osteoprotegerin and Hearing-Loss--Sensorineural

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.

Topics: Animals; Apoptosis; Cell Survival; Cells, Cultured; Cochlear Nerve; Ear, Inner; Enzyme-Linked Immunosorbent Assay; Hearing Loss, Sensorineural; Immunohistochemistry; In Situ Hybridization; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Degeneration; Neural Stem Cells; Osteoprotegerin; Oxidative Stress; Paraffin Embedding; Phenotype; Plastic Embedding; Schwann Cells; Spiral Ganglion; Vestibulocochlear Nerve Diseases

Otosclerosis is an inflammatory disease associated with persistent measles virus (MV) infection of the otic capsule. The nature of sensorineural hearing loss (SNHL) related to otosclerosis can be due to the chronic TNF-alpha release from the foci. TNF-alpha enters the inner ear fluid spaces in histologically active stages of otosclerosis and may cause outer hair cell functional disorder and subsequent SNHL without morphological changes of the organ of Corti. On the contrary, non-otosclerotic stapes ankylosis being a non-inflammatory disease is not harmful for hair cells. Theoretically, SNHL should not associate to this type of stapes fixation. Stapes footplates (N = 248) were examined by hematoxylin-eosin staining and corresponding MV-, OPG- and TNF-alpha-specific RT-PCR. Anti-measles IgG levels of serum specimens were measured by ELISA. Preoperative audiological results were correlated with otosclerotic and non-otosclerotic histopathologies. Among patients with stapes fixation, we found 93 active and 67 inactive otosclerosis, and 88 non-otosclerotic stapes ankylosis. MV could only be detected in otosclerotic stapes footplates. Audiometry revealed bone conduction threshold elevation toward the high frequencies in otosclerotic patients, which was associated to the duration of hearing loss. OPG mRNA expression was significantly lower in the TNF-alpha positive specimens, which was independent from virus positivity. In about one-third of stapes fixations, the etiology is non-otosclerotic stapes ankylosis. Histologic otosclerosis exhibits a strong correlation with MV presence in the bone as a sign of persistent MV infection and related inflammation with TNF-alpha release. This causes SNHL in the function of time. Non-otosclerotic stapes fixations do not cause high-frequency SNHL.

Topics: Adult; Aged; Ankylosis; Case-Control Studies; Female; Hearing Loss, Sensorineural; Humans; Male; Measles; Measles virus; Middle Aged; Osteoprotegerin; Otosclerosis; RNA, Messenger; RNA, Viral; Stapes; Time Factors; Tumor Necrosis Factor-alpha; Young Adult

Presented here is a first-person account of the evolution of the practice of surgical neurootology to that of medical neurootology shaped mainly by results of treatment directed at underlying otosclerosis-like lesions of the otic capsule and metabolic factors. With new technologies and rapidly evolving concepts, the changing treatment algorithms did not remain constant to provide the usual evidence-based outcome analyses. However, the majority of the patients presenting with neurootological symptoms had undergone previous medical or surgical treatment before undergoing the medical management herein described. The underlying ongoing basic science findings over this period were linked to the clinical observations. On the basis of the more effective results of treating neurootological disorders, recommendations are made for future areas of investigation-mostly basic science-into developing an investigative foundation for future effective management of patients with a variety of neurootological disorders.

Topics: Animals; Blood Glucose; Bone Density Conservation Agents; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Diabetes Mellitus, Type 2; Diphosphonates; Evidence-Based Medicine; Hair Cells, Auditory; Hearing Loss, Sensorineural; Humans; Insulin Resistance; Labyrinth Diseases; Meniere Disease; Mice; Mice, Knockout; Migraine Disorders; Osteoclasts; Osteoprotegerin; Otosclerosis; Tinnitus; Tumor Necrosis Factor-alpha

Otosclerosis is a bony dyscrasia characterized by histopathological findings of osteoclast production. Osteoclastogenesis explains the pathogenesis of otosclerosis. Basic science research in the experimental animal otic capsule has given insight into the process of evolution of otosclerosis. The normal otic capsule is preserved with very little bone turnover as a result of the production of osteoprotegerin (OPG) by the membranous inner ear that prevents the activation of osteoclasts. Animals genetically unable to produce OPG demonstrated the production of hearing loss and histopathology of the temporal bones consistent with that seen in otosclerosis. Applying the understanding of osteoclastogenesis to the treatment of otosclerosis has led to the clinical use of the class of drugs called bisphosphonates. The bisphosphonate group of drugs specifically targets osteoclasts by reducing production of osteoclasts and accelerating their early cell death. The rationale for use of bisphosphonates to treat the sensorineural hearing loss of otosclerosis is explained, with cases that illustrate the bisphosphonates treatment algorithms and the response to treatment.

Topics: Aged; Alendronate; Animals; Bone Density Conservation Agents; Bone Resorption; Cell Death; Combined Modality Therapy; Diphosphonates; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Ear, Inner; Ear, Middle; Etidronic Acid; Follow-Up Studies; Hearing Aids; Hearing Loss, Sensorineural; Humans; Male; Middle Aged; Osteoclasts; Osteoprotegerin; Otosclerosis; Risedronic Acid; Speech Discrimination Tests; Speech Reception Threshold Test; Stapes Surgery; Tinnitus