FGF23 Deficiency Leads to Mixed Hearing Loss and Middle Ear Malformation in Mice

Lysaght, Andrew C.; Yuan, Quan; Fan, Yi; Kalwani, Neil M; Caruso, Paul; Cunnane, Marybeth; Lanske, Beate; Stanković, Konstantina M.

doi:10.1371/journal.pone.0107681

Cited by 26 publications

(26 citation statements)

References 42 publications

(65 reference statements)

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“…Abnormal serum levels of FGF23 lead to systemic pathologies in humans, including renal phosphate wasting diseases and hyperphosphatemia. FGF23-deficient mice show a mixed hearing loss and middle ear malformations [36], and changes in circulating FGF23 have been observed in humans and mice with ENPP1 and PHEX deficiencies [16,37]. …”

Section: Discussionmentioning

confidence: 99%

Ectopic Mineralization and Conductive Hearing Loss in Enpp1asj Mutant Mice, a New Model for Otitis Media and Tympanosclerosis

2016

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Otitis media (OM), inflammation of the middle ear, is a common cause of hearing loss in children and in patients with many different syndromic diseases. Studies of the human population and mouse models have revealed that OM is a multifactorial disease with many environmental and genetic contributing factors. Here, we report on otitis media-related hearing loss in asj (ages with stiffened joints) mutant mice, which bear a point mutation in the Enpp1 gene. Auditory-evoked brainstem response (ABR) measurements revealed that around 90% of the mutant mice (Enpp1asj/asj) tested had moderate to severe hearing impairment in at least one ear. The ABR thresholds were variable and generally elevated with age. We found otitis media with effusion (OME) in all of the hearing-impaired Enpp1asj/asj mice by anatomic and histological examinations. The volume and inflammatory cell content of the effusion varied among the asj mutant mice, but all mutants exhibited a thickened middle ear epithelium with fibrous polyps and more mucin-secreting goblet cells than controls. Other abnormalities observed in the Enpp1 mutant mice include over-ossification at the round window ridge, thickened and over-calcified stapedial artery, fusion of malleus and incus, and white patches on the inside of tympanic membrane, some of which are typical symptoms of tympanosclerosis. An excessive yellow discharge was detected in the outer ear canal of older asj mutant mice, with 100% penetrance by 5 months of age, and contributes to the progressive nature of the hearing loss. This is the first report of hearing loss and ear pathology associated with an Enpp1 mutation in mice. The Enpp1asj mutant mouse provides a new animal model for studying tympanosclerotic otitis and otitis media with effusion, and also provides a specific model for the hearing loss recently reported to be associated with human ENPP1 mutations causing generalized arterial calcification of infancy and hypophosphatemic rickets.

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Section: Discussionmentioning

confidence: 99%

Ectopic Mineralization and Conductive Hearing Loss in Enpp1asj Mutant Mice, a New Model for Otitis Media and Tympanosclerosis

2016

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“…For example, FGF23 deficiency leads to mixed hearing loss and middle ear malformation in mice (Lysaght , et al 2014). FGF23 also regulates renal sodium handling and blood pressure (Andrukhova , et al 2014a), as well as cardiac structure and function (Agarwal , et al 2014).…”

Section: Discussionmentioning

confidence: 99%

FGF23 gene regulation by 1,25-dihydroxyvitamin D: opposing effects in adipocytes and osteocytes

Kaneko¹,

Saini²,

Griffin³

et al. 2015

Journal of Endocrinology

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In a closed endocrine loop, 1,25-dihydroxyvitamin D3 (1,25D) induces the expression of fibroblast growth factor-23 (FGF23) in bone, with the phosphaturic peptide in turn acting at kidney to feedback repress CYP27B1 and induce CYP24A1 to limit the levels of 1,25D. In 3T3-L1 differentiated adipocytes, 1,25D represses FGF23 and leptin expression, while not affecting leptin receptor transcription, but inducing C/EBP. Conversely, in UMR-106 osteoblast-like cells, FGF23 mRNA concentrations are upregulated by 1,25D, an effect that is blunted by lysophosphatidic acid, a cell-surface acting ligand. Progressive truncation of the mouse FGF23 proximal promoter linked in luciferase reporter constructs reveals a 1,25D-responsive region between −400 and −200 bp. A 0.6 kb fragment of the mouse FGF23 promoter, linked in a reporter construct, responds to 1,25D with a 4-fold enhancement of transcription in transfected K562 cells. Mutation of either an ETS1 site at −346 bp, or an adjacent candidate VDR/Nurr1-element, in the 0.6 kb reporter construct reduces the transcriptional activity elicited by 1,25D to a level that is not significantly different from a minimal promoter. This composite ETS1-VDR/Nurr1 cis-element may function as a switch between induction (osteocytes) and repression (adipocytes) of FGF23, depending on the cellular setting of transcription factors. Moreover, experiments demonstrate that a 1kb mouse FGF23 promoter-reporter construct, transfected into MC3T3 osteoblast-like cells, responds to high calcium challenge with a statistically significant 1.7–2.0-fold enhancement of transcription. Thus, the FGF23 proximal promoter harbors cis-elements that drive responsiveness to 1,25D and calcium, agents that induce FGF23 to curtail the pathologic consequences of their excess.

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“…Similarly, the Fgf23 knockout mice have smaller auditory bullae with reduced bone density (Lysaght et al. ). Further investigation into other knockdown mutants may help to understand the development of the auditory bulla; elucidating the genes and mechanisms that control the integration of the components of the auditory bulla, its positioning and final shape.…”

Section: The Development Of the Middle Ear Skeletal Structuresmentioning

confidence: 97%

The development of the mammalian outer and middle ear

2015

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The mammalian ear is a complex structure divided into three main parts: the outer; middle; and inner ear. These parts are formed from all three germ layers and neural crest cells, which have to integrate successfully in order to form a fully functioning organ of hearing. Any defect in development of the outer and middle ear leads to conductive hearing loss, while defects in the inner ear can lead to sensorineural hearing loss. This review focuses on the development of the parts of the ear involved with sound transduction into the inner ear, and the parts largely ignored in the world of hearing research: the outer and middle ear. The published data on the embryonic origin, signalling, genetic control, development and timing of the mammalian middle and outer ear are reviewed here along with new data showing the Eustachian tube cartilage is of dual embryonic origin. The embryonic origin of some of these structures has only recently been uncovered (Science, 339, 2013(Science, 339, , 1453 Development, 140, 2013, 4386), while the molecular mechanisms controlling the growth, structure and integration of many outer and middle ear components are hardly known. The genetic analysis of outer and middle ear development is rather limited, with a small number of genes often affecting either more than one part of the ear or having only very small effects on development. This review therefore highlights the necessity for further research into the development of outer and middle ear structures, which will be important for the understanding and treatment of conductive hearing loss.

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FGF23 Deficiency Leads to Mixed Hearing Loss and Middle Ear Malformation in Mice

Cited by 26 publications

References 42 publications

Ectopic Mineralization and Conductive Hearing Loss in Enpp1asj Mutant Mice, a New Model for Otitis Media and Tympanosclerosis

Ectopic Mineralization and Conductive Hearing Loss in Enpp1asj Mutant Mice, a New Model for Otitis Media and Tympanosclerosis

FGF23 gene regulation by 1,25-dihydroxyvitamin D: opposing effects in adipocytes and osteocytes

The development of the mammalian outer and middle ear

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