Otopathology in Osteogenesis Imperfecta

and ‡Department of Otolaryngology Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.
Otology & neurotology: official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology (Impact Factor: 1.79). 09/2012; 33(9). DOI: 10.1097/MAO.0b013e31826bf19b
Source: PubMed


BACKGROUND: Osteogenesis Imperfecta (OI) is a genetic disorder of connective tissue matrix. OI is caused by mutations that affect type I collagen. The hearing loss in OI is characterized by onset in early adulthood and can be conductive, sensorineural, or mixed. OBJECTIVES: To describe the temporal bone histopathology in 9 individuals with OI. MATERIALS AND METHODS: Four adult, 1 pediatric, and 4 infant specimens were identified. Temporal bones were removed at autopsy and studied using light microscopy. RESULTS: All adults and 1 pediatric specimen showed otosclerotic lesions. The findings included examples of clinical, histologic, and cochlear otosclerosis. The temporal bones of infants showed delayed ossification of the endochondral layer of bone and of the ossicles. There were no infant specimens with otosclerotic lesions. CONCLUSION: Hearing loss in OI may be the result of clinical or cochlear otosclerosis. Fracture or atrophy of the ossicles may also be present in OI. A third unidentified mechanism of hearing loss may lead to cochlear degeneration. The described findings of otosclerotic lesions have implications for the observed heterogeneity of hearing loss patterns and for the surgical management of hearing loss in OI.

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    • "The importance of this crosstalk is evident in bone syndromes where these pathways are disrupted. For example, otosclerosis and osteogenesis imperfecta tarda are characterized by sensorineural, conductive, and mixed forms of hearing loss [10]–[12]. "
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    ABSTRACT: Normal hearing requires exquisite cooperation between bony and sensorineural structures within the cochlea. For example, the inner ear secretes proteins such as osteoprotegrin (OPG) that can prevent cochlear bone remodeling. Accordingly, diseases that affect bone regulation can also result in hearing loss. Patients with fibrous dysplasia develop trabecular bone overgrowth resulting in hearing loss if the lesions affect the temporal bones. Unfortunately, the mechanisms responsible for this hearing loss, which could be sensorineural and/or conductive, remain unclear. In this study, we used a unique transgenic mouse model of increased Gs G-protein coupled receptor (GPCR) signaling induced by expression of an engineered receptor, Rs1, in osteoblastic cells. These ColI(2.3)+/Rs1+ mice showed dramatic bone lesions that histologically and radiologically resembled fibrous dysplasia. We found that ColI(2.3)+/Rs1+ mice showed progressive and severe conductive hearing loss. Ossicular chain impingement increased with the size and number of dysplastic lesions. While sensorineural structures were unaffected, ColI(2.3)+/Rs1+ cochleae had abnormally high osteoclast activity, together with elevated tartrate resistant acid phosphatase (TRAP) activity and receptor activator of nuclear factor kappa-B ligand (Rankl) mRNA expression. ColI(2.3)+/Rs1+ cochleae also showed decreased expression of Sclerostin (Sost), an antagonist of the Wnt signaling pathway that normally increases bone formation. The osteocyte canalicular networks of ColI(2.3)+/Rs1+ cochleae were disrupted and showed abnormal osteocyte morphology. The osteocytes in the ColI(2.3)+/Rs1+ cochleae showed increased expression of matrix metalloproteinase 13 (MMP-13) and TRAP, both of which can support osteocyte-mediated peri-lacunar remodeling. Thus, while the ossicular chain impingement is sufficient to account for the progressive hearing loss in fibrous dysplasia, the deregulation of bone remodeling extends to the cochlea as well. Our findings suggest that factors regulating bone remodeling, including peri-lacunar remodeling by osteocytes, may be useful targets for treating the bony overgrowths and hearing changes of fibrous dysplasia and other bony pathologies.
    PLoS ONE 05/2014; 9(5):e94989. DOI:10.1371/journal.pone.0094989 · 3.23 Impact Factor
  • Otology & neurotology: official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 07/2013; 34(7). DOI:10.1097/MAO.0b013e31829420e4 · 1.79 Impact Factor
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    ABSTRACT: Local delivery of bisphosphonates results in superior localization of these compounds for the treatment of cochlear otosclerosis, without ototoxicity. Otosclerosis is a common disorder of abnormal bone remodeling within the human otic capsule. It is a frequent cause of conductive hearing loss from stapes fixation. Large lesions that penetrate the cochlear endosteum and injure the spiral ligament result in sensorineural hearing loss. Nitrogen-containing bisphosphonates (e.g., zoledronate) are potent inhibitors of bone remodeling with proven efficacy in the treatment of metabolic bone diseases, including otosclerosis. Local delivery to the cochlea may allow for improved drug targeting, higher local concentrations, and the avoidance of systemic complications. In this study, we use a fluorescently labeled bisphosphonate compound (6-FAM-ZOL) to determine drug localization and concentration within the otic capsule. Various methods for delivery are compared. Ototoxicity is evaluated by auditory brainstem responses and distortion product otoacoustic emissions. 6-FAM-ZOL was administered to guinea pigs via intraperitoneal injection, placement of alginate beads onto the round window membrane, or microfluidic pump infusion via a cochleostomy. Hearing was evaluated. Specimens were embedded into resin blocks, ground to a mid-modiolar section, and quantitatively imaged using fluorescence microscopy. There was a dose-dependent increase in fluorescent signal after systemic 6-FAM-ZOL treatment. Local delivery via the round window membrane or a cochleostomy increased delivery efficiency. No significant ototoxicity was observed after either systemic or local 6-FAM-ZOL delivery. These findings establish important preclinical parameters for the treatment of cochlear otosclerosis in humans.
    Otology & neurotology: official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 05/2015; 36(6). DOI:10.1097/MAO.0000000000000786 · 1.79 Impact Factor