Journal
NEUROBIOLOGY OF DISEASE
Volume 56, Issue -, Pages 25-33Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2013.04.008
Keywords
Osteoprotegerin; Spiral ganglion cells; Cochlear neurons; Sensorineural hearing loss; Auditory stem cell
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Funding
- National Institute on Deafness and Other Communication Disorders [NIH-NIDCD K08 DC010419]
- Massachusetts Life Sciences Center
- Boston Foundation
- Bertarelli Foundation
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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. (c) 2013 Elsevier Inc. All rights reserved.
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