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Objectives: To review our current knowledge of the etiopathogenesis of otosclerotic bone remodeling including genetics, viral infection, autoimmunity and inflammation and to discuss disease pathogenesis with relevance for pharmacotherapy., Systematic Review Methodology: Relevant publications on the etiopathogenesis, molecular biology, genetics and histopathology of otosclerosis from 1984 to 2009 were analyzed., Results and Conclusions: Otosclerosis is a bone remodeling disorder of the human otic capsule, however, the etiopathogenesis remains unclear. Genetic predisposition, disturbed bone metabolism, persistent measles virus infection, autoimmunity, hormonal and environmental factors also may play contributing roles in the pathogenesis of otosclerosis. Since, diagnosis of otosclerosis is still based on histopathological examination of the removed stapes footplate, systemic prospective studies based on comprehensive histopathological and molecular biological analysis are necessary to get further information about the background of disease.

The etiology of otosclerosis is still unknown. Persistent measles virus infection of the otic capsule is supposed to be one of the etiologic factors in otosclerosis. The presence of measles virus was shown in otosclerotic patients by RT-PCR amplification of the viral RNA, detecting the viral proteins by immunohistochemistry and antimeasles immunoglobulin G in the perilymph samples. Nucleic acid (mRNA, vRNA, DNA) was extracted from pulverized, frozen stapes footplate samples of otosclerotic patients. Measles virus RNA was amplified by RT-PCR: reverse transcription and the first-round PCR amplification were performed by heat-stable recombinant Thermus thermophilus polymerase, while in the nested round PCR Taq polymerase was employed. Oligonucleotide primers specific to measles virus nucleoprotein and matrix protein RNA were used in these reactions. Edmonston- and Schwartze-type measles viruses served as positive controls and cortical bone fragments, stapes superstructures, cadaver stapes, incus and malleolar samples served as negative controls. Among 102 otosclerotic patients, 62 stapes footplate samples contained measles virus RNA. Measles virus RNA was not detected in other bone specimens of the patients. The etiologic role of measles virus in the pathogenesis of otosclerosis should be considered. The 40 negative samples may be genetically determined otosclerotic cases or stapes fixations due to other causes.

Hypothesis: Otosclerosis is a bone remodeling disorder of the otic capsule causing conductive and sensorineural hearing loss. Persistent measles virus infection of the temporal bone with increased tumor necrosis factor (TNF)-alpha and decreased osteoprotegerin mRNA expression is supposed to be the main etiologic factor in otosclerosis., Background: Determinants of measles virus infection and reactive inflammation were studied in otosclerosis. The presence of measles virus was shown in otosclerotic patients by reverse transcriptase-polymerase chain reaction (RT-PCR) amplification of the viral RNA. No report is available, however, about the role and interactions of bone-specific cytokines in otosclerosis., Methods: : Nucleic acid was extracted from stapes footplates of clinically otosclerotic patients. Measles virus nucleoprotein RNA was amplified by seminested RT-PCR. TNF-alpha and osteoprotegerin mRNA coexpression was detected by RT-PCR in otosclerotic bone and was correlated to measles virus positivity., Results: Among 154 clinically stapes fixation otosclerotic patients, 99 stapedes contained measles virus RNA. TNF-alpha mRNA was detectable in 88 virus-positive and in 6 virus-negative stapes footplates. Osteoprotegerin mRNA expression was significantly lower in the TNF-alpha-positive specimens (P < .0001) that was independent from virus positivity., Conclusion: Detection of TNF-alpha mRNA demonstrates activated osteoclast functions and inflammatory pathways in otosclerotic stapes footplates associated with measles virus presence. Increased expression of TNF-alpha and its action on RANK production inhibits the protective functions of osteoprotegerin on normal bone turnover in the otic capsule.

Hypothesis: Persistent measles virus infection of the otic capsule is suggested to be an etiologic factor in otosclerosis. Otosclerosis is a disease of complex unknown etiology causing progressive conductive and/or sensorineural hearing loss (HL)., Background: Diagnostic methods of otosclerosis are sensitive to ossicular chain fixation with low specificity for otosclerotic stapes ankylosis., Methods: Nucleic acid was extracted from stapes foot plates of clinically stapes fixation patients (N = 213). Measles virus nucleoprotein RNA was amplified by reverse-transcriptase polymerase chain reaction. Amplification results were correlated to histologic findings in 49 cases. Antimeasles IgG levels of all clinically stapes fixation as well as control sera specimens were measured by enzyme-linked immunosorbent assay., Results: Among clinically stapes fixation patients, 141 stapes foot plates contained measles virus RNA. Among 49 histologic specimens, viral RNA was detectable only in histologically otosclerotic stapes foot plates (n = 35). Histology for virus-negative foot plates (n = 14) excluded otosclerosis. Antimeasles IgG levels were significantly lower in the sera of patients with virus-positive stapes than in control sera., Conclusions: Combination of decreased antimeasles IgG serum level and conductive HL has a great specificity and sensitivity as a diagnostic method in the preoperative evaluation of ossicular chain fixations otosclerosis. Low antimeasles IgG level indicates otosclerosis, whereas high level suggests non-otosclerotic ossicular chain fixations. Preoperative elucidation of the cause of a conductive HL may suggest optional medical treatment in preference to surgical methods.

Hypothesis: Stapes ankylosis is a disease with variable histopathology and can be caused by otosclerosis or pseudo-otosclerosis. Viral pathogenesis of otosclerosis could be established only by correlative analysis: histologic examination of the stapes footplate and reverse-transcriptase polymerase chain reaction (RT-PCR) amplification of the viral RNA., Background: Presence of the RNA genome of measles virus was demonstrated in the footplates of clinically otosclerotic patients by RT-PCR, and also viral proteins were detected by immunohistochemistry., Methods: Nucleic acids were extracted from ankylotic stapes footplates of clinically stapes fixation patients (n = 104). Measles virus genomic nucleoprotein (NP) RNA was amplified by seminested RT-PCR. Amplification results were correlated to postoperative histologic and audiologic findings., Results: Measles virus RNA was detectable only in histologically otosclerotic stapes footplates (n = 67). Histology for virus negative footplates (n = 37) excluded otosclerosis. Virus negative stapes footplates showed nonotosclerotic, degenerative disorders., Conclusions: Stapes ankylosis is a heterogeneous disease causing conductive hearing loss with different etiologies. Nonotosclerotic stapes fixations could be established as pseudo-otosclerosis and may belong to nonspecific, degenerative disorders with variable and noncharacteristic histopathology. Otosclerosis is an inflammatory disease caused by persisting measles virus infection of the otic capsule.

Hypothesis: Otosclerosis is a disease of unknown etiology causing conductive or sensorineural hearing loss. Persistent measles virus infection of the otic capsule is considered to be one of the etiologic factors in otosclerosis., Background: Determinants of measles virus infection and reactive inflammation were studied in otosclerosis. The presence of measles virus was shown in otosclerotic patients by reverse-transcription polymerase chain reaction (RT-PCR) amplification of the viral RNA. No report is available, however, on the types and features of paracrine cytokines in otosclerosis., Methods: Nucleic acid was extracted from stapes footplate samples of clinically otosclerotic patients. Measles virus nucleoprotein RNA was amplified by seminested RT-PCR. Tumor necrosis factor (TNF)-alpha mRNA expression was detected by RT-PCR in otosclerotic bone and was correlated with preoperative audiologic findings and measles virus positivity., Results: Among 154 clinically otosclerotic patients, 99 stapes footplate specimens contained measles virus RNA. TNF-alpha mRNA was detectable in 88 virus-positive and in 6 virus-negative stapes footplates. There was no detectable TNF-alpha mRNA expression in virus negative cases., Conclusion: The etiologic role of measles virus in the pathogenesis of otosclerosis should be considered. Detection of TNF-alpha mRNA demonstrates activated osteoclast functions and inflammatory pathways in otosclerotic stapes footplates associated with measles virus presence. Virus-associated and virus-negative pathomechanisms of otosclerosis should be distinguished.

Hypothesis: The cause of otosclerosis is still unknown. Persistent measles virus infection of the otic capsule is supposed to be one of the etiologic factors in otosclerosis. Chronic viral antigen expression on the surface of infected cells can induce a secondary autoimmune reaction against the otic capsule., Background: In the past 15 years, some reports proposed the possible etiologic role of measles virus in otosclerosis. The presence of measles virus was shown in otosclerotic patients by reverse-transcriptase polymerase chain reaction amplification of the viral RNA, detecting the viral proteins by immunohistochemistry and detecting antimeasles immunoglobulin G in the perilymph samples. Many concerns were elicited by these results., Methods: Nucleic acid was extracted from pulverized, frozen stapes footplate samples of otosclerotic patients. Measles virus RNA was amplified by reverse-transcriptase polymerase chain reaction: reverse transcription and the first round polymerase chain reaction amplification was performed by heat stable recombinant Thermus thermophilus polymerase, whereas in the nested round, polymerase chain reaction Taq-polymerase was used. Measles virus nucleoprotein RNA-specific oligonucleotide primers were used in these reactions. An Edmonston-type measles virus served as a positive control and cortical bone fragments or stapes superstructures served as negative controls., Results: Among 34 otosclerotic patients, 20 stapes footplate samples contained measles virus RNA. Measles virus RNA was not detected in other bone specimens of the patients., Conclusion: The etiologic role of measles virus in the pathogenesis of otosclerosis should be considered. The 14 negative samples may be genetically determined otosclerotic cases.