1112. [PMID: 31407857 DOI: 10.1111/cid.12832] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 07/22/2019] [Accepted: 07/24/2019] [Indexed: 01/01/2023]
Abstract
BACKGROUND There are limited studies to date investigating vitamin D and fibroblast growth factor (FGF)-23 in different peri-implant conditions. PURPOSE To evaluate the peri-implant sulcus fluid (PISF) FGF-23 and 25-hydroxy-vitamin D3 (25(OH)D3 ) levels in peri-implant health and diseases. MATERIALS AND METHODS A total of 90 dental implant sites (peri-implant healthy group [n = 30], peri-implant mucositis group [n = 30], and peri-implantitis group [n = 30]) in 53 participants were included in the study. Probing depth (PD), clinical attachment level (CAL), suppuration (S), modified plaque index (mPI), gingival index (GI), modified sulcus bleeding index (mSBI), and keratinized mucosa width (KMW) were recorded as clinical parameters, and PISF samples were obtained. FGF-23 and 25(OH)D3 levels were analyzed by enzyme-linked immunosorbent assay. RESULTS There were no statistically significant differences in FGF-23 concentrations among the groups (P > .05). The 25(OH)D3 concentration was significantly lower in peri-implantitis group compared with the other two groups (P < .05). The mean total amount of FGF-23 in the peri-implantitis group was significantly higher than the peri-implant healthy group whereas 25(OH)D3 total amount was significantly lower in the peri-implantitis group than the peri-implant healthy group. The 25(OH)D3 concentration was significantly negatively correlated with CAL, PD, mPI, S, GI, and mSBI and statistically significant relationship was found between FGF-23 total amount and these clinical parameters (P < .05). There was a negligible positive correlation between 25(OH)D3 and FGF-23 concentrations (τ = 0.169; P = .018). CONCLUSION Within the limitations of this study, it can be concluded that FGF-23 and vitamin D seems to affect peri-implant bone health, and further studies are needed to explain the association between FGF-23 and 25(OH)D3 in peri-implant conditions.
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Affiliation(s)
- Sukran Acipinar
- Department of Periodontology, Kirikkale University Faculty of Dentistry, Turkey
| | | | - Ebru Olgun
- Department of Periodontology, Kirikkale University Faculty of Dentistry, Turkey
| | - Ucler Kisa
- Department of Biochemistry, Kirikkale University Faculty of Medicine, Turkey
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15
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Clinkenbeard EL, Noonan ML, Thomas JC, Ni P, Hum JM, Aref M, Swallow EA, Moe SM, Allen MR, White KE. Increased FGF23 protects against detrimental cardio-renal consequences during elevated blood phosphate in CKD. JCI Insight 2019; 4:123817. [PMID: 30830862 DOI: 10.1172/jci.insight.123817] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 01/14/2019] [Indexed: 12/23/2022] Open
Abstract
The phosphaturic hormone FGF23 is elevated in chronic kidney disease (CKD). The risk of premature death is substantially higher in the CKD patient population, with cardiovascular disease (CVD) as the leading mortality cause at all stages of CKD. Elevated FGF23 in CKD has been associated with increased odds for all-cause mortality; however, whether FGF23 is associated with positive adaptation in CKD is unknown. To test the role of FGF23 in CKD phenotypes, a late osteoblast/osteocyte conditional flox-Fgf23 mouse (Fgf23fl/fl/Dmp1-Cre+/-) was placed on an adenine-containing diet to induce CKD. Serum analysis showed casein-fed Cre+ mice had significantly higher serum phosphate and blood urea nitrogen (BUN) versus casein diet and Cre- genotype controls. Adenine significantly induced serum intact FGF23 in the Cre- mice over casein-fed mice, whereas Cre+ mice on adenine had 90% reduction in serum intact FGF23 and C-terminal FGF23 as well as bone Fgf23 mRNA. Parathyroid hormone was significantly elevated in mice fed adenine diet regardless of genotype, which significantly enhanced midshaft cortical porosity. Echocardiographs of the adenine-fed Cre+ hearts revealed profound aortic calcification and cardiac hypertrophy versus diet and genotype controls. Thus, these studies demonstrate that increased bone FGF23, although associated with poor outcomes in CKD, is necessary to protect against the cardio-renal consequences of elevated tissue phosphate.
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Affiliation(s)
| | | | | | - Pu Ni
- Department of Medical and Molecular Genetics
| | - Julia M Hum
- Department of Medical and Molecular Genetics
| | | | | | - Sharon M Moe
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | | | - Kenneth E White
- Department of Medical and Molecular Genetics.,Department of Anatomy and Cell Biology, and
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16
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Significance of urinary C-megalin excretion in vitamin D metabolism in pre-dialysis CKD patients. Sci Rep 2019; 9:2207. [PMID: 30778159 PMCID: PMC6379559 DOI: 10.1038/s41598-019-38613-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 12/27/2018] [Indexed: 11/08/2022] Open
Abstract
Serum 1,25(OH)2D and 24,25(OH)2D are decreased in CKD. Megalin in proximal tubular epithelial cells reabsorbs glomerular-filtered 25(OH)D-DBP complex to convert 25(OH)D to 1,25(OH)2D and 24,25(OH)2D. Urinary C-megalin excretion is increased via exocytosis from injured nephrons overloaded with megalin-mediated protein metabolism. This study investigated the significance of urinary C-megalin excretion in vitamin D metabolism in 153 pre-dialysis CKD patients. Urinary C-megalin was positively associated with urinary protein, β2MG and α1MG, and exhibited negative correlations with serum 25(OH)D, 1,25(OH)2D and 24,25(OH)2D. Multiple regression analysis showed that urinary C-megalin had a significantly negative association with 25(OH)D. Serum 1,25(OH)2D and 24,25(OH)2D, as well as 1,25(OH)2D/25(OH)D and 24,25(OH)2D/25(OH)D ratios, showed positive correlations with eGFR. Additionally, wholePTH was positively associated with 1,25(OH)2D/25(OH)D and 1,25(OH)2D/24,25(OH)2D, while FGF23 was positively associated with 24,25(OH)2D/25(OH)D and negatively with 1,25(OH)2D/24,25(OH)2D. Urinary C-megalin emerged as an independent factor positively associated with 1,25(OH)2D/25(OH)D and 1,25(OH)2D/24,25(OH)2D. Although 1,25(OH)2D and 24,25(OH)2D are decreased in CKD patient serum, our findings suggest that PTH and FGF23 retain their effects to regulate vitamin D metabolism even in the kidneys of these patients, while production of 1,25(OH)2D and 24,25(OH)2D from 25(OH)D is restricted due to either impairment of megalin-mediated reabsorption of the 25(OH)D-DBP complex or reduced renal mass.
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17
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Zhao R, Chen S, Yuan B, Chen X, Yang X, Song Y, Tang H, Yang X, Zhu X, Zhang X. Healing of osteoporotic bone defects by micro-/nano-structured calcium phosphate bioceramics. NANOSCALE 2019; 11:2721-2732. [PMID: 30672553 DOI: 10.1039/c8nr09417a] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The micro-/nano-structured calcium phosphate bioceramic exhibited a higher new bone substitution rate in an osteoporotic bone defect rat model.
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Affiliation(s)
- Rui Zhao
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu
- China
| | - Siyu Chen
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu
- China
| | - Bo Yuan
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu
- China
| | - Xuening Chen
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu
- China
| | - Xi Yang
- Department of Orthopaedics
- West China Hospital of Sichuan University
- Chengdu 610041
- China
| | - Yueming Song
- Department of Orthopaedics
- West China Hospital of Sichuan University
- Chengdu 610041
- China
| | - Hai Tang
- Department of Orthopedics
- Beijing Friendship Hospital
- Capital Medical University
- Beijing 100050
- China
| | - Xiao Yang
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu
- China
| | - Xiangdong Zhu
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu
- China
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials
- Sichuan University
- Chengdu
- China
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18
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Glosse P, Feger M, Mutig K, Chen H, Hirche F, Hasan AA, Gaballa MMS, Hocher B, Lang F, Föller M. AMP-activated kinase is a regulator of fibroblast growth factor 23 production. Kidney Int 2018; 94:491-501. [PMID: 29861059 DOI: 10.1016/j.kint.2018.03.006] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 03/01/2018] [Accepted: 03/08/2018] [Indexed: 12/20/2022]
Abstract
Fibroblast growth factor 23 (FGF23) is a proteohormone regulating renal phosphate transport and vitamin D metabolism as well as inducing left heart hypertrophy. FGF23-deficient mice suffer from severe tissue calcification, accelerated aging and a myriad of aging-associated diseases. Bone cells produce FGF23 upon store-operated calcium ion entry (SOCE) through the calcium selective ion channel Orai1. AMP-activated kinase (AMPK) is a powerful energy sensor helping cells survive states of energy deficiency, and AMPK down-regulates Orai1. Here we investigated the role of AMPK in FGF23 production. Fgf23 gene transcription was analyzed by qRT-PCR and SOCE by fluorescence optics in UMR106 osteoblast-like cells while the serum FGF23 concentration and phosphate metabolism were assessed in AMPKα1-knockout and wild-type mice. The AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) down-regulated, whereas the AMPK inhibitor, dorsomorphin dihydrochloride (compound C) and AMPK gene silencing induced Fgf23 transcription. AICAR decreased membrane abundance of Orai1 and SOCE. SOCE inhibitors lowered Fgf23 gene expression induced by AMPK inhibition. AMPKα1-knockout mice had a higher serum FGF23 concentration compared to wild-type mice. Thus, AMPK participates in the regulation of FGF23 production in vitro and in vivo. The inhibitory effect of AMPK on FGF23 production is at least in part mediated by Orai1-involving SOCE.
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Affiliation(s)
- Philipp Glosse
- Department of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Martina Feger
- Department of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Kerim Mutig
- Department of Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Hong Chen
- Department of Physiology I, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Frank Hirche
- Department of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | | | | | - Berthold Hocher
- Department of Nutritional Sciences, University of Potsdam, Potsdam, Germany
| | - Florian Lang
- Department of Physiology I, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Michael Föller
- Department of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
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Zhang L, Zhou Q, Song W, Wu K, Zhang Y, Zhao Y. Dual-Functionalized Graphene Oxide Based siRNA Delivery System for Implant Surface Biomodification with Enhanced Osteogenesis. ACS APPLIED MATERIALS & INTERFACES 2017; 9:34722-34735. [PMID: 28925678 DOI: 10.1021/acsami.7b12079] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Surface functionalization by small interfering RNA (siRNA) is a novel strategy for improved implant osseointegration. A gene delivery system with safety and high transfection activity is a crucial factor for an siRNA-functionalized implant to exert its biological function. To this end, polyethylene glycol (PEG) and polyethylenimine (PEI) dual-functionalized graphene oxide (GO; nGO-PEG-PEI) may present a promising siRNA vector. In this study, nanosized nGO-PEG-PEI was prepared and optimized for siRNA delivery. Titania nanotubes (NTs) fabricated by anodic oxidation were biomodified with nGO-PEG-PEI/siRNA by cathodic electrodeposition, designated as NT-GPP/siRNA. NT-GPP/siRNA possessed benign cytocompatibility, as evaluated by cell adhesion and proliferation. Cellular uptake and knockdown efficiency of the NT-GPP/siRNA were assessed by MC3T3-E1 cells, which exhibited high siRNA delivery efficiency and sustained target gene silencing. Casein kinase-2 interacting protein-1 (Ckip-1) is a negative regulator of bone formation. siRNA-targeting Ckip-1 (siCkip-1) was introduced to the implant, and a series of in vitro and in vivo experiments were carried out to evaluate the osteogenic capacity of NT-GPP/siCkip-1. NT-GPP/siCkip-1 dramatically improved the in vitro osteogenic differentiation of MC3T3-E1 cells in terms of improved osteogenesis-related gene expression, and increased alkaline phosphatase (ALP) production, collagen secretion, and extracellular matrix (ECM) mineralization. Moreover, NT-GPP/siCkip-1 led to apparently enhanced in vivo osseointegration, as indicated by histological staining and EDX line scanning. Collectively, these findings suggest that NT-GPP/siRNA represents a practicable and promising approach for implant functionalization, showing clinical potential for dental and orthopedic applications.
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Affiliation(s)
- Li Zhang
- The State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, and Shaanxi Key Laboratory of Oral Diseases, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University , Xi'an 710032, China
| | - Qing Zhou
- Department of Pharmaceutical Analysis, School of Pharmacy, The Fourth Military Medical University , Xi'an 710032, China
| | - Wen Song
- The State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, and Shaanxi Key Laboratory of Oral Diseases, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University , Xi'an 710032, China
| | - Kaimin Wu
- Department of Stomatology, 401 Military Hospital , Qingdao 266071, China
| | - Yumei Zhang
- The State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, and Shaanxi Key Laboratory of Oral Diseases, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University , Xi'an 710032, China
| | - Yimin Zhao
- The State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, and Shaanxi Key Laboratory of Oral Diseases, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University , Xi'an 710032, China
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20
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Yavropoulou MP, Vaios V, Pikilidou M, Chryssogonidis I, Sachinidou M, Tournis S, Makris K, Kotsa K, Daniilidis M, Haritanti A, Liakopoulos V. Bone Quality Assessment as Measured by Trabecular Bone Score in Patients With End-Stage Renal Disease on Dialysis. J Clin Densitom 2017; 20:490-497. [PMID: 28039046 DOI: 10.1016/j.jocd.2016.11.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 11/02/2016] [Accepted: 11/04/2016] [Indexed: 12/18/2022]
Abstract
Patients with end-stage renal disease (ESRD) on maintenance hemodialysis (HD) exhibit osteoporosis and increased fracture risk. Dual-energy X-ray absorptiometry scan measurements and calculation of fracture risk assessment toll score underestimate fracture risk in these patients and do not estimate bone quality. Trabecular bone score (TBS) has been recently proposed as an indirect measure of bone microarchitecture. In this study, we investigated alterations of bone quality in patients with ESRD on HD, using TBS. Fifty patients with ESRD on HD, with a mean age 62 years, and 52 healthy individuals matched for age, body mass index, and gender, were enrolled. All participants had a bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry scan at the lumbar spine, femoral neck, total hip, and 1/3 radius. TBS was evaluated using TBS iNsight. Serum fetuin-A and plasma fibroblast growth factor-23 (FGF-23) (C-terminal) were also measured. Patients on dialysis had significantly lower BMD values at all skeletal sites measured. Plasma FGF-23 levels significantly increased and serum fetuin-Α significantly decreased in patients on dialysis compared with controls. TBS was significantly reduced in patients on dialysis compared with controls (1.11 ± 0.16 vs 1.30 ± 0.13, p < 0.001, respectively) independently of age; BMD; duration of dialysis; and serum levels of alkaline phosphatase, 25-OH-vitamin D, parathyroid hormone, fetuin-A, or plasma FGF-23. Patients on HD who were diagnosed with an osteoporotic vertebral fracture had numerically lower TBS values, albeit without reaching statistical significance, compared with patients on dialysis without a fracture (1.044 ± 0.151 vs 1.124 ± 0.173, respectively, p = 0.079). Bone microarchitecture, as assessed by TBS, is significantly altered in ESRD on patients on HD independently of BMD values and metabolic changes that reflect chronic kidney disease-mineral and bone disorder.
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Affiliation(s)
- Maria P Yavropoulou
- Division of Endocrinology and Metabolism, 1st Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece
| | - Vasilios Vaios
- Nephrology Division, 1st Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece
| | - Maria Pikilidou
- 1st Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece
| | | | - Melina Sachinidou
- Radiology Unit AHEPA University Hospital, Aristotle University of Thessaloniki, Greece
| | - Symeon Tournis
- Laboratory of Research of Musculoskeletal System "Th. Garofalidis", Medical School, KAT Hospital, University of Athens, Athens, Greece
| | - Konstantinos Makris
- Laboratory of Research of Musculoskeletal System "Th. Garofalidis", Medical School, KAT Hospital, University of Athens, Athens, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism, 1st Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece
| | - Michalis Daniilidis
- 1st Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece
| | - Afroditi Haritanti
- Radiology Unit AHEPA University Hospital, Aristotle University of Thessaloniki, Greece
| | - Vassilios Liakopoulos
- Nephrology Division, 1st Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece.
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Yuan Q, Xiong QC, Gupta M, López-Pintor RM, Chen XL, Seriwatanachai D, Densmore M, Man Y, Gong P. Dental implant treatment for renal failure patients on dialysis: a clinical guideline. Int J Oral Sci 2017; 9:125-132. [PMID: 28644432 PMCID: PMC5709544 DOI: 10.1038/ijos.2017.23] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/17/2017] [Indexed: 02/05/2023] Open
Abstract
Chronic kidney disease (CKD) is a worldwide public health problem that is growing in prevalence and is associated with severe complications. During the progression of the disease, a majority of CKD patients suffer oral complications. Dental implants are currently the most reliable and successful treatment for missing teeth. However, due to complications of CKD such as infections, bone lesions, bleeding risks, and altered drug metabolism, dental implant treatment for renal failure patients on dialysis is more challenging. In this review, we have summarized the characteristics of CKD and previous publications regarding dental treatments for renal failure patients. In addition, we discuss our recent research results and clinical experience in order to provide dental implant practitioners with a clinical guideline for dental implant treatment for renal failure patients undergoing hemodialysis.
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Affiliation(s)
- Quan Yuan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Qiu-Chan Xiong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Megha Gupta
- Department of Preventive Dental Sciences, Division of Pedodontics, College of Dentistry, Al-Showajra Academic Campus, Jazan University, Gizan, Kingdom of Saudi Arabia
| | - Rosa María López-Pintor
- Department of Oral Medicine and Surgery, School of Dentistry, Complutense University, Madrid, Spain
| | - Xiao-Lei Chen
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | | | - Michael Densmore
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, USA
| | - Yi Man
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ping Gong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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22
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Feger M, Hase P, Zhang B, Hirche F, Glosse P, Lang F, Föller M. The production of fibroblast growth factor 23 is controlled by TGF-β2. Sci Rep 2017; 7:4982. [PMID: 28694529 PMCID: PMC5503987 DOI: 10.1038/s41598-017-05226-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 05/25/2017] [Indexed: 12/29/2022] Open
Abstract
Transforming growth factor-β (TGF-β) is a cytokine produced by many cell types and implicated in cell growth, differentiation, apoptosis, and inflammation. It stimulates store-operated calcium entry (SOCE) through the calcium release-activated calcium (CRAC) channel Orai1/Stim1 in endometrial Ishikawa cells. Bone cells generate fibroblast growth factor (FGF) 23, which inhibits renal phosphate reabsorption and 1,25(OH)2D3 formation in concert with its co-receptor Klotho. Moreover, Klotho and FGF23 counteract aging and age-related clinical conditions. FGF23 production is dependent on Orai1-mediated SOCE and inflammation. Here, we explored a putative role of TGF-β2 in FGF23 synthesis. To this end, UMR106 osteoblast-like cells were cultured, Fgf23 transcript levels determined by qRT-PCR, FGF23 protein measured by ELISA, and SOCE analyzed by fluorescence optics. UMR106 cells expressed TGF-β receptors 1 and 2. TGF-β2 enhanced SOCE and potently stimulated the production of FGF23, an effect significantly attenuated by SB431542, an inhibitor of the transforming growth factor-β (TGF-β) type I receptor activin receptor-like kinases ALK5, ALK4, and ALK7. Furthermore, the TGF-β2 effect on FGF23 production was blunted by SOCE inhibitor 2-APB. We conclude that TGF-β2 induces FGF23 production, an effect involving up-regulation of SOCE.
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Affiliation(s)
- Martina Feger
- Institute of Agricultural and Nutritional Sciences, Martin-Luther University Halle-Wittenberg, D-06120, Halle (Saale), Germany
| | - Philipp Hase
- Institute of Agricultural and Nutritional Sciences, Martin-Luther University Halle-Wittenberg, D-06120, Halle (Saale), Germany
| | - Bingbing Zhang
- Department of Physiology, Eberhard-Karls University of Tübingen, D-72076 Tübingen, Germany
- College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China
| | - Frank Hirche
- Institute of Agricultural and Nutritional Sciences, Martin-Luther University Halle-Wittenberg, D-06120, Halle (Saale), Germany
| | - Philipp Glosse
- Institute of Agricultural and Nutritional Sciences, Martin-Luther University Halle-Wittenberg, D-06120, Halle (Saale), Germany
| | - Florian Lang
- Department of Physiology, Eberhard-Karls University of Tübingen, D-72076 Tübingen, Germany
| | - Michael Föller
- Institute of Agricultural and Nutritional Sciences, Martin-Luther University Halle-Wittenberg, D-06120, Halle (Saale), Germany.
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23
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Qin Z, Liu X, Song M, Zhou Q, Yu J, Zhou B, Wu Y, He Y, Huang L. Fibroblast growth factor 23 as a predictor of cardiovascular and all-cause mortality in prospective studies. Atherosclerosis 2017; 261:1-11. [PMID: 28411494 DOI: 10.1016/j.atherosclerosis.2017.03.042] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Revised: 03/03/2017] [Accepted: 03/30/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS The prognostic value of fibroblast growth factor 23 (FGF23) for mortality remains controversial. We performed a meta-analysis of cohort studies to examine the controversial relationship between FGF23 and mortality. METHODS PubMed, EMBASE, the Cochrane Library databases and reference bibliographies were searched through September 2016 to identify prospective cohort studies with relative risks (RRs) and 95% confidence intervals (CIs) for FGF23 and mortality. A random effects model was used to pool the risk estimates. A dose-response analysis of the risk for all-cause mortality associated with FGF23 was conducted using the generalized least squares trend estimation method. RESULTS Nineteen prospective cohort studies were eligible for inclusion in this meta-analysis, of which 16 reported all-cause mortality and 9 reported cardiovascular mortality. During the follow-up periods ranging from 1 to 18.6 years, 5606 deaths occurred among 22,805 participants and 2458 cardiovascular deaths occurred among 28,845 participants. Elevated FGF23 was associated with an increased risk of all-cause mortality (RR 1.68; 95% CI 1.48-1.92) and cardiovascular mortality (RR 1.68; 95% CI 1.38-2.04) with moderate heterogeneity. These associations were not markedly modified by the geographic location, follow-up length, patient predisposition, FGF23 measurement or study quality. A sensitivity analysis yielded a similar effect on the pooled risk estimate. Evidence of a nonlinear relationship between FGF23 and all-cause mortality was observed in the dose-response analysis, with the risk gradually increasing as FGF23 increased. CONCLUSIONS This meta-analysis showed that individuals with increased plasma FGF23 levels might suffer a higher risk of all-cause mortality and cardiovascular mortality.
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Affiliation(s)
- Zhexue Qin
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Xi Liu
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Mingbao Song
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Quan Zhou
- Department of Science and Education, First People's Hospital of Changde City, No. 818 Renming Road, Changde, Hunan, 415003, China
| | - Jie Yu
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Baoshang Zhou
- Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Yazhou Wu
- Department of Health Statistics, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Yongming He
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Lan Huang
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
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24
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Song L, Linstedt AD. Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels. eLife 2017; 6:e24051. [PMID: 28362263 PMCID: PMC5407854 DOI: 10.7554/elife.24051] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 03/30/2017] [Indexed: 01/12/2023] Open
Abstract
Small molecule inhibitors of site-specific O-glycosylation by the polypeptide N-acetylgalactosaminyltransferase (ppGalNAc-T) family are currently unavailable but hold promise as therapeutics, especially if selective against individual ppGalNAc-T isozymes. To identify a compound targeting the ppGalNAc-T3 isozyme, we screened libraries to find compounds that act on a cell-based fluorescence sensor of ppGalNAc-T3 but not on a sensor of ppGalNAc-T2. This identified a hit that subsequent in vitro analysis showed directly binds and inhibits purified ppGalNAc-T3 with no detectable activity against either ppGalNAc-T2 or ppGalNAc-T6. Remarkably, the inhibitor was active in two medically relevant contexts. In cell culture, it opposed increased cancer cell invasiveness driven by upregulated ppGalNAc-T3 suggesting the inhibitor might be anti-metastatic. In cells and mice, it blocked ppGalNAc-T3-mediated glycan-masking of FGF23 thereby increasing its cleavage, a possible treatment of chronic kidney disease. These findings establish a pharmacological approach for the ppGalNAc-transferase family and suggest that targeting specific ppGalNAc-transferases will yield new therapeutics.
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Affiliation(s)
- Lina Song
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, United States
| | - Adam D Linstedt
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, United States
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25
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Fernandes TAP, Gonçalves LML, Brito JAA. Relationships between Bone Turnover and Energy Metabolism. J Diabetes Res 2017; 2017:9021314. [PMID: 28695134 PMCID: PMC5485508 DOI: 10.1155/2017/9021314] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 05/12/2017] [Accepted: 05/22/2017] [Indexed: 12/31/2022] Open
Abstract
It is well established that diabetes can be detrimental to bone health, and its chronic complications have been associated with an increased risk of osteoporotic fracture. However, there is growing evidence that the skeleton plays a key role in a whole-organism approach to physiology. The hypothesis that bone may be involved in the regulation of physiological functions, such as insulin sensitivity and energy metabolism, has been suggested. Given the roles of insulin, adipokines, and osteocalcin in these pathways, the need for a more integrative conceptual approach to physiology is emphasized. Recent findings suggest that bone plays an important role in regulating intermediary metabolism, being possibly both a target of diabetic complications and a potential pathophysiologic factor in the disease itself. Understanding the relationships between bone turnover and glucose metabolism is important in order to develop treatments that might reestablish energy metabolism and bone health. This review describes new insights relating bone turnover and energy metabolism that have been reported in the literature.
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Affiliation(s)
- Tânia A. P. Fernandes
- Instituto Superior de Ciências da Saúde Egas Moniz (ISCSEM), Campus Universitário-Quinta da Granja, 2829-511 Monte de Caparica, Portugal
- Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Campus Universitário-Quinta da Granja, 2829-511 Monte de Caparica, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal
- *Tânia A. P. Fernandes:
| | - Luísa M. L. Gonçalves
- Instituto Superior de Ciências da Saúde Egas Moniz (ISCSEM), Campus Universitário-Quinta da Granja, 2829-511 Monte de Caparica, Portugal
- Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Campus Universitário-Quinta da Granja, 2829-511 Monte de Caparica, Portugal
| | - José A. A. Brito
- Instituto Superior de Ciências da Saúde Egas Moniz (ISCSEM), Campus Universitário-Quinta da Granja, 2829-511 Monte de Caparica, Portugal
- Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Campus Universitário-Quinta da Granja, 2829-511 Monte de Caparica, Portugal
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26
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Lu X, Hu MC. Klotho/FGF23 Axis in Chronic Kidney Disease and Cardiovascular Disease. KIDNEY DISEASES 2016; 3:15-23. [PMID: 28785560 DOI: 10.1159/000452880] [Citation(s) in RCA: 135] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Accepted: 10/26/2016] [Indexed: 12/26/2022]
Abstract
BACKGROUND Membrane αKlotho (hereinafter called Klotho) is highly expressed in the kidney and functions as a coreceptor of FGF receptors (FGFRs) to activate specific fibroblast growth factor 23 (FGF23) signal pathway. FGF23 is produced in bones and participates in the maintenance of mineral homeostasis. The extracellular domain of transmembrane Klotho can be cleaved by secretases and released into the circulation as soluble Klotho. Soluble Klotho does not only weakly activate FGFRs to transduce the FGF23 signaling pathway, but also functions as an enzyme and hormonal substance to play a variety of biological functions. FGF23 exerts its biological effects through activation of FGFRs in a Klotho-dependent manner. However, extremely high FGF23 can exert its pathological action in a Klotho-independent manner. SUMMARY The decline in serum and urinary Klotho followed by a rise in serum FGF23 at an early stage of chronic kidney disease (CKD) functions as an early biomarker for kidney dysfunction and can also serve as a predictor for risk of cardiovascular disease (CVD) and mortality in both CKD patients and the general population. Moreover, Klotho deficiency is a pathogenic factor for CKD progression and CVD. FGF23 may also contribute to CVD. Prevention of Klotho decline, reactivation of endogenous Klotho production, or supplementation of exogenous Klotho attenuate renal fibrosis, retard CKD progression, improve mineral metabolism, ameliorate cardiomyopathy, and alleviate vascular calcification in CKD. However, the poor CVD outcome after depletion of FGF23 with FGF23 antibody stimulates the generation of a more specific inhibitor of FGF23 for CKD treatment. KEY MESSAGE Klotho/FGF23 may not only be diagnostic and/or prognostic biomarkers for CKD and CVD, but are also pathogenic contributors to CKD progression and CVD development. The Klotho/FGF23 axis should be a novel target for renal clinics.
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Affiliation(s)
- Xiang Lu
- Department of Geriatrics, Sir Run Run Hospital, Nanjing Medical University, Nanjing, PR China
| | - Ming Chang Hu
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Department of Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
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27
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Pan G, Sun S, Zhang W, Zhao R, Cui W, He F, Huang L, Lee SH, Shea KJ, Shi Q, Yang H. Biomimetic Design of Mussel-Derived Bioactive Peptides for Dual-Functionalization of Titanium-Based Biomaterials. J Am Chem Soc 2016; 138:15078-15086. [PMID: 27778505 DOI: 10.1021/jacs.6b09770] [Citation(s) in RCA: 108] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Guoqing Pan
- Department
of Orthopaedics, The First Affiliated Hospital of Soochow University,
Orthopaedic Institute, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China
| | - Shujin Sun
- Department
of Orthopaedics, The First Affiliated Hospital of Soochow University,
Orthopaedic Institute, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China
| | - Wen Zhang
- Department
of Orthopaedics, The First Affiliated Hospital of Soochow University,
Orthopaedic Institute, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China
| | - Ruobing Zhao
- Department
of Chemistry, University of California, Irvine, California 92697, United States
| | - Wenguo Cui
- Department
of Orthopaedics, The First Affiliated Hospital of Soochow University,
Orthopaedic Institute, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China
| | - Fan He
- Department
of Orthopaedics, The First Affiliated Hospital of Soochow University,
Orthopaedic Institute, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China
| | - Lixin Huang
- Department
of Orthopaedics, The First Affiliated Hospital of Soochow University,
Orthopaedic Institute, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China
| | - Shih-Hui Lee
- Department
of Chemistry, University of California, Irvine, California 92697, United States
| | - Kenneth J. Shea
- Department
of Chemistry, University of California, Irvine, California 92697, United States
| | - Qin Shi
- Department
of Orthopaedics, The First Affiliated Hospital of Soochow University,
Orthopaedic Institute, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China
| | - Huilin Yang
- Department
of Orthopaedics, The First Affiliated Hospital of Soochow University,
Orthopaedic Institute, Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, China
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28
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Dong Y, Liu W, Lei Y, Wu T, Zhang S, Guo Y, Liu Y, Chen D, Yuan Q, Wang Y. Effect of gelatin sponge with colloid silver on bone healing in infected cranial defects. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2016; 70:371-377. [PMID: 27770905 DOI: 10.1016/j.msec.2016.09.015] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 08/17/2016] [Accepted: 09/06/2016] [Indexed: 02/05/2023]
Abstract
Oral infectious diseases may lead to bone loss, which makes it difficult to achieve satisfactory restoration. The rise of multidrug resistant bacteria has put forward severe challenges to the use of antibiotics. Silver (Ag) has long been known as a strong antibacterial agent. In clinic, gelatin sponge with colloid silver is used to reduce tooth extraction complication. To investigate how this material affect infected bone defects, methicillin-resistant Staphylococcus aureus (MRSA) infected 3-mm-diameter cranial defects were created in adult female Sprague-Dawley rats. One week after infection, the defects were debrided of all nonviable tissue and then implanted with gelatin sponge with colloid silver (gelatin/Ag group) or gelatin alone (gelatin group). At 2 and 3days after debridement, significantly lower mRNA expression levels of IL-6 and TNF-α and lower plate colony count value were detected in gelatin/Ag group than control. Micro-CT analysis showed a significant increase of newly formed bone volume fraction (BV/TV) in gelatin/Ag treated defects. The HE stained cranium sections also showed a faster rate of defect closure in gelatin/Ag group than control. These findings demonstrated that gelatin sponge with colloid silver can effectively reduce the infection caused by MRSA in cranial defects and accelerate bone healing process.
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Affiliation(s)
- Yuliang Dong
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Weiqing Liu
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Yiling Lei
- Dental Implant Center, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Tingxi Wu
- Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles (UCLA), Los Angeles, California, USA
| | - Shiwen Zhang
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Yuchen Guo
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Yuan Liu
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Demeng Chen
- Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles (UCLA), Los Angeles, California, USA
| | - Quan Yuan
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, China; Dental Implant Center, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yongyue Wang
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, China; Dental Implant Center, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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29
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Du E, Xiao L, Hurley MM. FGF23 Neutralizing Antibody Ameliorates Hypophosphatemia and Impaired FGF Receptor Signaling in Kidneys of HMWFGF2 Transgenic Mice. J Cell Physiol 2016; 232:610-616. [PMID: 27306296 DOI: 10.1002/jcp.25458] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 06/14/2016] [Indexed: 01/15/2023]
Abstract
High molecular weight FGF2 transgenic mice (HMWTg) phenocopy the Hyp mouse, homolog of human X-linked hypophosphatemic rickets with phosphate wasting and abnormal fibroblast growth factor (FGF23), fibroblast growth factor receptor (FGFR), Klotho and mitogen activated protein kinases (MAPK) signaling in kidney. In this study, we assessed whether short-term (24 h) in vivo administration of FGF23 neutralizing antibody (FGF23Ab) could rescue hypophosphatemia and impaired FGFR signaling in kidneys of HMWTg male mice. Bone mineral density and bone mineral content in 1-month-old HMWTg mice were significantly reduced compared with Control/VectorTg mice. Serum FGF23 was significantly increased in HMWTg compared with VectorTg. Serum phosphate was significantly reduced in HMWTg and was rescued by FGF23Ab. Serum parathyroid hormone (PTH) was significantly increased in HMWTg but was not reduced by FGF23Ab. 1, 25(OH)2 D was inappropriately normal in serum of HMWTg and was significantly increased in both Vector and HMWTg by FGF23Ab. Analysis of HMWTg kidneys revealed significantly increased mRNA expression of the FGF23 co-receptor Klotho, transcription factor mRNAs for early growth response-1 transcription factor (Egr-1), and c-fos were all significantly decreased by FGF23Ab. A significant reduction in the phosphate transporter Npt2a mRNA was also observed in HMWTg kidneys, which was increased by FGF23Ab. FGF23Ab reduced p-FGFR1, p-FGFR3, KLOTHO, p-ERK1/2, C-FOS, and increased NPT2A protein in HMWTg kidneys. We conclude that FGF23 blockade rescued hypophosphatemia by regulating FGF23/FGFR downstream signaling in HMWTg kidneys. Furthermore, HMWFGF2 isoforms regulate PTH expression independent of FGF23/FGFR signaling. J. Cell. Physiol. 232: 610-616, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- E Du
- Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut
| | - L Xiao
- Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut
| | - M M Hurley
- Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut
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30
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Wei K, Yin Z, Xie Y. Roles of the kidney in the formation, remodeling and repair of bone. J Nephrol 2016; 29:349-357. [PMID: 26943181 PMCID: PMC4879154 DOI: 10.1007/s40620-016-0284-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Accepted: 02/05/2016] [Indexed: 12/14/2022]
Abstract
The relationship between the kidney and bone is highly complex, and the kidney plays an important role in the regulation of bone development and metabolism. The kidney is the major organ involved in the regulation of calcium and phosphate homeostasis, which is essential for bone mineralization and development. Many substances synthesized by the kidney, such as 1,25(OH)2D3, Klotho, bone morphogenetic protein-7, and erythropoietin, are involved in different stages of bone formation, remodeling and repair. In addition, some cytokines which can be affected by the kidney, such as osteoprotegerin, sclerostin, fibroblast growth factor -23 and parathyroid hormone, also play important roles in bone metabolism. In this paper, we summarize the possible effects of these kidney-related cytokines on bone and their possible mechanisms. Most of these cytokines can interact with one another, constituting an intricate network between the kidney and bone. Therefore, kidney diseases should be considered among patients presenting with osteodystrophy and disturbances in bone and mineral metabolism, and treatment for renal dysfunction may accelerate their recovery.
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Affiliation(s)
- Kai Wei
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, People's Republic of China.,Medical College, NanKai University, Tianjin, 300071, People's Republic of China
| | - Zhiwei Yin
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, People's Republic of China
| | - Yuansheng Xie
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28 Fuxing Road, Beijing, 100853, People's Republic of China.
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