title: FGF23 deficiency leads to mixed hearing loss and middle ear malformation in mice.
abstract: Fibroblast growth factor 23 (FGF23) is a circulating hormone important in phosphate homeostasis. Abnormal serum levels of FGF23 result in systemic pathologies in humans and mice, including renal phosphate wasting diseases and hyperphosphatemia. We sought to uncover the role FGF23 plays in the auditory system due to shared molecular mechanisms and genetic pathways between ear and kidney development, the critical roles multiple FGFs play in auditory development and the known hearing phenotype in mice deficient in klotho (KL), a critical co-factor for FGF23 signaling. Using functional assessments of hearing, we demonstrate that Fgf[Formula: see text] mice are profoundly deaf. Fgf[Formula: see text] mice have moderate hearing loss above 20 kHz, consistent with mixed conductive and sensorineural pathology of both middle and inner ear origin. Histology and high-voltage X-ray computed tomography of Fgf[Formula: see text] mice demonstrate dysplastic bulla and ossicles; Fgf[Formula: see text] mice have near-normal morphology. The cochleae of mutant mice appear nearly normal on gross and microscopic inspection. In wild type mice, FGF23 is ubiquitously expressed throughout the cochlea. Measurements from Fgf[Formula: see text] mice do not match the auditory phenotype of Kl-/- mice, suggesting that loss of FGF23 activity impacts the auditory system via mechanisms at least partially independent of KL. Given the extensive middle ear malformations and the overlap of initiation of FGF23 activity and Eustachian tube development, this work suggests a possible role for FGF23 in otitis media.
authors.affiliation: Program in Speech and Hearing Bioscience and Technology, Harvard/MIT Joint Division of Health Sciences and Technology, Cambridge, Massachusetts, United States of America; Eaton Peabody Laboratories, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States of America.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Lysaght
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, United States of America.
authors.forename: Quan
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Eaton Peabody Laboratories, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States of America.
authors.forename: Neil
authors.initials: N
authors.lastname: Kalwani
authors.affiliation: Department of Radiology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Caruso
authors.affiliation: Department of Radiology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: MaryBeth
authors.initials: M
authors.lastname: Cunnane
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, United States of America.
authors.forename: Beate
authors.initials: B
authors.lastname: Lanske
authors.affiliation: Eaton Peabody Laboratories, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States of America; Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States of America.
authors.forename: Konstantina M
authors.initials: KM
authors.lastname: Stanković
mesh_terms: D000818:Animals; D004432:Ear, Middle / Q000002:abnormalities* / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D046089:Hearing Loss, Mixed Conductive-Sensorineural / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23