title: Loss of osteoprotegerin expression in the inner ear causes degeneration of the cochlear nerve and sensorineural hearing loss.
abstract: Osteoprotegerin (OPG) is a key regulator of bone remodeling. Mutations and variations in the OPG gene cause many human diseases that are characterized by not only skeletal abnormalities but also poorly understood hearing loss: Paget's disease, osteoporosis, and celiac disease. To gain insight into the mechanisms of hearing loss in OPG deficiency, we studied OPG knockout (Opg(-/-)) mice. We show that they develop sensorineural hearing loss, in addition to conductive hearing loss due to abnormal middle-ear bones. OPG deficiency caused demyelination and degeneration of the cochlear nerve in vivo. It also activated ERK, sensitized spiral ganglion cells (SGC) to apoptosis, and inhibited proliferation and survival of cochlear stem cells in vitro, which could be rescued by treatment with exogenous OPG, an ERK inhibitor, or bisphosphonate. Our results demonstrate a novel role for OPG in the regulation of SGC survival, and suggest a mechanism for sensorineural hearing loss in OPG deficiency.
authors.affiliation: Eaton-Peabody Laboratories, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
authors.forename: Shyan-Yuan
authors.initials: SY
authors.lastname: Kao
authors.forename: Judith S
authors.initials: JS
authors.lastname: Kempfle
authors.forename: Jane B
authors.initials: JB
authors.lastname: Jensen
authors.forename: Deborah
authors.initials: D
authors.lastname: Perez-Fernandez
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Lysaght
authors.forename: Albert S
authors.initials: AS
authors.lastname: Edge
authors.forename: Konstantina M
authors.initials: KM
authors.lastname: Stankovic
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured; D003056:Cochlear Nerve / Q000378:metabolism / Q000473:pathology*; D007758:Ear, Inner / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D006319:Hearing Loss, Sensorineural / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology; D053244:Osteoprotegerin / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress / Q000502:physiology; D016612:Paraffin Embedding; D010641:Phenotype; D016613:Plastic Embedding; D012583:Schwann Cells / Q000378:metabolism; D013136:Spiral Ganglion / Q000166:cytology; D000160:Vestibulocochlear Nerve Diseases / Q000378:metabolism / Q000473:pathology*
chemical_list: D053244:Osteoprotegerin