title: On the biology of the bony otic capsule and the pathogenesis of otosclerosis.
abstract: In human otosclerosis, focal pathological bone remodeling occurs in significant amounts inside the normally anti-resorptive perilabyrinthine domain of the bony otic capsule. Otosclerosis causes hearing loss in 0.2-0.5% of the population by ankylosis of the footplate. The disease cannot be predicted, avoided or medically reversed as the pathogenesis remains unknown. Previously genetic research has failed to identify a specific otosclerosis-gene and earlier theories of virus infections, autoimmunity or association to generalized bone diseases have been unable to explain why otosclerosis only occurs in the bony otic capsule while the rest of the skeleton remains completely normal.  Studies from the otopathological laboratory (RH) have revealed how the bone turnover rates increase centrifugally from a sub-normal 0.1% adjacent to the inner ear space towards a normal 10% per year at the capsular periphery. This graded restriction of bone remodeling is most likely caused by the anti-resorptive action of the cytokine osteoprotegerin (OPG), which is expressed in high levels (1000 x normal bone levels) by inner ear structures to inhibit perilabyrinthine osteoclast formation and function. OPG knockout mice develop excessive, irregular bone remodeling, stapes fixation and progressive hearing loss. The lacuno-canalicular porosity is the candidate anatomical routes for the transmission of OPG-derived signals to the surrounding bone. This extracellular signaling pathway depends crucially on the viability of individual osteocytes. When bone remodeling is low, the average age of the bone matrix and osteocytes increases. We detected a high fetal density of labyrinthine osteocytes, which may secure a life-long anatomical route for inner ear OPG despite accumulation of non-viable osteocytes. Moreover, 3-D reconstructions and vector-based stereology revealed a co-existence between non-viable osteocytes and otosclerosis. We suggest that bone remodeling may commence when the effect of anti-resorptive OPG fails locally within regions of non-viable osteocytes. A sustained OPG signal from surrounding osteocyte survivors might distort the process and account for the otosclerotic morphology.
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark. sunebloch@hotmail.com
authors.forename: Sune Land
authors.initials: SL
authors.lastname: Bloch
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D004429:Ear Ossicles / Q000473:pathology*; D006801:Humans; D021621:Imaging, Three-Dimensional; D051379:Mice; D010011:Osteocytes / Q000473:pathology; D010040:Otosclerosis / Q000209:etiology* / Q000473:pathology