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1
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Gerber JS, Arroyo EMP, Pastor J, Correia M, Rudloff S, Moe OW, Egli-Spichtig D, Mohebbi N, Wagner CA. Controlled dietary phosphate loading in healthy young men elevates plasma phosphate and FGF23 levels. Pflugers Arch 2025; 477:495-508. [PMID: 39601886 PMCID: PMC11825603 DOI: 10.1007/s00424-024-03046-4] [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: 07/16/2024] [Revised: 11/01/2024] [Accepted: 11/18/2024] [Indexed: 11/29/2024]
Abstract
Increased dietary inorganic phosphate (Pi) intake stimulates renal Pi excretion, in part, by parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23) or dopamine. High dietary Pi may also stimulate sympathetic outflow. Rodent studies provided evidence for these regulatory loops, while controlled experiments in healthy humans examined periods of either a few hours or several weeks, and often varied dietary calcium intake. The effects of controlled, isolated changes in dietary Pi intake over shorter periods are unknown. We studied the effects of a low or high Pi diet on parameters of mineral metabolism in 10 healthy young men. Participants received a standardized diet (1000 mg phosphorus equivalent/day) supplemented with either a phosphate binder (low Pi diet) or phosphate capsules (750 mg phosphorus, high Pi diet) in a randomized cross-over trial for 5 days with a 7-day washout between diets. High Pi intake increased plasma Pi levels and 24-h excretion and decreased urinary calcium excretion. High Pi intake increased intact FGF23 (iFGF23) and suppressed plasma Klotho without affecting cFGF23, PTH, calcidiol, calcitriol, Fetuin-A, dopamine, epinephrine, norepinephrine, metanephrine, or aldosterone. Higher iFGF23 correlated with lower calcitriol and higher PTH. These data support a role for iFGF23 in increasing renal Pi excretion and reducing calcitriol in healthy young men during steady-state high dietary Pi intake. High dietary Pi intake elevated blood Pi levels in healthy young subjects with normal renal function and may therefore be a health risk, as higher serum Pi levels are associated with cardiovascular risk in the general population.
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Affiliation(s)
- Jennifer Scotti Gerber
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
- Division of Nephrology, Ente Ospedaliero Cantonale, Lugano, Switzerland
| | - Eva Maria Pastor Arroyo
- Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland
| | - Johanne Pastor
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Miguel Correia
- Division of Nephrology and Hypertension, University of Bern and University Hospital Bern, Bern, Switzerland
| | - Stefan Rudloff
- Division of Nephrology and Hypertension, University of Bern and University Hospital Bern, Bern, Switzerland
| | - Orson W Moe
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Daniela Egli-Spichtig
- Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland
- National Center of Competence in Research, NCCR Kidney.CH, Zurich, Switzerland
| | - Nilufar Mohebbi
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
- National Center of Competence in Research, NCCR Kidney.CH, Zurich, Switzerland
| | - Carsten A Wagner
- Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
- National Center of Competence in Research, NCCR Kidney.CH, Zurich, Switzerland.
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Simic P, Xie H, Zhang Q, Zhou W, Cherukuru R, Adams MA, Turner ME, Rhee EP. Glycerol-3-phosphate contributes to the increase in FGF23 production in chronic kidney disease. Am J Physiol Renal Physiol 2025; 328:F165-F172. [PMID: 39716914 DOI: 10.1152/ajprenal.00311.2024] [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: 11/07/2024] [Revised: 12/04/2024] [Accepted: 12/18/2024] [Indexed: 12/25/2024] Open
Abstract
Why fibroblast growth factor 23 (FGF23) levels increase markedly in chronic kidney disease (CKD) is unknown. Recently, we found that phosphate stimulates renal production of glycerol-3-phosphate (G-3-P), which circulates to the bone to trigger FGF23 production. To assess the impact of G-3-P on FGF23 production in CKD, we compared the effect of adenine-induced CKD in mice deficient in glycerol-3-phosphate dehydrogenase 1 (Gpd1), an enzyme that synthesizes G-3-P, along with wild-type littermates. We found that an adenine diet causes a similar degree of renal insufficiency across genotypes and that adenine-induced CKD increases blood G-3-P and FGF23 levels in wild-type mice. Furthermore, we found that the increases in both G-3-P and FGF23 are significantly attenuated, but not fully abrogated, in Gpd1-/- compared with Gpd1+/+ mice with CKD. There is no difference in blood phosphate or parathyroid hormone between Gpd1-/- and Gpd1+/+ mice on an adenine diet, but adenine-induced CKD causes greater cortical bone loss in Gpd1-/- mice. In a separate cohort of rats fed an adenine or control diet, we confirmed that CKD causes an increase in blood G-3-P levels. Importantly, an acute phosphate load increases G-3-P production in both CKD and non-CKD rats, with a significant correlation between measured kidney phosphate uptake and blood G-3-P levels. Together, these findings establish a key role for G-3-P in mineral metabolism in CKD, although more work is required to parse the factors that regulate both Gpd1-dependent and Gpd1-independent G-3-P production in this context.NEW & NOTEWORTHY This study shows that glycerol-3-phosphate, a glycolytic by-product recently implicated in a kidney-to-bone signaling axis that regulates FGF23 production, increases in mice and rats with CKD. Furthermore, mice deficient in a key enzyme that synthesizes glycerol-3-phosphate have attenuated increases in both glycerol-3-phosphate and FGF23 in CKD, along with enhanced cortical bone loss. These studies identify glycerol-3-phosphate as a novel regulator of FGF23 and mineral metabolism in CKD.
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Affiliation(s)
- Petra Simic
- Nephrology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States
| | - Han Xie
- Nephrology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States
| | - Qian Zhang
- Nephrology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States
- Division of Nephrology, Department of Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Wen Zhou
- Nephrology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States
| | - Rohan Cherukuru
- Nephrology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States
| | - Michael A Adams
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Mandy E Turner
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Eugene P Rhee
- Nephrology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States
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3
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Yang F, Wu Y, Zhang W. Risk factors for developing osteoporosis in diabetic kidney disease and its correlation with calcium-phosphorus metabolism, FGF23, and Klotho. World J Diabetes 2025; 16:98714. [PMID: 39817221 PMCID: PMC11718466 DOI: 10.4239/wjd.v16.i1.98714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 09/15/2024] [Accepted: 11/05/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND The progression of diabetic kidney disease (DKD) affects the patient's kidney glomeruli and tubules, whose normal functioning is essential for maintaining normal calcium (Ca) and phosphorus (P) metabolism in the body. The risk of developing osteoporosis (OP) in patients with DKD increases with the aggravation of the disease, including a higher risk of fractures, which not only affects the quality of life of patients but also increases the risk of death. AIM To analyze the risk factors for the development of OP in patients with DKD and their correlation with Ca-P metabolic indices, fibroblast growth factor 23 (FGF23), and Klotho. METHODS One hundred and fifty-eight patients with DKD who were admitted into the Wuhu Second People's Hospital from September 2019 to May 2021 were selected and divided into an OP group (n = 103) and a normal bone mass group (n = 55) according to their X-ray bone densitometry results. Baseline data and differences in Ca-P biochemical indices, FGF23, and Klotho were compared. The correlation of Ca-P metabolic indices with FGF23 and Klotho was discussed, and the related factors affecting OP in patients with DKD were examined by multivariate logistic regression analysis. RESULTS The OP group had a higher proportion of females, an older age, and a longer diabetes mellitus duration than the normal group (all P < 0.05). Patients in the OP group exhibited significantly higher levels of intact parathyroid hormone (iPTH), blood P, Ca-P product (Ca × P), fractional excretion of phosphate (FeP), and FGF23, as well as lower estimated glomerular filtration rate, blood Ca, 24-hour urinary phosphate excretion (24-hour UPE), and Klotho levels (all P < 0.05). In the OP group, 25-(OH)-D3, blood Ca, and 24-hour UPE were negatively correlated with FGF23 and positively correlated with Klotho. In contrast, iPTH, blood Ca, Ca × P, and FeP exhibited a positive correlation with FGF23 and an inverse association with Klotho (all P < 0.05). Moreover, 25-(OH)-D3, iPTH, blood Ca, FePO4, FGF23, Klotho, age, and female gender were key factors that affected the lumbar and left femoral neck bone mineral density. CONCLUSION The Ca-P metabolism metabolic indexes, FGF23, and Klotho in patients with DKD are closely related to the occurrence and development of OP.
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Affiliation(s)
- Fan Yang
- Department of Endocrinology, Wuhu Second People's Hospital, Wuhu 241000, Anhui Province, China
| | - Yan Wu
- Department of Nephrology, Wuhu Second People's Hospital, Wuhu 241000, Anhui Province, China
| | - Wei Zhang
- Department of Endocrinology, Wuhu Second People's Hospital, Wuhu 241000, Anhui Province, China
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Deng C, Wu Y. Vitamin D-Parathyroid Hormone-Fibroblast Growth Factor 23 Axis and Cardiac Remodeling. Am J Cardiovasc Drugs 2025; 25:25-36. [PMID: 39392562 DOI: 10.1007/s40256-024-00688-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/26/2024] [Indexed: 10/12/2024]
Abstract
Cardiac remodeling is a compensatory adaptive response to chronic heart failure (HF) altering the structure, function, and metabolism of the heart. Many nutritional and metabolic diseases can aggravate the pathophysiological development of cardiac remodeling. Vitamin D deficiency leads to cardiac remodeling by activating the renin-angiotensin-aldosterone system (RAAS), resulting in enhanced inflammation and directly promoting cardiac fibrosis and extracellular matrix deposition. Hyperparathyroidism upregulates protein kinase A or protein kinase C, enhances intracellular calcium influx, promotes oxidative stress, activates RAAS, and increases aldosterone levels, thereby aggravating cardiac remodeling. Besides, fibroblast growth factor 23 (FGF23) plays a direct role in the heart, resulting in ventricular hypertrophy and myocardial fibrosis. Vitamin D deficiency leads to hyperparathyroidism, which in turn increases the level of FGF23. Elevated levels of FGF23 further inhibit vitamin D synthesis. Evidence exists that vitamin D deficiency, hyperparathyroidism, and marked elevations in FGF23 concentration form a vicious cycle and are believed to contribute directly to cardiac remodeling. Therefore, the purpose of this article is to introduce the specific effects of the above substances on the heart and to explain the significance of understanding the vitamin D-parathyroid hormone-FGF23 axis in improving or even reversing cardiac remodeling, thus contributing to the treatment of patients with HF.
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Affiliation(s)
- Cuiyun Deng
- Special Demand Medical Care Ward, Beijing Anzhen Hospital Jilin Hospital (Changchun Central Hospital), Changchun, China
| | - Yihang Wu
- Interventional Center of Valvular Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
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5
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Feger M, Hammerschmidt K, Liesche I, Rausch S, Alber J, Föller M. Prostaglandin E 2 signaling through prostaglandin E receptor subtype 2 and Nurr1 induces fibroblast growth factor 23 production. Biomed Pharmacother 2024; 180:117475. [PMID: 39332190 DOI: 10.1016/j.biopha.2024.117475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 09/20/2024] [Accepted: 09/20/2024] [Indexed: 09/29/2024] Open
Abstract
Bone cells produce fibroblast growth factor 23 (FGF23), a hormone regulating renal phosphate and vitamin D homeostasis, and a paracrine factor produced in further tissues. Chronic kidney disease and cardiovascular disorders are associated with early elevations of plasma FGF23 levels associated with clinical outcomes. FGF23 production is dependent on many conditions including inflammation. Prostaglandin E2 (PGE2) is a major eicosanoid with a broad role in pain, inflammation, and fever. Moreover, it regulates renal blood flow, renin secretion, natriuresis as well as bone formation through prostaglandin E receptor 2 (EP2). Here, we studied the role of PGE2 and its signaling for the production of FGF23. Osteoblast-like UMR-106 cells were exposed to EP receptor agonists, antagonists or RNAi. Wild type and EP2 knockout mice were treated with stable EP2 agonist misoprostol. Fgf23 or Nurr1 gene expression was determined by quantitative real-time PCR, hormone and further blood parameters by enzyme-linked immunosorbent assay and colorimetric methods. PGE2 and EP2 agonists misoprostol and butaprost enhanced FGF23 production in UMR-106 cells, effects mediated by EP2 and transcription factor Nurr1. A single dose of misoprostol up-regulated bone Fgf23 expression and FGF23 serum levels in wild type mice with subtle effects on parameters of mineral metabolism only. Compared to wild type mice, the FGF23 effect of misoprostol was significantly lower in EP2-deficient mice. To conclude, PGE2 signaling through EP2 and Nurr1 induces FGF23 production. Given the broad physiological and pathophysiological implications of PGE2 signaling, this effect is likely of clinical relevance.
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MESH Headings
- Animals
- Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism
- Nuclear Receptor Subfamily 4, Group A, Member 2/genetics
- Dinoprostone/metabolism
- Fibroblast Growth Factor-23
- Signal Transduction
- Fibroblast Growth Factors/metabolism
- Fibroblast Growth Factors/genetics
- Mice, Knockout
- Receptors, Prostaglandin E, EP2 Subtype/metabolism
- Receptors, Prostaglandin E, EP2 Subtype/genetics
- Receptors, Prostaglandin E, EP2 Subtype/agonists
- Mice
- Osteoblasts/metabolism
- Osteoblasts/drug effects
- Cell Line
- Mice, Inbred C57BL
- Misoprostol/pharmacology
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Affiliation(s)
- Martina Feger
- University of Hohenheim, Department of Physiology, 70599 Stuttgart, Germany
| | | | - Ilona Liesche
- University of Hohenheim, Department of Physiology, 70599 Stuttgart, Germany
| | - Steffen Rausch
- University of Hohenheim, Department of Physiology, 70599 Stuttgart, Germany
| | - Jana Alber
- University of Hohenheim, Department of Physiology, 70599 Stuttgart, Germany
| | - Michael Föller
- University of Hohenheim, Department of Physiology, 70599 Stuttgart, Germany.
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6
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Suzuki K, Soeda K, Komaba H. Crosstalk between kidney and bone: insights from CKD-MBD. J Bone Miner Metab 2024; 42:463-469. [PMID: 39060498 DOI: 10.1007/s00774-024-01528-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 06/17/2024] [Indexed: 07/28/2024]
Abstract
The kidneys play an important role in the regulation of phosphate and calcium balance and serum concentrations, coordinated by fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D (1,25D). In patients with chronic kidney disease (CKD), this regulation is impaired, leading to CKD-mineral and bone disorder (CKD-MBD), characterized by decreased 1,25D, elevated FGF23, secondary hyperparathyroidism, hyperphosphatemia, bone abnormalities, and vascular and soft-tissue calcification. While bone abnormalities associated with CKD-MBD, known as renal osteodystrophy, have been recognized as the most typical interaction between the kidney and bone, a number of other kidney-bone interactions have been identified, for which our knowledge of the pathogenesis of CKD-MBD has played an important role. This article summarizes recent findings on CKD-MBD and explores the crosstalk between the kidney and bone from the perspective of CKD-MBD.
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Affiliation(s)
- Kodai Suzuki
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, 143 Shimokasuya, Isehara, 259-1193, Japan
- Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Keisuke Soeda
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, 143 Shimokasuya, Isehara, 259-1193, Japan
| | - Hirotaka Komaba
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, 143 Shimokasuya, Isehara, 259-1193, Japan.
- The Institute of Medical Sciences, Tokai University, Isehara, Japan.
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7
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Walker V. The Intricacies of Renal Phosphate Reabsorption-An Overview. Int J Mol Sci 2024; 25:4684. [PMID: 38731904 PMCID: PMC11083860 DOI: 10.3390/ijms25094684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 04/17/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024] Open
Abstract
To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This amazing feat is accomplished through synchronised phosphate transport by myriads of ciliated cells lining the renal proximal tubules. These respond in real time to changes in phosphate and composition of the renal filtrate and to hormonal instructions. How they do this has stimulated decades of research. New analytical techniques, coupled with incredible advances in computer technology, have opened new avenues for investigation at a sub-cellular level. There has been a surge of research into different aspects of the process. These have verified long-held beliefs and are also dramatically extending our vision of the intense, integrated, intracellular activity which mediates phosphate absorption. Already, some have indicated new approaches for pharmacological intervention to regulate phosphate in common conditions, including chronic renal failure and osteoporosis, as well as rare inherited biochemical disorders. It is a rapidly evolving field. The aim here is to provide an overview of our current knowledge, to show where it is leading, and where there are uncertainties. Hopefully, this will raise questions and stimulate new ideas for further research.
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Affiliation(s)
- Valerie Walker
- Department of Clinical Biochemistry, University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton S016 6YD, UK
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8
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Ay B, Cyr SM, Klovdahl K, Zhou W, Tognoni CM, Iwasaki Y, Rhee EP, Dedeoglu A, Simic P, Bastepe M. Gα11 deficiency increases fibroblast growth factor 23 levels in a mouse model of familial hypocalciuric hypercalcemia. JCI Insight 2024; 9:e178993. [PMID: 38530370 PMCID: PMC11141917 DOI: 10.1172/jci.insight.178993] [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: 01/03/2024] [Accepted: 03/14/2024] [Indexed: 03/28/2024] Open
Abstract
Fibroblast growth factor 23 (FGF23) production has recently been shown to increase downstream of Gαq/11-PKC signaling in osteocytes. Inactivating mutations in the gene encoding Gα11 (GNA11) cause familial hypocalciuric hypercalcemia (FHH) due to impaired calcium-sensing receptor signaling. We explored the effect of Gα11 deficiency on FGF23 production in mice with heterozygous (Gna11+/-) or homozygous (Gna11-/-) ablation of Gna11. Both Gna11+/- and Gna11-/- mice demonstrated hypercalcemia and mildly raised parathyroid hormone levels, consistent with FHH. Strikingly, these mice also displayed increased serum levels of total and intact FGF23 and hypophosphatemia. Gna11-/- mice showed augmented Fgf23 mRNA levels in the liver and heart, but not in bone or bone marrow, and also showed evidence of systemic inflammation with elevated serum IL-1β levels. Furin gene expression was significantly increased in the Gna11-/- liver, suggesting enhanced FGF23 cleavage despite the observed rise in circulating intact FGF23 levels. Gna11-/- mice had normal renal function and reduced serum levels of glycerol-3-phosphate, excluding kidney injury as the primary cause of elevated intact FGF23 levels. Thus, Gα11 ablation caused systemic inflammation and excess serum FGF23 in mice, suggesting that patients with FHH - at least those with GNA11 mutations - may be at risk for these complications.
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Affiliation(s)
- Birol Ay
- Endocrine Unit, Department of Medicine, and
| | | | | | - Wen Zhou
- Endocrine Unit, Department of Medicine, and
- Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Christina M. Tognoni
- Department of Veterans Affairs, VA Boston Healthcare System, Boston, Massachusetts, USA
- Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA
| | | | - Eugene P Rhee
- Endocrine Unit, Department of Medicine, and
- Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Alpaslan Dedeoglu
- Department of Veterans Affairs, VA Boston Healthcare System, Boston, Massachusetts, USA
- Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Massachusetts, USA
| | - Petra Simic
- Endocrine Unit, Department of Medicine, and
- Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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9
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Feger M, Alber J, Strotmann J, Grund A, Leifheit-Nestler M, Haffner D, Föller M. Short-term fasting of mice elevates circulating fibroblast growth factor 23 (FGF23). Acta Physiol (Oxf) 2023; 239:e14049. [PMID: 37746883 DOI: 10.1111/apha.14049] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 08/24/2023] [Accepted: 09/04/2023] [Indexed: 09/26/2023]
Abstract
AIMS Phosphate and vitamin D homeostasis are controlled by fibroblast growth factor 23 (FGF23) from bone suppressing renal phosphate transport and enhancing 24-hydroxylase (Cyp24a1), thereby inactivating 1,25(OH)2 D3 . Serum FGF23 is correlated with outcomes in several diseases. Fasting stimulates the production of ketone bodies. We hypothesized that fasting can induce FGF23 synthesis through the production of ketone bodies. METHODS UMR106 cells and isolated neonatal rat ventricular myocytes (NRVM) were treated with ketone body β-hydroxybutyrate. Mice were fasted overnight, fed ad libitum, or treated with β-hydroxybutyrate. Proteins and further blood parameters were determined by enzyme-linked immunoassay (ELISA), western blotting, immunohistochemistry, fluorometric or colorimetric methods, and gene expression by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS β-Hydroxybutyrate stimulated FGF23 production in UMR106 cells in a nuclear factor kappa-light-chain enhancer of activated B-cells (NFκB)-dependent manner, and in NRVMs. Compared to fed animals, fasted mice exhibited higher β-hydroxybutyrate and FGF23 serum levels (based on assays either detecting C-terminal or intact, biologically active FGF23 only), cardiac, pancreatic, and thymic Fgf23 and renal Cyp24a1 expression, and lower 1,25(OH)2 D3 serum concentration as well as renal Slc34a1 and αKlotho (Kl) expression. In contrast, Fgf23 expression in bone and serum phosphate, calcium, plasma parathyroid hormone (PTH) concentration, and renal Cyp27b1 expression were not significantly affected by fasting. CONCLUSION Short-term fasting increased FGF23 production, as did administration of β-hydroxybutyrate, effects possibly of clinical relevance in view of the increasing use of FGF23 as a surrogate parameter in clinical monitoring of diseases. The fasting state of patients might therefore affect FGF23 tests.
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Affiliation(s)
- Martina Feger
- Department of Physiology, University of Hohenheim, Stuttgart, Germany
| | - Jana Alber
- Department of Physiology, University of Hohenheim, Stuttgart, Germany
| | - Jörg Strotmann
- Department of Physiology, University of Hohenheim, Stuttgart, Germany
| | - Andrea Grund
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Pediatric Research Center, Hannover Medical School, Hannover, Germany
| | - Maren Leifheit-Nestler
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Pediatric Research Center, Hannover Medical School, Hannover, Germany
| | - Dieter Haffner
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Pediatric Research Center, Hannover Medical School, Hannover, Germany
| | - Michael Föller
- Department of Physiology, University of Hohenheim, Stuttgart, Germany
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10
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Egli-Spichtig D, Hamid AK, Arroyo EMP, Ketteler M, Wiecek A, Rosenkranz AR, Pasch A, Lorenz H, Hellmann B, Karus M, Ammer R, Rubio-Aliaga I, Wagner CA. Intact FGF23 predicts serum phosphate improvement after combined nicotinamide and phosphate binder treatment in hemodialysis patients. Clin Kidney J 2023; 16:1622-1633. [PMID: 37779856 PMCID: PMC10539220 DOI: 10.1093/ckj/sfad040] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Indexed: 10/03/2023] Open
Abstract
Background Hyperphosphatemia is associated with increased mortality and cardiovascular morbidity of end-stage kidney failure (ESKF) patients. Managing serum phosphate in ESKF patients is challenging and mostly based on limiting intestinal phosphate absorption with low phosphate diets and phosphate binders (PB). In a multi-centric, double-blinded, placebo-controlled study cohort of maintenance hemodialysis patients with hyperphosphatemia, we demonstrated the efficacy of nicotinamide modified release (NAMR) formulation treatment in addition to standard PB therapy in decreasing serum phosphate. Here we aimed to assess the relationship between phosphate, FGF23, inflammation and iron metabolism in this cohort. Methods We measured the plasma concentrations of intact fibroblast growth factor 23 (iFGF23) and selected proinflammatory cytokines at baseline and Week 12 after initiating treatment. Results We observed a strong correlation between iFGF23 and cFGF23 (C-terminal fragment plus iFGF23). We identified iFGF23 as a better predictor of changes in serum phosphate induced by NAMR and PB treatment compared with cFGF23. Recursive partitioning revealed at baseline and Week 12, that iFGF23 and cFGF23 together with T50 propensity were the most important predictors of serum phosphate, whereas intact parathyroid hormone (iPTH) played a minor role in this model. Furthermore, we found serum phosphate and iPTH as the best predictors of iFGF23 and cFGF23. Sex, age, body mass index, and markers of inflammation and iron metabolism had only a minor impact in predicting FGF23. Conclusion Lowering serum phosphate in ESKF patients may depend highly on iFGF23 which is correlated to cFGF23 levels. Serum phosphate was the most important predictor of plasma FGF23 in this ESKF cohort.
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Affiliation(s)
- Daniela Egli-Spichtig
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland, and National Center of Competence in Research NCCR Kidney.CH
| | - Ahmad Kamal Hamid
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland, and National Center of Competence in Research NCCR Kidney.CH
| | - Eva Maria Pastor Arroyo
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland, and National Center of Competence in Research NCCR Kidney.CH
| | - Markus Ketteler
- Robert Bosch Hospital, Department of General Internal Medicine and Nephrology, Stuttgart, Germany
| | - Andrzej Wiecek
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland
| | - Alexander R Rosenkranz
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Andreas Pasch
- Calciscon AG, 2503 Biel, Switzerland
- Department of Nephrology, Lindenhofspital, 3012 Bern, Switzerland
- Department of Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria
| | - Horst Lorenz
- Buero fuer Biometrie und Statistik, Neuberg, Germany
| | | | - Michael Karus
- MEDICE Arzneimittel Pütter GmbH & Co KG, Iserlohn, Germany
| | - Richard Ammer
- MEDICE Arzneimittel Pütter GmbH & Co KG, Iserlohn, Germany
- Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Münster, Münster, Germany
| | - Isabel Rubio-Aliaga
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland, and National Center of Competence in Research NCCR Kidney.CH
| | - Carsten A Wagner
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland, and National Center of Competence in Research NCCR Kidney.CH
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11
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Li X, Lozovatsky L, Tommasini SM, Fretz J, Finberg KE. Bone marrow sinusoidal endothelial cells are a site of Fgf23 upregulation in a mouse model of iron deficiency anemia. Blood Adv 2023; 7:5156-5171. [PMID: 37417950 PMCID: PMC10480544 DOI: 10.1182/bloodadvances.2022009524] [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: 12/12/2022] [Revised: 06/16/2023] [Accepted: 07/05/2023] [Indexed: 07/08/2023] Open
Abstract
Iron deficiency is a potent stimulator of fibroblast growth factor 23 (FGF23), a hormonal regulator of phosphate and vitamin D metabolism, that is classically thought to be produced by bone-embedded osteocytes. Here, we show that iron-deficient transmembrane serine protease 6 knockout (Tmprss6-/-) mice exhibit elevated circulating FGF23 and Fgf23 messenger RNA (mRNA) upregulation in the bone marrow (BM) but not the cortical bone. To clarify sites of Fgf23 promoter activity in Tmprss6-/- mice, we introduced a heterozygous enhanced green fluorescent protein (eGFP) reporter allele at the endogenous Fgf23 locus. Heterozygous Fgf23 disruption did not alter the severity of systemic iron deficiency or anemia in the Tmprss6-/- mice. Tmprss6-/-Fgf23+/eGFP mice showed green fluorescence in the vascular regions of BM sections and showed a subset of BM endothelial cells that were GFPbright by flow cytometry. Mining of transcriptomic data sets from mice with normal iron balance revealed higher Fgf23 mRNA in BM sinusoidal endothelial cells (BM-SECs) than that in other BM endothelial cell populations. Anti-GFP immunohistochemistry of fixed BM sections from Tmprss6-/-Fgf23+/eGFP mice revealed GFP expression in BM-SECs, which was more intense than in nonanemic controls. In addition, in mice with intact Tmprss6 alleles, Fgf23-eGFP reporter expression increased in BM-SECs following large-volume phlebotomy and also following erythropoietin treatment both ex vivo and in vivo. Collectively, our results identified BM-SECs as a novel site for Fgf23 upregulation in both acute and chronic anemia. Given the elevated serum erythropoietin in both anemic models, our findings raise the possibility that erythropoietin may act directly on BM-SECs to promote FGF23 production during anemia.
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Affiliation(s)
- Xiuqi Li
- Department of Pathology, Yale School of Medicine, New Haven, CT
| | | | - Steven M. Tommasini
- Department of Orthopaedics & Rehabilitation, Yale School of Medicine, New Haven, CT
| | - Jackie Fretz
- Department of Orthopaedics & Rehabilitation, Yale School of Medicine, New Haven, CT
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12
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Fan Y, Kim HJ, Jung YS, Na SY, Radhakrishnan K, Choi HS. Chenodeoxycholic acid regulates fibroblast growth factor 23 gene expression via estrogen-related receptor γ in human hepatoma Huh7 cells. Steroids 2023; 197:109257. [DOI: https:/doi.org/10.1016/j.steroids.2023.109257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/18/2023]
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13
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Liu D, Yang F, Zhang S, Guo Z, Peng S. Significance of changes in FGF23 levels in childhood primary nephrotic syndrome and children who progress to end‑stage renal disease. Exp Ther Med 2023; 26:390. [PMID: 37456167 PMCID: PMC10347369 DOI: 10.3892/etm.2023.12089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 06/01/2023] [Indexed: 07/18/2023] Open
Abstract
Fibroblast growth factor 23 (FGF23) is an important phosphaturic hormone, yet few studies have focused on FGF23 in children with primary nephrotic syndrome (PNS) and children who progressed to end-stage renal disease (ESRD). This cross-sectional study investigated the significance of changes in FGF23 levels in childhood PNS and children who progressed to ESRD. Of the 41 children included in the study, 17 had PNS with proteinuria and normal renal function (PNS group), 4 had ESRD (ESRD group), and 20 were healthy (control group). Following corticosteroid treatment, patients with PNS and proteinuria entered the remission phase. Serum levels of FGF23, phosphate, parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OH-D), and calcium were measured. It was found that FGF23 levels in the PNS and ESRD groups were higher than those in the control group, while serum 25-OH-D levels were lower. Serum PTH levels increased significantly in the ESRD group. In the control group, FGF23 levels were negatively correlated with serum PTH and positively correlated with serum 25-OH-D. FGF23 levels were positively correlated with serum calcium and corrected calcium levels in children with PNS during the remission phase. Increased FGF23 levels in children with PNS, particularly in children who progressed to ESRD. It was also confirmed that serum FGF23 levels begin to rise in children with PNS prior to Stage 1 chronic kidney disease. These findings indicated that increased FGF23 levels may be associated with the progression and severity of nephrosis in children, and that serum FGF23 levels were useful for early detection of abnormal mineral metabolism in children with PNS.
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Affiliation(s)
- Ding Liu
- Department of Pediatrics, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Fang Yang
- Department of Pediatrics, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Sui Zhang
- Department of Pediatrics, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Zhiqiang Guo
- Department of Pediatrics, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Shuting Peng
- Department of Pediatrics, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
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14
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Clinkenbeard E. Fibroblast Growth Factor 23 Bone Regulation and Downstream Hormonal Activity. Calcif Tissue Int 2023; 113:4-20. [PMID: 37306735 DOI: 10.1007/s00223-023-01092-1] [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: 03/05/2023] [Accepted: 05/01/2023] [Indexed: 06/13/2023]
Abstract
Mineral homeostasis of calcium and phosphate levels is one critical component to the maintenance of bone mineral density (BMD) and strength. Diseases that disrupt calcium and phosphate balanced have highlighted not only the role these minerals play in overall bone homeostasis, but also the factors, hormones and downstream transporters, responsible for mineral metabolism. The key phosphaturic hormone elucidated from studying rare heritable disorders of hypophosphatemia is Fibroblast Growth Factor 23 (FGF23). FGF23 is predominantly secreted from bone cells in an effort to maintain phosphate balance by directly controlling renal reabsorption and indirectly affecting intestinal uptake of this mineral. Multiple factors have been shown to enhance bone mRNA expression; however, FGF23 can also undergo proteolytic cleavage to control secretion of the biologically active form of the hormone. The review focuses specifically on the regulation of FGF23 and its secretion from bone as well as its hormonal actions under physiological and disease conditions.
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Affiliation(s)
- Erica Clinkenbeard
- Department of Medical and Molecular Genetics, School of Medicine, Indiana University, 635 Barnhill Drive MS 5023, Indianapolis, IN, 46202, USA.
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15
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Pike JW, Lee SM, Meyer MB. Molecular insights into mineralotropic hormone inter-regulation. Front Endocrinol (Lausanne) 2023; 14:1213361. [PMID: 37441497 PMCID: PMC10334211 DOI: 10.3389/fendo.2023.1213361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 06/13/2023] [Indexed: 07/15/2023] Open
Abstract
The regulation of mineral homeostasis involves the three mineralotropic hormones PTH, FGF23 and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Early research efforts focused on PTH and 1,25(OH)2D3 and more recently on FGF23 have revealed that each of these hormones regulates the expression of the other two. Despite early suggestions of transcriptional processes, it has been only recently that research effort have begun to delineate the genomic mechanisms underpinning this regulation for 1,25(OH)2D3 and FGF23; the regulation of PTH by 1,25(OH)2D3, however, remains obscure. We review here our molecular understanding of how PTH induces Cyp27b1 expression, the gene encoding the enzyme responsible for the synthesis of 1,25(OH)2D3. FGF23 and 1,25(OH)2D3, on the other hand, function by suppressing production of 1,25(OH)2D3. PTH stimulates the PKA-induced recruitment of CREB and its coactivator CBP at CREB occupied sites within the kidney-specific regulatory regions of Cyp27b1. PKA activation also promotes the nuclear translocation of SIK bound coactivators such as CRTC2, where it similarly interacts with CREB occupied Cyp27b1 sites. The negative actions of both FGF23 and 1,25(OH)2D3 appear to suppress Cyp27b1 expression by opposing the recruitment of CREB coactivators at this gene. Reciprocal gene actions are seen at Cyp24a1, the gene encoding the enzyme that degrades 1,25(OH)2D3, thereby contributing to the overall regulation of blood levels of 1,25(OH)2D3. Relative to PTH regulation, we summarize what is known of how 1,25(OH)2D3 regulates PTH suppression. These studies suggest that it is not 1,25(OH)2D3 that controls PTH levels in healthy subjects, but rather calcium itself. Finally, we describe current progress using an in vivo approach that furthers our understanding of the regulation of Fgf23 expression by PTH and 1,25(OH)2D3 and provide the first evidence that P may act to induce Fgf23 expression via a complex transcriptional mechanism in bone. It is clear, however, that additional advances will need to be made to further our understanding of the inter-regulation of each of these hormonal genes.
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Affiliation(s)
- J. Wesley Pike
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, United States
| | - Seong Min Lee
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Mark B. Meyer
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, United States
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16
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Fan Y, Kim HJ, Seok Jung Y, Na SY, Radhakrishnan K, Sik Choi H. Chenodeoxycholic acid regulates fibroblast growth factor 23 gene expression via estrogen-related receptor γ in human hepatoma Huh7 cells. Steroids 2023:109257. [PMID: 37301529 DOI: 10.1016/j.steroids.2023.109257] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/31/2023] [Accepted: 06/04/2023] [Indexed: 06/12/2023]
Abstract
Fibroblast growth factor 23 (FGF23) is a glycoprotein that belongs to the FGF19 subfamily and participates in phosphate and vitamin D homeostasis. Chenodeoxycholic acid (CDCA), one of the primary bile acids, is reported to induce the secretion of FGF19 subfamily members, FGF21 and FGF19, in hepatocytes. However, whether and how CDCA influences FGF23 gene expression are largely unknown. Thus, we performed real-time polymerase chain reaction and Western blot analyses to determine the mRNA and protein expression levels of FGF23 in Huh7 cells. CDCA upregulated estrogen-related receptor γ (ERRγ) alongside FGF23 mRNA and protein levels, while, the knockdown of ERRγ ablated the induction effect of CDCA on FGF23 expression. Promoter studies showed that CDCA-induced FGF23 promoter activity occurred partly through ERRγ binding directly to the ERR response element (ERRE) in the human FGF23 gene promoter. Finally, the inverse agonist of ERRγ, GSK5182 inhibited the induction of FGF23 by CDCA. Overall, our results revealed the mechanism of CDCA-mediated FGF23 gene upregulation in the human hepatoma cell line. Moreover, the ability of GSK5182 to reduce CDCA-induced FGF23 gene expression might represent a therapeutic strategy to control abnormal FGF23 induction in conditions that involve elevated levels of bile acids, such as nonalcoholic fatty liver disease and biliary atresia.
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Affiliation(s)
- Yiwen Fan
- School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Hyo-Jin Kim
- School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Yoon Seok Jung
- School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Soon-Young Na
- School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Kamalakannan Radhakrishnan
- School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Hueng Sik Choi
- School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea.
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17
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Wang M, Zhang J, Kalantar-Zadeh K, Chen J. Focusing on Phosphorus Loads: From Healthy People to Chronic Kidney Disease. Nutrients 2023; 15:nu15051236. [PMID: 36904234 PMCID: PMC10004810 DOI: 10.3390/nu15051236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 02/25/2023] [Accepted: 02/27/2023] [Indexed: 03/05/2023] Open
Abstract
Phosphorus is an essential micromineral with a key role in cellular metabolism and tissue structure. Serum phosphorus is maintained in a homeostatic range by the intestines, bones, and kidneys. This process is coordinated by the endocrine system through the highly integrated actions of several hormones, including FGF23, PTH, Klotho, and 1,25D. The excretion kinetics of the kidney after diet phosphorus load or the serum phosphorus kinetics during hemodialysis support that there is a "pool" for temporary phosphorus storage, leading to the maintenance of stable serum phosphorus levels. Phosphorus overload refers to a state where the phosphorus load is higher than is physiologically necessary. It can be caused by a persistently high-phosphorus diet, renal function decline, bone disease, insufficient dialysis, and inappropriate medications, and includes but is not limited to hyperphosphatemia. Serum phosphorus is still the most commonly used indicator of phosphorus overload. Trending phosphorus levels to see if they are chronically elevated is recommended instead of a single test when judging phosphorus overload. Future studies are needed to validate the prognostic role of a new marker or markers of phosphorus overload.
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Affiliation(s)
- Mengjing Wang
- Nephrology, Huashan Hospital, Fudan University, Shanghai 200040, China
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Jiaying Zhang
- Nutritional Department, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Kamyar Kalantar-Zadeh
- Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of California Irvine Medical Center, Orange, CA 92868, USA
- Fielding School of Public Health at UCLA, Los Angeles, CA 90095, USA
- Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA 90502, USA
| | - Jing Chen
- Nephrology, Huashan Hospital, Fudan University, Shanghai 200040, China
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
- Correspondence: ; Tel.: +86-021-52889387
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18
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Heijboer AC, Cavalier E. The Measurement and Interpretation of Fibroblast Growth Factor 23 (FGF23) Concentrations. Calcif Tissue Int 2023; 112:258-270. [PMID: 35665817 PMCID: PMC9859838 DOI: 10.1007/s00223-022-00987-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 05/06/2022] [Indexed: 02/05/2023]
Abstract
Two decades after the discovery of the hormone FGF23, we know more about phosphate homeostasis as it turned out that FGF23 is the central hormone that regulates this. Hereditary hypophosphatemic rickets and tumor-induced osteomalacia could by then be explained, by autonomous FGF23 production, and the nephrology field was excited by this new marker as it turned out to be independently associated with mortality in people treated by hemodialysis. This led to the development of several immunoassays to be able to measure FGF23 in blood. In the past years we learned that FGF23 is a rather stable peptide, the precision of the assays is acceptable but assays are not standardized and therefore not comparable. This means that reference values and cutoff values need to be assay specific. For several assays reference values have been established and gender and age did not seem of high importance. The phosphate content of the diet, which can be culturally dependent, however, should be taken into account when interpreting results, but to what extent is not totally clear. Currently, clinical application of the immunoassays is established in the diagnosis of hereditary hypophosphatemic rickets and diagnosis and follow-up of tumor-induced osteomalacia. Definite conclusions on the usefulness of the FGF23 measurement in people with CKD either as a marker for risk prediction or a as target for treatment remains to be determined. The latter applications would require dedicated prospective clinical trials, which may take years, before providing answers. To improve the standardization of the FGF23 assays and to shed light on the biological functions that fragments might have we might aim for an LC-MS/MS-based method to quantify both intact and fragmented FGF23. In this literature review we will summarize the current knowledge on the physiological role of FGF23, its quantification, and the clinical usefulness of its determination.
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Affiliation(s)
- Annemieke C Heijboer
- Endocrine Laboratory, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology & Metabolism, Amsterdam UMC, Vrije Universiteit Amsterdam and University of Amsterdam, de Boelelaan 1117 and Meibergdreef 9, Amsterdam, The Netherlands.
| | - Etienne Cavalier
- Department of Clinical Chemistry, CHU de Liège, University of Liège, 4000, Liège, Belgium
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19
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Abstract
Fibroblast growth factor-23 (FGF23) controls the homeostasis of both phosphate and vitamin D. Bone-derived FGF23 can suppress the transcription of 1α-hydroxylase (1α(OH)ase) to reduce renal activation of vitamin D (1,25(OH)2D3). FGF23 can also activate the transcription of 24-hydroxylase to enhance the renal degradation process of vitamin D. There is a counter-regulation for FGF23 and vitamin D; 1,25(OH)2D3 induces the skeletal synthesis and the release of FGF23, while FGF23 can suppress the production of 1,25(OH)2D3 by inhibiting 1α(OH)ase synthesis. Genetically ablating FGF23 activities in mice resulted in higher levels of renal 1α(OH)ase, which is also reflected in an increased level of serum 1,25(OH)2D3, while genetically ablating 1α(OH)ase activities in mice reduced the serum levels of FGF23. Similar feedback control of FGF23 and vitamin D is also detected in various human diseases. Further studies are required to understand the subcellular molecular regulation of FGF23 and vitamin D in health and disease.
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Affiliation(s)
- Mohammed S Razzaque
- Department of Pathology, Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania, USA
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20
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Cianciolo G, Tondolo F, Barbuto S, Angelini A, Ferrara F, Iacovella F, Raimondi C, La Manna G, Serra C, De Molo C, Cavicchi O, Piccin O, D'Alessio P, De Pasquale L, Felisati G, Ciceri P, Galassi A, Cozzolino M. A roadmap to parathyroidectomy for kidney transplant candidates. Clin Kidney J 2022; 15:1459-1474. [PMID: 35892022 PMCID: PMC9308095 DOI: 10.1093/ckj/sfac050] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Indexed: 11/25/2022] Open
Abstract
Chronic kidney disease mineral and bone disorder may persist after successful kidney transplantation. Persistent hyperparathyroidism has been identified in up to 80% of patients throughout the first year after kidney transplantation. International guidelines lack strict recommendations about the management of persistent hyperparathyroidism. However, it is associated with adverse graft and patient outcomes, including higher fracture risk and an increased risk of all-cause mortality and allograft loss. Secondary hyperparathyroidism may be treated medically (vitamin D, phosphate binders and calcimimetics) or surgically (parathyroidectomy). Guideline recommendations suggest medical therapy first but do not clarify optimal parathyroid hormone targets or indications and timing of parathyroidectomy. There are no clear guidelines or long-term studies about the impact of hyperparathyroidism therapy. Parathyroidectomy is more effective than medical treatment, although it is associated with increased short-term risks. Ideally parathyroidectomy should be performed before kidney transplantation to prevent persistent hyperparathyroidism and improve graft outcomes. We now propose a roadmap for the management of secondary hyperparathyroidism in patients eligible for kidney transplantation that includes the indications and timing (pre- or post-kidney transplantation) of parathyroidectomy, the evaluation of parathyroid gland size and the integration of parathyroid gland size in the decision-making process by a multidisciplinary team of nephrologists, radiologists and surgeons.
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Affiliation(s)
- Giuseppe Cianciolo
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Italy
| | - Francesco Tondolo
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Italy
| | - Simona Barbuto
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Italy
| | - Andrea Angelini
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Italy
| | - Francesca Ferrara
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Italy
| | - Francesca Iacovella
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Italy
| | - Concettina Raimondi
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Italy
| | - Gaetano La Manna
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Italy
| | - Carla Serra
- Interventional, Diagnostic and Therapeutic Ultrasound Unit, Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria Sant’Orsola Malpighi Hospital, Bologna, Italy
| | - Chiara De Molo
- Interventional, Diagnostic and Therapeutic Ultrasound Unit, Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria Sant’Orsola Malpighi Hospital, Bologna, Italy
| | - Ottavio Cavicchi
- Department of Otolaryngology Head and Neck Surgery, IRCSS Azienda Ospedaliero Universitaria di Bologna, Policlinico Sant'Orsola, Bologna, Italy
| | - Ottavio Piccin
- Department of Otolaryngology Head and Neck Surgery, IRCSS Azienda Ospedaliero Universitaria di Bologna, Policlinico Sant'Orsola, Bologna, Italy
| | - Pasquale D'Alessio
- Department of Otolaryngology Head and Neck Surgery, IRCSS Azienda Ospedaliero Universitaria di Bologna, Policlinico Sant'Orsola, Bologna, Italy
| | - Loredana De Pasquale
- Department of Otolaryngology, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy
| | - Giovanni Felisati
- Department of Otolaryngology, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy
| | - Paola Ciceri
- Renal Division, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy
| | - Andrea Galassi
- Renal Division, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy
| | - Mario Cozzolino
- Renal Division, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy
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Gronskaia SA, Belaya ZE, Melnichenko GA. [FGF23 tumor induced osteomalacia]. PROBLEMY ENDOKRINOLOGII 2022; 68:56-66. [PMID: 36337019 DOI: 10.14341/probl13130] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/11/2022] [Accepted: 07/11/2022] [Indexed: 11/09/2022]
Abstract
Tumor induced osteomalacia is a rare acquired disease. The cause is a mesenchymal tumor secreting fibroblast growth factor 23 (FGF23). An excessive amount of FGF 23 disrupts the metabolism of phosphorus and vitamin D, which leads to severe paraneoplastic syndrome, manifested in the form of multiple fractures, severe pain in the bones and generalized myopathy. With oncogenic osteomalacia, a complete cure is possible with radical resection of the tumor. Unfortunately, localization, small size of formations and rare frequency of occurrence lead to the fact that the disease remains unrecognized for a long time and leads to severe, disabling consequences. A step-by-step approach to diagnosis improves treatment outcomes. First, a thorough anamnesis is collected, then functional visualization is performed and the diagnosis is confirmed by anatomical visualization of the tumor. After that, the method of choice is a surgical treatment. If resection is not possible, then conservative therapy with active metabolites of vitamin D and phosphorus salts is indicated. New therapeutic approaches, such as the antibody to FGF23 or the pan-inhibitor of receptors to FGF, are actively developing. This article provides an overview of modern approaches to the diagnosis and treatment of this disease.
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22
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Okada M, Tominaga Y, Sato T, Tomosugi T, Futamura K, Hiramitsu T, Ichimori T, Goto N, Narumi S, Kobayashi T, Uchida K, Watarai Y. Elevated parathyroid hormone one year after kidney transplantation is an independent risk factor for graft loss even without hypercalcemia. BMC Nephrol 2022; 23:212. [PMID: 35710357 PMCID: PMC9205154 DOI: 10.1186/s12882-022-02840-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 06/06/2022] [Indexed: 12/02/2022] Open
Abstract
Background Hypercalcemic hyperparathyroidism has been associated with poor outcomes after kidney transplantation (KTx). However, the clinical implications of normocalcemic hyperparathyroidism after KTx are unclear. This retrospective cohort study attempted to identify these implications. Methods Normocalcemic recipients who underwent KTx between 2000 and 2016 without a history of parathyroidectomy were included in the study. Those who lost their graft within 1 year posttransplant were excluded. Normocalcemia was defined as total serum calcium levels of 8.5–10.5 mg/dL, while hyperparathyroidism was defined as when intact parathyroid hormone levels exceeded 80 pg/mL. The patients were divided into two groups based on the presence of hyperparathyroidism 1 year after KTx. The primary outcome was the risk of graft loss. Results Among the 892 consecutive patients, 493 did not have hyperparathyroidism (HPT-free group), and 399 had normocalcemic hyperparathyroidism (NC-HPT group). Ninety-five patients lost their grafts. Death-censored graft survival after KTx was significantly lower in the NC-HPT group than in the HPT-free group (96.7% vs. 99.6% after 5 years, respectively, P < 0.001). Cox hazard analysis revealed that normocalcemic hyperparathyroidism was an independent risk factor for graft loss (P = 0.002; hazard ratio, 1.94; 95% confidence interval, 1.27–2.98). Conclusions Normocalcemic hyperparathyroidism 1 year after KTx was an independent risk factor for death-censored graft loss. Early intervention of elevated parathyroid hormone levels may lead to better graft outcomes, even without overt hypercalcemia. Supplementary Information The online version contains supplementary material available at 10.1186/s12882-022-02840-5.
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Affiliation(s)
- Manabu Okada
- Department of Transplant and Endocrine Surgery, Japanese Red Cross Nagoya Daini Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya, Aichi, 4668650, Japan.
| | - Yoshihiro Tominaga
- Department of Transplant and Endocrine Surgery, Japanese Red Cross Nagoya Daini Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya, Aichi, 4668650, Japan
| | - Tetsuhiko Sato
- Department of Diabetes and Endocrinology, Japanese Red Cross Nagoya Daini Hospital, Showa-ku, Nagoya, Aichi, Japan
| | - Toshihide Tomosugi
- Department of Transplant and Endocrine Surgery, Japanese Red Cross Nagoya Daini Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya, Aichi, 4668650, Japan
| | - Kenta Futamura
- Department of Transplant and Endocrine Surgery, Japanese Red Cross Nagoya Daini Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya, Aichi, 4668650, Japan
| | - Takahisa Hiramitsu
- Department of Transplant and Endocrine Surgery, Japanese Red Cross Nagoya Daini Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya, Aichi, 4668650, Japan
| | - Toshihiro Ichimori
- Department of Transplant and Endocrine Surgery, Japanese Red Cross Nagoya Daini Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya, Aichi, 4668650, Japan
| | - Norihiko Goto
- Department of Transplant and Endocrine Surgery, Japanese Red Cross Nagoya Daini Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya, Aichi, 4668650, Japan
| | - Shunji Narumi
- Department of Transplant and Endocrine Surgery, Japanese Red Cross Nagoya Daini Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya, Aichi, 4668650, Japan
| | - Takaaki Kobayashi
- Department of Renal Transplant Surgery, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
| | - Kazuharu Uchida
- Department of Renal Transplant Surgery, Masuko Memorial Hospital, Nakamura-ku, Nagoya, Aichi, Japan
| | - Yoshihiko Watarai
- Department of Transplant and Endocrine Surgery, Japanese Red Cross Nagoya Daini Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya, Aichi, 4668650, Japan
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Tsuboi Y, Ichida Y, Murai A, Maeda A, Iida M, Kato A, Ohtomo S, Horiba N. EOS789, pan-phosphate transporter inhibitor, ameliorates the progression of kidney injury in anti-GBM-induced glomerulonephritis rats. Pharmacol Res Perspect 2022; 10:e00973. [PMID: 35621227 PMCID: PMC9137114 DOI: 10.1002/prp2.973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 05/09/2022] [Indexed: 11/08/2022] Open
Abstract
Hyperphosphatemia associated with chronic kidney disease (CKD) not only dysregulates mineral metabolism and bone diseases, but also strongly contributes to the progression of kidney disease itself. We have identified a novel drug for hyperphosphatemia, EOS789, that interacts with several sodium-dependent phosphate transporters (NaPi-IIb, PiT-1, and PiT-2) known to contribute to intestinal phosphate absorption. In this study, we investigated whether EOS789 could ameliorate kidney disease progression in glomerulonephritis rats. Anti-glomerular basement membrane (GBM) nephritis was induced in rats by intravenously administering two types of anti-rat GBM antibodies. We evaluated the effect of EOS789 administered in food admixture on hyperphosphatemia and kidney disease progression. In an anti-GBM nephritis rats, which exhibit a significant increase in serum phosphate and a decline in renal function, EOS789 dose-dependently improved hyperphosphatemia and EOS789 at 0.3% food admixture significantly ameliorated kidney dysfunction as shown in the decline of serum creatinine and BUN. Renal histopathology analysis showed that EOS789 significantly decreased crescent formation in glomeruli. To elucidate the mechanism underlying glomerular disease progression, human mesangial cells were used. High phosphate concentration in media significantly increased the expression of Collagen 1A1, 3A1, and αSMA mRNA in human mesangial cells and EOS789 dose-dependently suppressed these fibrotic markers. These results indicate that EOS789 prevented glomerular crescent formation caused by mesangial fibrosis by ameliorating hyperphosphatemia. In conclusion, EOS789 would not only be useful against hyperphosphatemia but may also have the potential to relieve mesangial proliferative glomerulonephritis with crescent formation.
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Affiliation(s)
- Yoshinori Tsuboi
- Research DivisionChugai Pharmaceutical Co., Ltd.GotembaShizuokaJapan
| | - Yasuhiro Ichida
- Research DivisionChugai Pharmaceutical Co., Ltd.GotembaShizuokaJapan
| | - Atsuko Murai
- Translational Research DivisionChugai Pharmaceutical Co., Ltd.GotembaShizuokaJapan
| | - Akira Maeda
- Research DivisionChugai Pharmaceutical Co., Ltd.GotembaShizuokaJapan
| | - Manami Iida
- Research DivisionChugai Pharmaceutical Co., Ltd.GotembaShizuokaJapan
| | - Atsuhiko Kato
- Translational Research DivisionChugai Pharmaceutical Co., Ltd.GotembaShizuokaJapan
| | - Shuichi Ohtomo
- Translational Research DivisionChugai Pharmaceutical Co., Ltd.GotembaShizuokaJapan
| | - Naoshi Horiba
- Research DivisionChugai Pharmaceutical Co., Ltd.GotembaShizuokaJapan
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Daryadel A, Haykir B, Küng CJ, Bugarski M, Bettoni C, Schnitzbauer U, Hernando N, Hall AM, Wagner CA. Acute adaptation of renal phosphate transporters in the murine kidney to oral phosphate intake requires multiple signals. Acta Physiol (Oxf) 2022; 235:e13815. [PMID: 35334154 DOI: 10.1111/apha.13815] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 12/01/2022]
Abstract
AIMS Dietary inorganic phosphate (Pi) modulates renal Pi reabsorption by regulating the expression of the NaPi-IIa and NaPi-IIc Pi transporters. Here, we aimed to clarify the role of several Pi-regulatory mechanisms including parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23) and inositol hexakisphosphate kinases (IP6-kinases) in the acute regulation of NaPi-IIa and NaPi-IIc. METHODS Wildtype (WT) and PTH-deficient mice (PTH-KO) with/without inhibition of FGF23 signalling were gavaged with Pi/saline and examined at 1, 4 and 12 h. RESULTS Pi-gavage elevated plasma Pi and decreased plasma Ca2+ in both genotypes after 1 h Within 1 h, Pi-gavage decreased NaPi-IIa abundance in WT and PTH-KO mice. NaPi-IIc was downregulated 1 h post-administration in WT and after 4 h in PTH-KO. PTH increased after 1 h in WT animals. After 4 h Pi-gavage, FGF23 increased in both genotypes being higher in the KO group. PTHrp and dopamine were not altered by Pi-gavage. Blocking FGF23 signalling blunted PTH upregulation in WT mice and reduced NaPi-IIa downregulation in PTH-KO mice 4 h after Pi-gavage. Inhibition of IP6-kinases had no effect. CONCLUSIONS (1) Acute downregulation of renal Pi transporters in response to Pi intake occurs also in the absence of PTH and FGF23 signalling, (2) when FGF23 signalling is blocked, a partial contribution of PTH is revealed, (3) IP6 kinases, intracellular Pi-sensors in yeast and bacteria, are not involved, and (4) Acute Pi does not alter PTHrp and dopamine. Thus, signals other than PTH, PTHrp, FGF23 and dopamine contribute to renal adaption.
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Affiliation(s)
- Arezoo Daryadel
- Institute of Physiology University of Zürich Zürich Switzerland
- National Center of Competence in Research Kidney.CH Zürich Switzerland
| | - Betül Haykir
- Institute of Physiology University of Zürich Zürich Switzerland
| | | | - Milica Bugarski
- National Center of Competence in Research Kidney.CH Zürich Switzerland
- Institute of Anatomy University of Zürich Zürich Switzerland
| | - Carla Bettoni
- Institute of Physiology University of Zürich Zürich Switzerland
| | | | - Nati Hernando
- Institute of Physiology University of Zürich Zürich Switzerland
| | - Andrew M. Hall
- National Center of Competence in Research Kidney.CH Zürich Switzerland
- Institute of Anatomy University of Zürich Zürich Switzerland
| | - Carsten A. Wagner
- Institute of Physiology University of Zürich Zürich Switzerland
- National Center of Competence in Research Kidney.CH Zürich Switzerland
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Vervloet MG. Shedding Light on the Complex Regulation of FGF23. Metabolites 2022; 12:metabo12050401. [PMID: 35629904 PMCID: PMC9147863 DOI: 10.3390/metabo12050401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/23/2022] [Accepted: 04/26/2022] [Indexed: 12/10/2022] Open
Abstract
Early research has suggested a rather straightforward relation between phosphate exposure, increased serum FGF23 (Fibroblast Growth Factor 23) concentrations and clinical endpoints. Unsurprisingly, however, subsequent studies have revealed a much more complex interplay between autocrine and paracrine factors locally in bone like PHEX and DMP1, concentrations of minerals in particular calcium and phosphate, calciprotein particles, and endocrine systems like parathyroid hormone PTH and the vitamin D system. In addition to these physiological regulators, an expanding list of disease states are shown to influence FGF23 levels, usually increasing it, and as such increase the burden of disease. While some of these physiological or pathological factors, like inflammatory cytokines, may partially confound the association of FGF23 and clinical endpoints, others are in the same causal path, are targetable and hence hold the promise of future treatment options to alleviate FGF23-driven toxicity, for instance in chronic kidney disease, the FGF23-associated disease with the highest prevalence by far. These factors will be reviewed here and their relative importance described, thereby possibly opening potential means for future therapeutic strategies.
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Affiliation(s)
- Marc G. Vervloet
- Amsterdam UMC, Location Vrije Universiteit Amsterdam, Nephrology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; ; Tel.: +31-20-4442671
- Amsterdam Cardiovascular Sciences, Diabetes and Metabolism, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
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26
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The human pathogenic 91del7 mutation in SLC34A1 has no effect in mineral homeostasis in mice. Sci Rep 2022; 12:6102. [PMID: 35414099 PMCID: PMC9005600 DOI: 10.1038/s41598-022-10046-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 04/01/2022] [Indexed: 11/29/2022] Open
Abstract
Kidneys are key regulators of phosphate homeostasis. Biallelic mutations of the renal Na+/phosphate cotransporter SLC34A1/NaPi-IIa cause idiopathic infantile hypercalcemia, whereas monoallelic mutations were frequently noted in adults with kidney stones. Genome-wide-association studies identified SLC34A1 as a risk locus for chronic kidney disease. Pathogenic mutations in SLC34A1 are present in 4% of the general population. Here, we characterize a mouse model carrying the 91del7 in-frame deletion, a frequent mutation whose significance remains unclear. Under normal dietary conditions, 12 weeks old heterozygous and homozygous males have similar plasma and urinary levels of phosphate as their wild type (WT) littermates, and comparable concentrations of parathyroid hormone, fibroblast growth factor 23 (FGF-23) and 1,25(OH)2 vitamin D3. Renal phosphate transport, and expression of NaPi-IIa and NaPi-IIc cotransporters, was indistinguishable in the three genotypes. Challenging mice with low dietary phosphate did not result in differences between genotypes with regard to urinary and plasma phosphate. Urinary and plasma phosphate, plasma FGF-23 and expression of cotransporters were similar in all genotypes after weaning. Urinary phosphate and bone mineral density were also comparable in 300 days old WT and mutant mice. In conclusion, mice carrying the 91del7 truncation do not show signs of impaired phosphate homeostasis.
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27
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Endocrine Fibroblast Growth Factors in Relation to Stress Signaling. Cells 2022; 11:cells11030505. [PMID: 35159314 PMCID: PMC8834311 DOI: 10.3390/cells11030505] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/30/2022] [Accepted: 01/31/2022] [Indexed: 01/10/2023] Open
Abstract
Fibroblast growth factors (FGFs) play important roles in various growth signaling processes, including proliferation, development, and differentiation. Endocrine FGFs, i.e., atypical FGFs, including FGF15/19, FGF21, and FGF23, function as endocrine hormones that regulate energy metabolism. Nutritional status is known to regulate the expression of endocrine FGFs through nuclear hormone receptors. The increased expression of endocrine FGFs regulates energy metabolism processes, such as fatty acid metabolism and glucose metabolism. Recently, a relationship was found between the FGF19 subfamily and stress signaling during stresses such as endoplasmic reticulum stress and oxidative stress. This review focuses on endocrine FGFs and the recent progress in FGF studies in relation to stress signaling. In addition, the relevance of the stress-FGF pathway to disease and human health is discussed.
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28
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BMS-470539 Attenuates Oxidative Stress and Neuronal Apoptosis via MC1R/cAMP/PKA/Nurr1 Signaling Pathway in a Neonatal Hypoxic-Ischemic Rat Model. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4054938. [PMID: 35140838 PMCID: PMC8820941 DOI: 10.1155/2022/4054938] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 12/28/2021] [Indexed: 12/25/2022]
Abstract
Neuronal apoptosis induced by oxidative stress plays an important role in the pathogenesis and progression of hypoxic-ischemic encephalopathy (HIE). Previous studies reported that activation of melanocortin-1 receptor (MC1R) exerts antioxidative stress, antiapoptotic, and neuroprotective effects in various neurological diseases. However, whether MC1R activation can attenuate oxidative stress and neuronal apoptosis after hypoxic-ischemic- (HI-) induced brain injury remains unknown. Herein, we have investigated the role of MC1R activation with BMS-470539 in attenuating oxidative stress and neuronal apoptosis induced by HI and the underlying mechanisms. 159 ten-day-old unsexed Sprague-Dawley rat pups were used. HI was induced by right common carotid artery ligation followed by 2.5 h of hypoxia. The novel-selective MC1R agonist BMS-470539 was administered intranasally at 1 h after HI induction. MC1R CRISPR KO plasmid and Nurr1 CRISPR KO plasmid were administered intracerebroventricularly at 48 h before HI induction. Percent brain infarct area, short-term neurobehavioral tests, Western blot, immunofluorescence staining, Fluoro-Jade C staining, and MitoSox Staining were performed. We found that the expression of MC1R and Nurr1 increased, peaking at 48 h post-HI. MC1R and Nurr1 were expressed on neurons at 48 h post-HI. BMS-470539 administration significantly attenuated short-term neurological deficits and infarct area, accompanied by a reduction in cleaved caspase-3-positive neurons at 48 h post-HI. Moreover, BMS-470539 administration significantly upregulated the expression of MC1R, cAMP, p-PKA, Nurr1, HO-1, and Bcl-2. However, it downregulated the expression of 4-HNE and Bax, as well as reduced FJC-positive cells, MitoSox-positive cells, and 8-OHdG-positive cells at 48 h post-HI. MC1R CRISPR and Nurr1 CRISPR abolished the antioxidative stress, antiapoptotic, and neuroprotective effects of BMS-470539. In conclusion, our findings demonstrated that BMS-470539 administration attenuated oxidative stress and neuronal apoptosis and improved neurological deficits in a neonatal HI rat model, partially via the MC1R/cAMP/PKA/Nurr1 signaling pathway. Early administration of BMS-470539 may be a novel therapeutic strategy for infants with HIE.
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The regulation of FGF23 under physiological and pathophysiological conditions. Pflugers Arch 2022; 474:281-292. [PMID: 35084563 PMCID: PMC8837506 DOI: 10.1007/s00424-022-02668-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/18/2022] [Accepted: 01/19/2022] [Indexed: 12/18/2022]
Abstract
Fibroblast growth factor 23 (FGF23) is an important bone hormone that regulates phosphate homeostasis in the kidney along with active vitamin D (1,25(OH)2D3) and parathyroid hormone (PTH). Endocrine effects of FGF23 depend, at least in part, on αKlotho functioning as a co-receptor whereas further paracrine effects in other tissues are αKlotho-independent. Regulation of FGF23 production is complex under both, physiological and pathophysiological conditions. Physiological regulators of FGF23 include, but are not limited to, 1,25(OH)2D3, PTH, dietary phosphorus intake, and further intracellular and extracellular factors, kinases, cytokines, and hormones. Moreover, several acute and chronic diseases including chronic kidney disease (CKD) or further cardiovascular disorders are characterized by early rises in the plasma FGF23 level pointing to further mechanisms effective in the regulation of FGF23 under pathophysiological conditions. Therefore, FGF23 also serves as a prognostic marker in several diseases. Our review aims to comprehensively summarize the regulation of FGF23 in health and disease.
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30
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Li Y, Gu Z, Wang J, Wang Y, Chen X, Dong B. The Emerging Role of Bone-Derived Hormones in Diabetes Mellitus and Diabetic Kidney Disease. Front Endocrinol (Lausanne) 2022; 13:938830. [PMID: 35966090 PMCID: PMC9367194 DOI: 10.3389/fendo.2022.938830] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic kidney disease (DKD) causes the greatest proportion of end-stage renal disease (ESRD)-related mortality and has become a high concern in patients with diabetes mellitus (DM). Bone is considered an endocrine organ, playing an emerging role in regulating glucose and energy metabolism. Accumulating research has proven that bone-derived hormones are involved in glucose metabolism and the pathogenesis of DM complications, especially DKD. Furthermore, these hormones are considered to be promising predictors and prospective treatment targets for DM and DKD. In this review, we focused on bone-derived hormones, including fibroblast growth factor 23, osteocalcin, sclerostin, and lipocalin 2, and summarized their role in regulating glucose metabolism and DKD.
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Affiliation(s)
- Yixuan Li
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zuhua Gu
- Department of Endocrinology and Nephropathy, Weihai Hospital, Weihai, China
| | - Jun Wang
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yangang Wang
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xian Chen
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, China
- *Correspondence: Bingzi Dong, ; Xian Chen,
| | - Bingzi Dong
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China
- *Correspondence: Bingzi Dong, ; Xian Chen,
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31
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Münz S, Feger M, Edemir B, Föller M. Up-Regulation of Fibroblast Growth Factor 23 Gene Expression in UMR106 Osteoblast-like Cells with Reduced Viability. Cells 2021; 11:40. [PMID: 35011602 PMCID: PMC8750768 DOI: 10.3390/cells11010040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 12/17/2021] [Accepted: 12/20/2021] [Indexed: 02/07/2023] Open
Abstract
Fibroblast growth factor 23 (FGF23) controls vitamin D and phosphate homeostasis in the kidney and has additional paracrine effects elsewhere. As a biomarker, its plasma concentration is associated with progression of inflammatory, renal, and cardiovascular diseases. Major stimuli of FGF23 synthesis include active vitamin D and inflammation. Antineoplastic chemotherapy treats cancer by inducing cellular damage ultimately favoring cell death (apoptosis and necrosis) and causing inflammation. Our study explored whether chemotherapeutics and other apoptosis inducers impact on Fgf23 expression. Experiments were performed in osteoblast-like UMR106 cells, Fgf23 gene expression and protein synthesis were determined by qRT-PCR and ELISA, respectively. Viability was assessed by MTT assay and NFκB activity by Western Blotting. Antineoplastic drugs cisplatin and doxorubicin as well as apoptosis inducers procaspase-activating compound 1 (PAC-1), a caspase 3 activator, and serum depletion up-regulated Fgf23 transcripts while reducing cell proliferation and viability. The effect of cisplatin on Fgf23 transcription was paralleled by Il-6 up-regulation and NFκB activation and attenuated by Il-6 and NFκB signaling inhibitors. To conclude, cell viability-decreasing chemotherapeutics as well as apoptosis stimulants PAC-1 and serum depletion up-regulate Fgf23 gene expression. At least in part, Il-6 and NFκB may contribute to this effect.
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Affiliation(s)
- Sina Münz
- Department of Physiology, University of Hohenheim, 70599 Stuttgart, Germany; (S.M.); (M.F.)
| | - Martina Feger
- Department of Physiology, University of Hohenheim, 70599 Stuttgart, Germany; (S.M.); (M.F.)
| | - Bayram Edemir
- Department of Hematology and Oncology, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany;
| | - Michael Föller
- Department of Physiology, University of Hohenheim, 70599 Stuttgart, Germany; (S.M.); (M.F.)
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32
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Lyu P, Li B, Li P, Bi R, Cui C, Zhao Z, Zhou X, Fan Y. Parathyroid Hormone 1 Receptor Signaling in Dental Mesenchymal Stem Cells: Basic and Clinical Implications. Front Cell Dev Biol 2021; 9:654715. [PMID: 34760881 PMCID: PMC8573197 DOI: 10.3389/fcell.2021.654715] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 09/28/2021] [Indexed: 02/05/2023] Open
Abstract
Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) are two peptides that regulate mineral ion homeostasis, skeletal development, and bone turnover by activating parathyroid hormone 1 receptor (PTH1R). PTH1R signaling is of profound clinical interest for its potential to stimulate bone formation and regeneration. Recent pre-clinical animal studies and clinical trials have investigated the effects of PTH and PTHrP analogs in the orofacial region. Dental mesenchymal stem cells (MSCs) are targets of PTH1R signaling and have long been known as major factors in tissue repair and regeneration. Previous studies have begun to reveal important roles for PTH1R signaling in modulating the proliferation and differentiation of MSCs in the orofacial region. A better understanding of the molecular networks and underlying mechanisms for modulating MSCs in dental diseases will pave the way for the therapeutic applications of PTH and PTHrP in the future. Here we review recent studies involving dental MSCs, focusing on relationships with PTH1R. We also summarize recent basic and clinical observations of PTH and PTHrP treatment to help understand their use in MSCs-based dental and bone regeneration.
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Affiliation(s)
- Ping Lyu
- State Key Laboratory of Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China
| | - Bo Li
- State Key Laboratory of Oral Diseases, Department of Orthodontics, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Peiran Li
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ruiye Bi
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chen Cui
- Guangdong Province Key Laboratory of Stomatology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong, China
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases, Department of Orthodontics, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China
| | - Yi Fan
- State Key Laboratory of Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China
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Xiong L, Pan JX, Guo HH, Mei L, Xiong WC. Parkinson's in the bone. Cell Biosci 2021; 11:190. [PMID: 34740382 PMCID: PMC8569842 DOI: 10.1186/s13578-021-00702-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 10/26/2021] [Indexed: 12/20/2022] Open
Abstract
Patients with Parkinson’s disease (PD) exhibit systemic deficits, including arthritis and osteoporosis-like symptoms. However, the questions, how the deficits in periphery organs or tissues occur in PD patients, and what are the relationship (s) of the periphery tissue deficits with the brain pathology (e.g., dopamine neuron loss), are at the beginning stage to be investigated. Notice that both PD and osteoporosis are the products of a complex interaction of genetic and environmental risk factors. Genetic mutations in numerous genes have been identified in patients either with recessive or autosomal dominant PD. Most of these PD risk genes are ubiquitously expressed; and many of them are involved in regulation of bone metabolism. Here, we review the functions of the PD risk genes in regulating bone remodeling and homeostasis. The knowledge gaps in our understanding of the bone-to-brain axis in PD development are also outlined.
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Affiliation(s)
- Lei Xiong
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.,Louis Stoke VA Medical Center, Cleveland, OH, 44106, USA
| | - Jin-Xiu Pan
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.,Louis Stoke VA Medical Center, Cleveland, OH, 44106, USA
| | - Hao-Han Guo
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Lin Mei
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.,Louis Stoke VA Medical Center, Cleveland, OH, 44106, USA
| | - Wen-Cheng Xiong
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA. .,Louis Stoke VA Medical Center, Cleveland, OH, 44106, USA.
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Lipocalin 2 stimulates bone fibroblast growth factor 23 production in chronic kidney disease. Bone Res 2021; 9:35. [PMID: 34334787 PMCID: PMC8326281 DOI: 10.1038/s41413-021-00154-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 03/23/2021] [Accepted: 04/20/2021] [Indexed: 12/15/2022] Open
Abstract
Bone-produced fibroblast growth factor 23 (FGF23) increases in response to inflammation and iron deficiency and contributes to cardiovascular mortality in chronic kidney disease (CKD). Neutrophil gelatinase-associated lipocalin (NGAL or lipocalin 2; LCN2 the murine homolog) is a pro-inflammatory and iron-shuttling molecule that is secreted in response to kidney injury and may promote CKD progression. We investigated bone FGF23 regulation by circulating LCN2. At 23 weeks, Col4a3KO mice showed impaired kidney function, increased levels of kidney and serum LCN2, increased bone and serum FGF23, anemia, and left ventricular hypertrophy (LVH). Deletion of Lcn2 in CKD mice did not improve kidney function or anemia but prevented the development of LVH and improved survival in association with marked reductions in serum FGF23. Lcn2 deletion specifically prevented FGF23 elevations in response to inflammation, but not iron deficiency or phosphate, and administration of LCN2 increased serum FGF23 in healthy and CKD mice by stimulating Fgf23 transcription via activation of cAMP-mediated signaling in bone cells. These results show that kidney-produced LCN2 is an important mediator of increased FGF23 production by bone in response to inflammation and in CKD. LCN2 inhibition might represent a potential therapeutic approach to lower FGF23 and improve outcomes in CKD.
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Habas E, Eledrisi M, Khan F, Elzouki ANY. Secondary Hyperparathyroidism in Chronic Kidney Disease: Pathophysiology and Management. Cureus 2021; 13:e16388. [PMID: 34408941 PMCID: PMC8362860 DOI: 10.7759/cureus.16388] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/14/2021] [Indexed: 12/25/2022] Open
Abstract
Serum calcium concentration is the main determinant of parathyroid hormone (PTH) release. Defect in the activation of vitamin D in the kidneys due to chronic kidney disease (CKD) leads to hypocalcemia and hyperphosphatemia, resulting in a compensatory increase in parathyroid gland cellularity and parathyroid hormone production and causing secondary hyperparathyroidism (SHP). Correction and maintenance of normal serum calcium and phosphate are essential to preventing SHP, hungry bone disease, cardiovascular events, and anemia development. Understanding the pathophysiology of PTH and possible therapeutic agents can reduce the development and associated complications of SHP in patients with CKD. Medical interventions to control serum calcium, phosphate, and PTH such as vitamin D analogs, calcium receptor blockers, and parathyroidectomy are needed in some CKD patients. In this review, we discuss the pathophysiology, clinical presentation, and management of SHP in CKD patients.
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Affiliation(s)
| | | | - Fahmi Khan
- Internal Medicine, Hamad General Hospital, Doha, QAT
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Rickets in Children: An Update. Biomedicines 2021; 9:biomedicines9070738. [PMID: 34199067 PMCID: PMC8301330 DOI: 10.3390/biomedicines9070738] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/15/2021] [Accepted: 06/24/2021] [Indexed: 12/16/2022] Open
Abstract
Rickets refers to a deficient mineralization of the growth plate cartilage, predominantly affecting longer bones. Despite the fact that preventive measures are available, it is still a common disease worldwide; nutritional rickets, due to vitamin D deficiency or dietary calcium inadequate intake, remains the most common form. Medical history, physical examination, radiologic features and biochemical tests are essential for diagnosis. Although recent studies suggest hypophosphatemia as the leading alteration, rickets is classically divided into two categories: calcipenic rickets and phosphopenic rickets. Knowledge of this categorization and of respective clinical and laboratory features is essential for rapid diagnosis and correct management. The aim of this review is to analyze the epidemiological, pathogenetic, clinical, and therapeutic aspects of the different forms of rickets, describing the novelties on this “long-lived” disease.
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The Influence of Dietary Interventions on Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Nutrients 2021; 13:nu13062065. [PMID: 34208727 PMCID: PMC8235119 DOI: 10.3390/nu13062065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/06/2021] [Accepted: 06/07/2021] [Indexed: 12/14/2022] Open
Abstract
Chronic kidney disease is a health problem whose prevalence is increasing worldwide. The kidney plays an important role in the metabolism of minerals and bone health and therefore, even at the early stages of CKD, disturbances in bone metabolism are observed. In the course of CKD, various bone turnover or mineralization disturbances can develop including adynamic hyperparathyroid, mixed renal bone disease, osteomalacia. The increased risk of fragility fractures is present at any age in these patients. Nutritional treatment of patients with advanced stages of CKD is aiming at prevention or correction of signs, symptoms of renal failure, avoidance of protein-energy wasting (PEW), delaying or prevention of the occurrence of mineral/bone disturbances, and delaying the start of dialysis. The results of studies suggest that progressive protein restriction is beneficial with the progression of renal insufficiency; however, other aspects of dietary management of CKD patients, including changes in sodium, phosphorus, and energy intake, as well as the source of protein and lipids (animal or plant origin) should also be considered carefully. Energy intake must cover patients' energy requirement, in order to enable correct metabolic adaptation in the course of protein-restricted regimens and prevent negative nitrogen balance and protein-energy wasting.
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Bayer J, Vaghela R, Drechsler S, Osuchowski MF, Erben RG, Andrukhova O. The bone is the major source of high circulating intact fibroblast growth factor-23 in acute murine polymicrobial sepsis induced by cecum ligation puncture. PLoS One 2021; 16:e0251317. [PMID: 33989306 PMCID: PMC8121358 DOI: 10.1371/journal.pone.0251317] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 04/23/2021] [Indexed: 12/20/2022] Open
Abstract
Fibroblast growth factor-23 (FGF23), a bone-produced hormone, plays a critical role in mineral homeostasis. Human diseases associated with excessive intact circulating FGF23 (iFGF23) result in hypophosphatemia and low vitamin D hormone in patients with normal kidney function. In addition, there is accumulating evidence linking FGF23 with inflammation. Based on these studies and the frequent observation of hypophosphatemia among septic patients, we sought to elucidate further the relationship between FGF23 and mineral homeostasis in a clinically relevant murine polymicrobial sepsis model. Medium-severity sepsis was induced by cecum ligation puncture (CLP) in adult CD-1 mice of both sexes. Healthy CD-1 mice (without CLP) were used as controls. Forty-eight hours post-CLP, spontaneous urine was collected, and serum, organs and bones were sampled at necropsy. Serum iFGF23 increased ~20-fold in CLP compared to control mice. FGF23 protein concentration was increased in the bones, but not in spleen or liver of CLP mice. Despite the ~20-fold iFGF23 increase, we did not observe any significant changes in mineral homeostasis or parathyroid hormone levels in the blood of CLP animals. Urinary excretion of phosphate, calcium, and sodium remained unchanged in male CLP mice, whereas female CLP mice exhibited lower urinary calcium excretion, relative to healthy controls. In line with renal FGF23 resistance, expression of phosphate-, calcium- and sodium-transporting proteins did not show consistent changes in the kidneys of male and female CLP mice. Renal expression of the co-receptor αKlotho was downregulated in female, but not in male CLP mice. In conclusion, our data demonstrate that the dramatic, sex-independent rise in serum iFGF23 post-CLP was mainly caused by an upregulation of FGF23 secretion in the bone. Surprisingly, the upsurge in circulating iFGF23 did not alter humoral mineral homeostasis in the acutely septic mice. Hence, the biological function of elevated FGF23 in sepsis remains unclear and warrants further studies.
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Affiliation(s)
- Jessica Bayer
- Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Ravikumar Vaghela
- Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Susanne Drechsler
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria
| | - Marcin F. Osuchowski
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria
| | - Reinhold G. Erben
- Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Olena Andrukhova
- Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria
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Radhakrishnan K, Kim YH, Jung YS, Kim DK, Na SY, Lim D, Kim DH, Kim J, Kim HS, Choy HE, Cho SJ, Lee IK, Ayvaz Ş, Nittka S, Fliser D, Schunk SJ, Speer T, Dooley S, Lee CH, Choi HS. Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury. Proc Natl Acad Sci U S A 2021; 118. [DOI: https:/doi.org/10.1073/pnas.2022841118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/18/2023] Open
Abstract
Significance
Bone is the main source of fibroblast growth factor 23 (FGF23), which is important for phosphate and vitamin D homeostasis. In acute kidney injury (AKI), high blood levels of FGF23 are positively correlated with disease progression and increased risk of mortality. Reducing adverse plasma FGF23 levels in AKI patients is favorable. We showed here that hepatocytes are the major source of circulating FGF23, and orphan nuclear receptor ERR-γ is a novel transcriptional regulator of hepatic FGF23 production in AKI. Liver-specific depletion of ERR-γ or ERR-γ inverse agonist, GSK5182, significantly reduced plasma levels of FGF23 in AKI. This study reveals liver is the source of FGF23 and a therapeutic strategy to control pathologically adverse plasma FGF23 levels in AKI.
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Affiliation(s)
- Kamalakannan Radhakrishnan
- School of Biological Sciences and Technology, Chonnam National University, 61186 Gwangju, Republic of Korea
| | - Yong-Hoon Kim
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 34141 Daejeon, Republic of Korea
- Department of Functional Genomics, Korea Research Institute of Biosciences and Biotechnology School of Bioscience, University of Science and Technology, 34141 Daejeon, Republic of Korea
| | - Yoon Seok Jung
- School of Biological Sciences and Technology, Chonnam National University, 61186 Gwangju, Republic of Korea
| | - Don-Kyu Kim
- Department of Molecular Biotechnology, Chonnam National University, 61186 Gwangju, Republic of Korea
| | - Soon-Young Na
- School of Biological Sciences and Technology, Chonnam National University, 61186 Gwangju, Republic of Korea
| | - Daejin Lim
- Department of Microbiology, Chonnam National University Medical School, 61468 Gwangju, Republic of Korea
| | - Dong Hun Kim
- Department of Biomedical Science, Graduate School, Kyungpook National University, 41404 Daegu, Republic of Korea
| | - Jina Kim
- New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation, 41061 Daegu, Republic of Korea
| | - Hyung-Seok Kim
- Department of Forensic Medicine, Chonnam National University Medical School, 61468 Gwangju, Republic of Korea
| | - Hyon E. Choy
- Department of Microbiology, Chonnam National University Medical School, 61468 Gwangju, Republic of Korea
| | - Sung Jin Cho
- New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation, 41061 Daegu, Republic of Korea
- Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, 41404 Daegu, Republic of Korea
| | - In-Kyu Lee
- Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, 41404 Daegu, Republic of Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, 41944 Daegu, Republic of Korea
| | - Şamil Ayvaz
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Stefanie Nittka
- Institute for Clinical Chemistry, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Danilo Fliser
- Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University, D-66421 Homburg/Saar, Germany
| | - Stefan J. Schunk
- Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University, D-66421 Homburg/Saar, Germany
| | - Thimoteus Speer
- Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University, D-66421 Homburg/Saar, Germany
| | - Steven Dooley
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Chul-Ho Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 34141 Daejeon, Republic of Korea
- Department of Functional Genomics, Korea Research Institute of Biosciences and Biotechnology School of Bioscience, University of Science and Technology, 34141 Daejeon, Republic of Korea
| | - Hueng-Sik Choi
- School of Biological Sciences and Technology, Chonnam National University, 61186 Gwangju, Republic of Korea
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40
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Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury. Proc Natl Acad Sci U S A 2021; 118:2022841118. [PMID: 33853949 DOI: 10.1073/pnas.2022841118] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Fibroblast growth factor 23 (FGF23), a hormone generally derived from bone, is important in phosphate and vitamin D homeostasis. In acute kidney injury (AKI) patients, high-circulating FGF23 levels are associated with disease progression and mortality. However, the organ and cell type of FGF23 production in AKI and the molecular mechanism of its excessive production are still unidentified. For insight, we investigated folic acid (FA)-induced AKI in mice. Interestingly, simultaneous with FGF23, orphan nuclear receptor ERR-γ expression is increased in the liver of FA-treated mice, and ectopic overexpression of ERR-γ was sufficient to induce hepatic FGF23 production. In patients and in mice, AKI is accompanied by up-regulated systemic IL-6, which was previously identified as an upstream regulator of ERR-γ expression in the liver. Administration of IL-6 neutralizing antibody to FA-treated mice or of recombinant IL-6 to healthy mice confirms IL-6 as an upstream regulator of hepatic ERR-γ-mediated FGF23 production. A significant (P < 0.001) interconnection between high IL-6 and FGF23 levels as a predictor of AKI in patients that underwent cardiac surgery was also found, suggesting the clinical relevance of the finding. Finally, liver-specific depletion of ERR-γ or treatment with an inverse ERR-γ agonist decreased hepatic FGF23 expression and plasma FGF23 levels in mice with FA-induced AKI. Thus, inverse agonist of ERR-γ may represent a therapeutic strategy to reduce adverse plasma FGF23 levels in AKI.
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Haussler MR, Livingston S, Sabir ZL, Haussler CA, Jurutka PW. Vitamin D Receptor Mediates a Myriad of Biological Actions Dependent on Its 1,25-Dihydroxyvitamin D Ligand: Distinct Regulatory Themes Revealed by Induction of Klotho and Fibroblast Growth Factor-23. JBMR Plus 2021; 5:e10432. [PMID: 33553988 PMCID: PMC7839824 DOI: 10.1002/jbm4.10432] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 11/01/2020] [Indexed: 11/21/2022] Open
Abstract
The hormonal vitamin D metabolite, 1,25‐dihydroxyvitamin D [1,25(OH)2D], produced in kidney, acts in numerous end organs via the nuclear vitamin D receptor (VDR) to trigger molecular events that orchestrate bone mineral homeostasis. VDR is a ligand‐controlled transcription factor that obligatorily heterodimerizes with retinoid X receptor (RXR) to target vitamin D responsive elements (VDREs) in the vicinity of vitamin D‐regulated genes. Circulating 1,25(OH)2D concentrations are governed by PTH, an inducer of renal D‐hormone biosynthesis catalyzed by CYP27B1 that functions as the key player in a calcemic endocrine circuit, and by fibroblast growth factor‐23 (FGF23), a repressor of the CYP27B1 renal enzyme, creating a hypophosphatemic endocrine loop. 1,25(OH)2D/VDR–RXR acts in kidney to induce Klotho (a phosphaturic coreceptor for FGF23) to correct hyperphosphatemia, NPT2a/c to correct hypophosphatemia, and TRPV5 and CaBP28k to enhance calcium reabsorption. 1,25(OH)2D‐liganded VDR–RXR functions in osteoblasts/osteocytes by augmenting RANK‐ligand expression to paracrine signal osteoclastic bone resorption, while simultaneously inducing FGF23, SPP1, BGLP, LRP5, ANK1, ENPP1, and TNAP, and conversely repressing RUNX2 and PHEX expression, effecting localized control of mineralization to sculpt the skeleton. Herein, we document the history of 1,25(OH)2D/VDR and summarize recent advances in characterizing their physiology, biochemistry, and mechanism of action by highlighting two examples of 1,25(OH)2D/VDR molecular function. The first is VDR‐mediated primary induction of Klotho mRNA by 1,25(OH)2D in kidney via a mechanism initiated by the docking of liganded VDR–RXR on a VDRE at −35 kb in the mouse Klotho gene. In contrast, the secondary induction of FGF23 by 1,25(OH)2D in bone is proposed to involve rapid nongenomic action of 1,25(OH)2D/VDR to acutely activate PI3K, in turn signaling the induction of MZF1, a transcription factor that, in cooperation with c‐ets1‐P, binds to an enhancer element centered at −263 bp in the promoter‐proximal region of the mouse fgf23 gene. Chronically, 1,25(OH)2D‐induced osteopontin apparently potentiates MZF1. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Mark R Haussler
- Department of Basic Medical Sciences University of Arizona College of Medicine-Phoenix Phoenix AZ
| | - Sarah Livingston
- School of Mathematical and Natural Sciences Arizona State University Glendale AZ
| | - Zhela L Sabir
- School of Mathematical and Natural Sciences Arizona State University Glendale AZ
| | - Carol A Haussler
- Department of Basic Medical Sciences University of Arizona College of Medicine-Phoenix Phoenix AZ
| | - Peter W Jurutka
- Department of Basic Medical Sciences University of Arizona College of Medicine-Phoenix Phoenix AZ.,School of Mathematical and Natural Sciences Arizona State University Glendale AZ
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Simultaneous management of disordered phosphate and iron homeostasis to correct fibroblast growth factor 23 and associated outcomes in chronic kidney disease. Curr Opin Nephrol Hypertens 2021; 29:359-366. [PMID: 32452919 DOI: 10.1097/mnh.0000000000000614] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Hyperphosphatemia, iron deficiency, and anemia are powerful stimuli of fibroblast growth factor 23 (FGF23) production and are highly prevalent complications of chronic kidney disease (CKD). In this manuscript, we put in perspective the newest insights on FGF23 regulation by iron and phosphate and their effects on CKD progression and associated outcomes. We especially focus on new studies aiming to reduce FGF23 levels, and we present new data that suggest major benefits of combined corrections of iron, phosphate, and FGF23 in CKD. RECENT FINDINGS New studies show that simultaneously correcting iron deficiency and hyperphosphatemia in CKD reduces the magnitude of FGF23 increase. Promising therapies using iron-based phosphate binders in CKD might mitigate cardiac and renal injury and improve survival. SUMMARY New strategies to lower FGF23 have emerged, and we discuss their benefits and risks in the context of CKD. Novel clinical and preclinical studies highlight the effects of phosphate restriction and iron repletion on FGF23 regulation.
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Glucocorticoids dexamethasone and prednisolone suppress fibroblast growth factor 23 (FGF23). J Mol Med (Berl) 2021; 99:699-711. [PMID: 33517471 PMCID: PMC8055636 DOI: 10.1007/s00109-021-02036-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 12/29/2020] [Accepted: 01/05/2021] [Indexed: 01/02/2023]
Abstract
Fibroblast growth factor 23 (FGF23) is a hormone mainly secreted by bone cells. Its most prominent effects are the regulation of renal phosphate reabsorption and calcitriol (active vitamin D, 1,25(OH)2D3) formation, effects dependent on its co-receptor αKlotho. Besides these actions, further paracrine and endocrine effects exist. The production of FGF23 is regulated by 1,25(OH)2D3, parathyroid hormone, dietary phosphate intake, iron status, as well as inflammation. Glucocorticoids are hormones with anti-inflammatory properties and are, therefore, widely used for acute and chronic inflammatory diseases, autoimmune disorders, and malignancies. The present study explored whether glucocorticoids influence the production of FGF23 in vitro as well as in mice. Fgf23 transcription was analyzed by semi-quantitative real-time PCR. Serum concentrations of FGF23 and 1,25(OH)2D3 were measured by ELISA. Urinary phosphate and Ca2+ excretion were determined in metabolic cages. As a result, in UMR106 rat osteoblast-like cells and in MC3T3-E1 cells, both, dexamethasone and prednisolone, downregulated Fgf23 transcription and FGF23 protein synthesis. Dexamethasone increased Dmp1 and Phex (encoding FGF23-regulating genes) as well as Nfkbia (encoding NFκB inhibitor IκBα) transcription in UMR106 cells. In mice, a single injection of dexamethasone or prednisolone was followed by a significant decrease of serum C-terminal and intact FGF23 concentration and bone Fgf23 mRNA expression within 12 h. These effects were paralleled by increased renal phosphate excretion and enhanced 1,25(OH)2D3 formation. We conclude that a single glucocorticoid treatment strongly downregulates the FGF23 plasma concentration. KEY MESSAGES: Glucocorticoids dexamethasone and prednisolone suppress the formation of bone-derived hormone fibroblast growth factor 23 (FGF23) in vitro. The effect is accompanied by an upregulation of Dmp1, Phex, and IκBα, negative regulators of FGF23, in UMR106 osteoblast-like cells. Glucocorticoid receptor antagonist RU-486 attenuates the effect of dexamethasone on FGF23, Dmp1, and Phex. In mice, a single glucocorticoid dose suppresses FGF23 and enhances 1,25(OH)2D3 (active vitamin D).
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Activation of MC1R with BMS-470539 attenuates neuroinflammation via cAMP/PKA/Nurr1 pathway after neonatal hypoxic-ischemic brain injury in rats. J Neuroinflammation 2021; 18:26. [PMID: 33468172 PMCID: PMC7814630 DOI: 10.1186/s12974-021-02078-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 01/07/2021] [Indexed: 12/17/2022] Open
Abstract
Background Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of hypoxic-ischemic (HI)-induced brain injury. Activation of melanocortin-1 receptor (MC1R) has been shown to exert anti-inflammatory and neuroprotective effects in several neurological diseases. In the present study, we have explored the role of MC1R activation on neuroinflammation and the potential underlying mechanisms after neonatal hypoxic-ischemic brain injury in rats. Methods A total of 169 post-natal day 10 unsexed rat pups were used. HI was induced by right common carotid artery ligation followed by 2.5 h of hypoxia. BMS-470539, a specific selective MC1R agonist, was administered intranasally at 1 h after HI induction. To elucidate the potential underlying mechanism, MC1R CRISPR KO plasmid or Nurr1 CRISPR KO plasmid was administered via intracerebroventricular injection at 48 h before HI induction. Percent brain infarct area, short- and long-term neurobehavioral tests, Nissl staining, immunofluorescence staining, and Western blot were conducted. Results The expression levels of MC1R and Nurr1 increased over time post-HI. MC1R and Nurr1 were expressed on microglia at 48 h post-HI. Activation of MC1R with BMS-470539 significantly reduced the percent infarct area, brain atrophy, and inflammation, and improved short- and long-term neurological deficits at 48 h and 28 days post-HI. MC1R activation increased the expression of CD206 (a microglial M2 marker) and reduced the expression of MPO. Moreover, activation of MC1R with BMS-470539 significantly increased the expression levels of MC1R, cAMP, p-PKA, and Nurr1, while downregulating the expression of pro-inflammatory cytokines (TNFα, IL-6, and IL-1β) at 48 h post-HI. However, knockout of MC1R or Nurr1 by specific CRISPR reversed the neuroprotective effects of MC1R activation post-HI. Conclusions Our study demonstrated that activation of MC1R with BMS-470539 attenuated neuroinflammation, and improved neurological deficits after neonatal hypoxic-ischemic brain injury in rats. Such anti-inflammatory and neuroprotective effects were mediated, at least in part, via the cAMP/PKA/Nurr1 signaling pathway. Therefore, MC1R activation might be a promising therapeutic target for infants with hypoxic-ischemic encephalopathy (HIE). Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02078-2.
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Ratsma DMA, Zillikens MC, van der Eerden BCJ. Upstream Regulators of Fibroblast Growth Factor 23. Front Endocrinol (Lausanne) 2021; 12:588096. [PMID: 33716961 PMCID: PMC7952762 DOI: 10.3389/fendo.2021.588096] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 01/11/2021] [Indexed: 12/11/2022] Open
Abstract
Fibroblast growth factor 23 (FGF23) has been described as an important regulator of mineral homeostasis, but has lately also been linked to iron deficiency, inflammation, and erythropoiesis. FGF23 is essential for the maintenance of phosphate homeostasis in the body and activating mutations in the gene itself or inactivating mutations in its upstream regulators can result in severe chronic hypophosphatemia, where an unbalanced mineral homeostasis often leads to rickets in children and osteomalacia in adults. FGF23 can be regulated by changes in transcriptional activity or by changes at the post-translational level. The balance between O-glycosylation and phosphorylation is an important determinant of how much active intact or inactive cleaved FGF23 will be released in the circulation. In the past years, it has become evident that iron deficiency and inflammation regulate FGF23 in a way that is not associated with its classical role in mineral metabolism. These conditions will not only result in an upregulation of FGF23 transcription, but also in increased cleavage, leaving the levels of active intact FGF23 unchanged. The exact mechanisms behind and function of this process are still unclear. However, a deeper understanding of FGF23 regulation in both the classical and non-classical way is important to develop better treatment options for diseases associated with disturbed FGF23 biology. In this review, we describe how the currently known upstream regulators of FGF23 change FGF23 transcription and affect its post-translational modifications at the molecular level.
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Chacar FC, Kogika MM, Zafalon RVA, Brunetto MA. Vitamin D Metabolism and Its Role in Mineral and Bone Disorders in Chronic Kidney Disease in Humans, Dogs and Cats. Metabolites 2020; 10:E499. [PMID: 33291777 PMCID: PMC7761928 DOI: 10.3390/metabo10120499] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/21/2020] [Accepted: 11/24/2020] [Indexed: 11/17/2022] Open
Abstract
Some differences regarding Vitamin D metabolism are described in dogs and cats in comparison with humans, which may be explained by an evolutionary drive among these species. Similarly, vitamin D is one of the most important regulators of mineral metabolism in dogs and cats, as well as in humans. Mineral metabolism is intrinsically related to bone metabolism, thus disturbances in vitamin D have been implicated in the development of chronic kidney disease mineral and bone disorders (CKD-MBD) in people, in addition to dogs and cats. Vitamin D deficiency may be associated with Renal Secondary Hyperparathyroidism (RSHPT), which is the most common mineral disorder in later stages of CKD in dogs and cats. Herein, we review the peculiarities of vitamin D metabolism in these species in comparison with humans, and the role of vitamin D disturbances in the development of CKD-MBD among dogs, cats, and people. Comparative studies may offer some evidence to help further research about vitamin D metabolism and bone disorders in CKD.
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Affiliation(s)
- Fernanda C. Chacar
- Department of Internal Medicine, Federal Institute of Education, Science and Technology of South of Minas Gerais (IFSULDEMINAS), Muzambinho 37890-000, Brazil;
| | - Márcia M. Kogika
- Department of Internal Medicine, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo 05508-270, Brazil;
| | - Rafael V. A. Zafalon
- Pet Nutrology Research Center, Nutrition and Production Department, School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga 13635-900, Brazil;
| | - Marcio A. Brunetto
- Pet Nutrology Research Center, Nutrition and Production Department, School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga 13635-900, Brazil;
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Mace ML, Olgaard K, Lewin E. New Aspects of the Kidney in the Regulation of Fibroblast Growth Factor 23 (FGF23) and Mineral Homeostasis. Int J Mol Sci 2020; 21:E8810. [PMID: 33233840 PMCID: PMC7699902 DOI: 10.3390/ijms21228810] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/16/2020] [Accepted: 11/19/2020] [Indexed: 02/07/2023] Open
Abstract
The bone-derived hormone fibroblast growth factor 23 (FGF23) acts in concert with parathyroid hormone (PTH) and the active vitamin D metabolite calcitriol in the regulation of calcium (Ca) and phosphate (P) homeostasis. More factors are being identified to regulate FGF23 levels and the endocrine loops between the three hormones. The present review summarizes the complex regulation of FGF23 and the disturbed FGF23/Klotho system in chronic kidney disease (CKD). In addition to the reduced ability of the injured kidney to regulate plasma levels of FGF23, several CKD-related factors have been shown to stimulate FGF23 production. The high circulating FGF23 levels have detrimental effects on erythropoiesis, the cardio-vascular system and the immune system, all contributing to the disturbed system biology in CKD. Moreover, new factors secreted by the injured kidney and the uremic calcified vasculature play a role in the mineral and bone disorder in CKD and create a vicious pathological crosstalk.
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Affiliation(s)
- Maria L. Mace
- Department of Nephrology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (K.O.); (E.L.)
| | - Klaus Olgaard
- Department of Nephrology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (K.O.); (E.L.)
| | - Ewa Lewin
- Department of Nephrology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (K.O.); (E.L.)
- Department of Nephrology, Herlev Hospital, University of Copenhagen, 2730 Herlev, Denmark
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Rausch S, Barholz M, Föller M, Feger M. Vitamin A regulates fibroblast growth factor 23 (FGF23). Nutrition 2020; 79-80:110988. [PMID: 32961447 DOI: 10.1016/j.nut.2020.110988] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/02/2020] [Accepted: 07/28/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Renal phosphate and vitamin D metabolism are regulated by proteohormone fibroblast growth factor 23 (FGF23), which is secreted by bone cells. FGF23 inhibits phosphate reabsorption and the production of calcitriol, active vitamin D (1,25(OH)2D3). FGF23 generated by other cells exerts further paracrine effects in the liver, heart, and immune system. The FGF23 plasma concentration is positively associated with the onset and progression of kidney and cardiovascular diseases, disclosing FGF23 as a potential disease biomarker. The effects of vitamin A on the expression of FGF23 are controversial. Vitamin A components, retinoids, are mainly effective through nuclear retinoic acid receptors (RAR) and exert different effects on bone. The aim of this study was to clarify whether vitamin A modulates the production of FGF23. METHODS We studied the relevance of vitamin A for FGF23 production. Fgf23 transcripts were determined by real-time quantitative polymerase chain reaction in UMR106 osteoblast-like cells and IDG-SW3 osteocytes. FGF23 protein in the cell culture supernatant was measured by enzyme-linked immunosorbent assay. RESULTS All-trans-retinoic acid, retinyl acetate, RAR agonist TTNPB (4-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid), and 13-cis-retinoic acid downregulated the expression of the Fgf23 gene in a dose-dependent manner. This effect was significantly attenuated by RAR antagonist AGN193109 (4-[2-[5,6-Dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl]ethynyl]benzoic acid). CONCLUSION The present study demonstrated that vitamin A is a potent suppressor of FGF23 production through RAR.
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Affiliation(s)
- Steffen Rausch
- Department of Physiology, University of Hohenheim, Stuttgart, Germany
| | - Michelle Barholz
- Department of Physiology, University of Hohenheim, Stuttgart, Germany
| | - Michael Föller
- Department of Physiology, University of Hohenheim, Stuttgart, Germany
| | - Martina Feger
- Department of Physiology, University of Hohenheim, Stuttgart, Germany.
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Zeng S, Querfeld U, Feger M, Haffner D, Hasan AA, Chu C, Slowinski T, Bernd Dschietzig T, Schäfer F, Xiong Y, Zhang B, Rausch S, Horvathova K, Lang F, Karl Krämer B, Föller M, Hocher B. Relationship between GFR, intact PTH, oxidized PTH, non-oxidized PTH as well as FGF23 in patients with CKD. FASEB J 2020; 34:15269-15281. [PMID: 32964520 DOI: 10.1096/fj.202000596r] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 08/07/2020] [Accepted: 09/08/2020] [Indexed: 12/20/2022]
Abstract
Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are regulators of renal phosphate excretion and vitamin D metabolism. In chronic kidney disease (CKD), circulating FGF23 and PTH concentrations progressively increase as renal function declines. Oxidation of PTH at two methionine residues (positions 8 and 18) causes a loss of function. The impact of n-oxPTH and oxPTH on FGF23 synthesis, however, and how n-oxPTH and oxPTH concentrations are affected by CKD, is yet unknown. The effects of oxidized and non-oxidized PTH 1-34 on Fgf23 gene expression were analyzed in UMR106 osteoblast-like cells. Furthermore, we investigated the relationship between n-oxPTH and oxPTH, respectively, with FGF23 in two independent patients' cohorts (620 children with CKD and 600 kidney transplant recipients). While n-oxPTH stimulated Fgf23 mRNA synthesis in vitro, oxidation of PTH in particular at Met8 led to a markedly weaker stimulation of Fgf23. The effect was even stronger when both Met8 and Met18 were oxidized. In both clinical cohorts, n-oxPTH-but not oxPTH-was significantly associated with FGF23 concentrations, independent of known confounding factors. Moreover, with progressive deterioration of kidney function, intact PTH (iPTH) and oxPTH increased substantially, whereas n-oxPTH increased only moderately. In conclusion, n-oxPTH, but not oxPTH, stimulates Fgf23 gene expression. The increase in PTH with decreasing GFR is mainly due to an increase in oxPTH in more advanced stages of CKD.
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Affiliation(s)
- Shufei Zeng
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.,Department of Nephrology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Uwe Querfeld
- Division of Gastroenterology, Nephrology and Metabolic Diseases, Department of Pediatrics, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Martina Feger
- Department of Physiology, University of Hohenheim, Stuttgart, Germany
| | - Dieter Haffner
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Pediatric Research Center, Hannover Medical School, Hannover, Germany
| | - Ahmed A Hasan
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.,Institute of Nutritional Science, University of Potsdam, Potsdam, Germany
| | - Chang Chu
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.,Department of Nephrology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Torsten Slowinski
- Department of Nephrology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | | | - Franz Schäfer
- Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany
| | - Yingquan Xiong
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.,Institute of Nutritional Science, University of Potsdam, Potsdam, Germany
| | - Bingbing Zhang
- Institute of Physiology, University of Tübingen, Tübingen, Germany.,College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Steffen Rausch
- Department of Physiology, University of Hohenheim, Stuttgart, Germany
| | | | - Florian Lang
- Institute of Nutritional Science, University of Potsdam, Potsdam, Germany
| | - Bernhard Karl Krämer
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Michael Föller
- Department of Physiology, University of Hohenheim, Stuttgart, Germany
| | - Berthold Hocher
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.,Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China.,Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China.,Institute of Medical Diagnostics, IMD, Berlin, , Berlin, Germany
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50
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Xie Y, Su N, Yang J, Tan Q, Huang S, Jin M, Ni Z, Zhang B, Zhang D, Luo F, Chen H, Sun X, Feng JQ, Qi H, Chen L. FGF/FGFR signaling in health and disease. Signal Transduct Target Ther 2020; 5:181. [PMID: 32879300 PMCID: PMC7468161 DOI: 10.1038/s41392-020-00222-7] [Citation(s) in RCA: 470] [Impact Index Per Article: 94.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/28/2020] [Accepted: 06/15/2020] [Indexed: 12/13/2022] Open
Abstract
Growing evidences suggest that the fibroblast growth factor/FGF receptor (FGF/FGFR) signaling has crucial roles in a multitude of processes during embryonic development and adult homeostasis by regulating cellular lineage commitment, differentiation, proliferation, and apoptosis of various types of cells. In this review, we provide a comprehensive overview of the current understanding of FGF signaling and its roles in organ development, injury repair, and the pathophysiology of spectrum of diseases, which is a consequence of FGF signaling dysregulation, including cancers and chronic kidney disease (CKD). In this context, the agonists and antagonists for FGF-FGFRs might have therapeutic benefits in multiple systems.
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Affiliation(s)
- Yangli Xie
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
| | - Nan Su
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Jing Yang
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Qiaoyan Tan
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Shuo Huang
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Min Jin
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Zhenhong Ni
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Bin Zhang
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Dali Zhang
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Fengtao Luo
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Hangang Chen
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Xianding Sun
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Jian Q Feng
- Department of Biomedical Sciences, Texas A&M University College of Dentistry, Dallas, TX, 75246, USA
| | - Huabing Qi
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
| | - Lin Chen
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
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