Transgenic Mice Overexpressing Human Fibroblast Growth Factor 23 (R176Q) Delineate a Putative Role for Parathyroid Hormone in Renal Phosphate Wasting Disorders

Xiu-juan, Bai; Miao, Dengshun; Li, Jiarong; Goltzman, David; Karaplis, Andrew C.

doi:10.1210/en.2004-0233

Cited by 305 publications

(245 citation statements)

References 54 publications

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“…Transgenic mice over-expressing FGF-23 exhibit hypophosphatemia, with no significant changes in serum levels of calcium (Bai et al, 2004;Larsson et al, 2004;Shimada et al, 2004b), while an opposing effect of high serum levels of phosphate, and increased vitamin D activities are documented in Fgf-23 null mice (Shimada et al, 2004a;Sitara et al, 2004). More importantly, the phenotype of Fgf-23 null animals mimics patients with familial tumoral calcinosis (FTC), an autosomal recessive disorder characterized by ectopic calcifications and elevated serum levels of phosphate due to inactivating mutations in the FGF-23 gene (Benet-Pages et al, 2005;Frishberg et al, 2006).…”

Section: Fibroblast Growth Factor 23mentioning

confidence: 98%

“…It is however, interesting to note that despite extremely high serum levels of Fgf-23 (about 2,000 fold higher) in klotho mutants, Fgf-23 is unable to exert its phosphaturic effects in these mice. Both human diseases with increased FGF-23 activity, and experimental studies with over-expression of FGF-23 in transgenic animals have convincingly demonstrated that FGF-23 is a potent phosphaturic factor that induces renal phosphate wasting (ADHR_Consortium, 2000;Bai et al, 2004). However, the lack of phosphaturic activity despite extremely high levels of Fgf-23, signifies that Fgf-23 is unable to exert its physiological functions in the absence of klotho.…”

Section: Why Klotho Mutants Show Similar Phenotypes As Fgf-23 Mutants?mentioning

confidence: 99%

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Premature aging in klotho mutant mice: Cause or consequence?

Lanske¹,

Razzaque²

2007

Ageing Research Reviews

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Suitable mammalian models for aging with wide range of age-associated pathology are desirable to study molecular mechanisms of human aging. Recent studies have identified that fibroblast growth factor 23 (Fgf-23) null mice and klotho hypomorphs could generate multiple premature aging-like features, including shortened lifespan, infertility, kyphosis, atherosclerosis, extensive soft tissue calcifications, skin atrophy, muscle wasting, T-cell dysregulation, pulmonary emphysema, osteoporosis/osteopenia, abnormal mineral ion metabolism, and impaired vitamin-D homeostasis. The strikingly similar in vivo phenotypes of two separate genetically altered mouse lines implicate that the premature aging-like features may be partly regulated through a common signaling pathway involving both Fgf-23 and klotho; such speculation is experimentally supported by the observation that Fgf-23 requires klotho as a cofactor to exert its functions. Despite about 2,000 fold higher serum levels of Fgf-23 in klotho mutants (compared to wild-type animals), these mice show physical, biochemical and morphological features similar to Fgf-23 null mice, but not as Fgf-23 transgenic mice; these observations suggest that widely encountered premature aging-like features in klotho mutant mice are due to the inability of Fgf-23 to exert its bioactivities in absence of klotho. The results of recent studies showing klotho as a cofactor in Fgf-23 signaling consequently explains that the premature aging-like features in klotho deficient mice is not a primary cause, rather a consequence of lacking Fgf-23 activity. These understandings will help us to redefine the role of klotho as an aging factor. Keywords FGF-23; Kotho; Vitamin-D; Calcification; Premature aging Phosphate homeostasisMaintaining phosphate homeostasis is of crucial biological importance, as it regulates fundamental cellular functions and skeletal mineralization; it is also an important component of nucleic acids, biologically active signaling proteins, coenzymes, and lipid bilayer of the cell membranes. Ingested phosphate is mostly absorbed in the small intestine and is either incorporated in cells in organic forms, deposited as a component of bone mineral, or eliminated by the kidney; the rate of renal reabsorption and/or excretion is determined by the specific needs of the body.Roughly 70% of the phosphate is absorbed in the duodenum and jejunum, through a sodiumdependent active transport, a process stimulated by 1,25-dihydroxyvitamin D 3 [1,25 (OH) 2 D 3 ]; besides parathyroid hormone (PTH) and low-phosphate diets can also stimulate Corresponding authors: Tel.

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Section: Fibroblast Growth Factor 23mentioning

confidence: 98%

Section: Why Klotho Mutants Show Similar Phenotypes As Fgf-23 Mutants?mentioning

confidence: 99%

Premature aging in klotho mutant mice: Cause or consequence?

Lanske¹,

Razzaque²

2007

Ageing Research Reviews

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“…Emerging evidence from clinical and animal studies demonstrates pivotal roles of fibroblast growth factor 23 (FGF23) 2 signaling in the regulation of phosphate homeostasis (1)(2)(3)(4)(5). Osteoblast-lineage specific cells, especially osteocytes, produces large amounts of FGF23, but other tissues including small intestine, heart, and ventrolateral thalamic nucleus and thymus produce FGF23 as well although the physiological significance of FGF23 produced from these tissues remain to be defined (6,7).…”

mentioning

confidence: 99%

FGF23 Suppresses Chondrocyte Proliferation in the Presence of Soluble α-Klotho both in Vitro and in Vivo

Kawai

Kinoshita

Kimoto

et al. 2013

Journal of Biological Chemistry

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Background:The role of elevated FGF23 in the development of growth retardation associated with X-linked hypophosphatemic rickets (XLH) remains elusive. Results: FGF23 suppresses chondrocyte proliferation in cooperation with soluble ␣-Klotho. Conclusion: Elevated FGF23 could have a causative role in the development of growth retardation in XLH. Significance: This may provide insights into the unrecognized function of FGF23 signaling in chondrocyte biology.

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“…Genetic modifications of FGF-23 in animals have shown phenotypes similar to those of human diseases. Transgenic mice overexpressing FGF-23 exhibit hypophosphatemia, reduced serum 1,25(OH) 2 D 3 levels, and rickets (15)(16)(17), while Fgf-23 null mice exhibit hyperphosphatemia, elevated serum 1,25 (OH) 2 D 3 levels with abnormal skeletogenesis (17,18). FGF-23 transgenic mice mimic autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemia (XLH), and oncogenic osteomalacia (OOM) in humans, while the Fgf-23 null mice mimic the features consistent with human familial tumoral calcinosis (FTC) (12,19,20).…”

mentioning

confidence: 99%

Premature aging‐like phenotype in fibroblast growth factor 23 null mice is a vitamin D‐mediated process

et al. 2006

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Fibroblast growth factor 23 null mice (Fgf-23 −/− ) have a short lifespan and show numerous biochemical and morphological features consistent with premature aging-like phenotypes, including kyphosis, severe muscle wasting, hypogonadism, osteopenia, emphysema, uncoordinated movement, T cell dysregulation, and atrophy of the intestinal villi, skin, thymus, and spleen. Aging is a complex biological process controlled by multiple genetic and environmental factors (1-4). Studies involving molecular mechanisms of human aging and its progression are challenging, as it takes decades to develop some of the age-related features. Since extensive subsets of age-associated phenotypes define human aging, the availability of animal models exhibiting multiple aging features are useful, not only to analyze the molecular mechanisms of age-related changes in various organs, but also for the in vivo screening of molecules that counteract age-associated syndromes including anti-oxidant agents and hormones (5,6). DNA damage through oxidative stress, among others, is thought to be an important contributing factor in aging, and has been extensively studied in animals (1,3,(7)(8)(9)(10)(11). However, the potential role of humoral factor(s) regulating the aging process has not been studied in similar depth and detail. In this study, we show that genetic ablation of Fgf-23 results in a syndrome that resembles premature aging. (12,19,20).In this study, using in vivo genetic manipulation approaches, we present a novel role of Fgf-23 in premature aging and show that the premature aging-like phenotype in Fgf-23 −/− mice is partly mediated through increased vitamin D activities. MATERIALS AND METHODS Experimental miceWe recently generated . Animals were maintained in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were employed using protocols approved by the institution's subcommittee on animal care (IACUC). Macroscopic phenotypeThe total body weight of all mice was taken every 3-5 days starting at 2.5 wk of age until death. Survival of various groups of animals was recorded until death of control, Fgf-23 −/− , and double mutant Fgf-23 −/− /1α(OH)ase −/− mice. Biochemical measurementsBlood was obtained either by retro-orbital or tail bleeding of 3-, 6-, 9-and 11-wk-old wildtype, Fgf-23 −/− , and Fgf-23 −/− /1α(OH)ase −/− littermates. Serum was isolated by centrifugation at 3000 g for 10 min and stored at −80°C. Serum phosphorus and serum calcium were determined by colorometric measurements using the Stanbio Phosphorus Liqui-UV Test and Calcium (Arsenazo) LiquiColor Test, respectively. Total blood of 4-wk-old mice was used to determine routine hematological parameters such as cell counts. Skeletal analysesSkeletal changes in Fgf-23 −/− mice and their control littermates were analyzed by X-ray, quantitative CT (pQCT) and PIXImus measurements. Alizarin red S staining of total body skeletons, routine histology, and von Kossa staining were executed as described in our earlier studies (22). Immunohistochemica...

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Transgenic Mice Overexpressing Human Fibroblast Growth Factor 23 (R176Q) Delineate a Putative Role for Parathyroid Hormone in Renal Phosphate Wasting Disorders

Cited by 305 publications

References 54 publications

Premature aging in klotho mutant mice: Cause or consequence?

Premature aging in klotho mutant mice: Cause or consequence?

FGF23 Suppresses Chondrocyte Proliferation in the Presence of Soluble α-Klotho both in Vitro and in Vivo

Premature aging‐like phenotype in fibroblast growth factor 23 null mice is a vitamin D‐mediated process

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