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Bone is continuously remodeled to repair and strengthen degenerative bone with accumulating dead osteocytes and microfractures. Inner ear osteoprotegerin (OPG)-mediated inhibition of otic capsular bone remodeling causes excessive perilabyrinthine bone degeneration. Consequently, microcracks accumulate around the inner ear. Microcracks cause osteocyte apoptosis and may disrupt the canalicular network connecting osteocytes. Despite their linear microscopic appearance, microcracks are three-dimensional disruption planes and represent surface areas inside a tissue space. With an elevated microcrack burden the number of disconnected osteocytes is expected to increase. This may prove relevant to ongoing research in otic focal pathologies like otosclerosis. Therefore, an unbiased quantification of the microcrack surface density (mm 2 /mm 3 ) in the human otic capsule is essential. In this study unbiased stereology was applied to undecalcified bulk stained human temporal bones to demonstrate its feasibility in describing the three-dimensional reality behind two dimensional observations of microcracks. A total of 28 human temporal bones and five ribs were bulk stained in basic fuchsin, serially sectioned and hand-ground to a thickness of 80-120 μm. Both horizontal and vertical sections were produced and compared. This study showed that surface density of microcracks was significantly higher around the inner ear compared to ribs. Furthermore, no significant difference in microcrack surface density between horizontal and vertical sections in the temporal bone was demonstrated., (© 2021 American Association for Anatomy.)

Conclusions: Age-dependent microdamage (MDx) accumulates excessively in human perilabyrinthine bone, where the bone turnover is almost absent. This may have pathological implications for bone-specific disorders such as otosclerosis. The role of MDx accumulation is discussed from an osteodynamic perspective., Objectives: Bone remodelling is highly inhibited within the otic capsule compared with the rest of the skeleton. Consequently excessive accumulation of age-dependent capsular MDx is expected. This study describes the prevalence, size and topographical distribution of MDx in the human otic capsule., Methods: A total of 241 undecalcified human temporal bones were examined. Bulk staining and the cutting-grinding technique were used to separate in vivo MDx from microcrack artefacts induced post mortem by the milling procedure. Quantitative data were obtained by fluorescence microscopy by counting and measuring and by the use of stereology., Results: Microcracks accumulated continuously and extensively in the human otic capsule throughout life. Both the number and total length of MDx were higher close to the inner ear space as compared with the capsular periphery. The mean length of the MDx remained constant with age. There was no statistically significant sex difference.

Hypothesis: A number of bone-related genes may be responsible for the unique suppression of perilabyrinthine bone remodeling., Background: Bone remodeling is highly inhibited around the inner ear space most likely because of osteoprotegerin (OPG), which is a well-known potent inhibitor of osteoclast formation and function. However, other signaling molecules may also be responsible for the inhibition of bone remodeling within the otic capsule., Methods: Microarray technology was used to determine bone-related genes differentially expressed between the lining tissues of the otic capsule (spiral ligament and stria vascularis) and the lining tissues from the middle ear of the rat. Data was analyzed with statistical bioinformatics tools. Gene expression levels of selected genes were validated using quantitative polymerase chain reaction., Results: A total of 413 genes were identified when young inner bulla (growing) were compared with young otic capsule and 358 genes were identified when adult inner bulla (quiescent) were compared with adult otic capsule. Fourteen genes were involved in bone metabolism of which four genes have been previously discussed in the literature of perilabyrinthine bone biology., Conclusion: The gene expression of the otic capsule was significantly different from that of the middle ear. This study identified a number of differentially expressed bone-related mRNAs of potential significance and confirmed the OPG/receptor activator of nuclear factor kappa-B (RANK)/RANK ligand (RANKL) pathway as the key signaling system for the unique behavior of bone cells within the otic capsule. No differentially expressed up- or downstream messengers in the OPG/RANK/RANKL pathway were found.

Bone remodeling is highly inhibited around the inner ear space, most likely by the anti-resorptive action of the inner ear cytokine osteoprotegerin (OPG) entering perilabyrinthine bone through the lacuno-canalicular porosity (LCP). This extracellular signaling pathway depends on the viability of individual osteocytes. The objective of this study was to evaluate the patency of the LCP at different ages. Sixty-five bulk-stained undecalcified human temporal bones and 19 ribs were selected to span the ages from the 30th gestational week to 95 years. Osteocytes from inside a 2-mm wide perilabyrinthine zone of bone were identified by 3D vector calculations and the numerical densities estimated with an optical dissector and compared to age-matched ribs. From a high fetal count of 90,000 cells/mm(3), the density of viable capsular osteocytes declined rapidly to 73,000 cells/mm(3) at three years of age, and non-viable osteocytes increased inversely. After 3 years, this decline/increase continued at a much slower rate. The densities of viable as well as non-viable osteocytes and the rates of change were much higher in perilabyrinthine bone compared to ribs. Only after the age of 80 years had the density of viable capsular osteocytes declined to the level of ribs. The bi-phasic osteocyte kinetics reflects different development stages. The high initial density of viable osteocytes may secure a life-long anatomical route for inner-ear OPG despite the unique accumulation of non-viable osteocytes. Clustering of non-viable osteocytes may cause local aberrations in the signaling system by closure of the LCP., (Copyright © 2012 Wiley Periodicals, Inc.)

This paper is a review of our most recent findings concerning the osteo-dynamics of the bony otic capsule and pathogenesis of otosclerosis. By exploring the spatial relationship between normal perilabyrinthine bone remodeling, the viability and spatial distribution of labyrinthine osteocytes, and the location of otosclerosis, a unique spatial pattern emerged. Bone remodeling is highly inhibited around the inner ear space. Most likely, inner ear anti-resorptive signals enter the bony otic capsule through the lacuno-canalicular porosity. The patency of this signaling pathway depends on the viability of individual osteocytes. In the young otic capsule the density of viable osteocytes is high and centripetally distributed. This arrangement may sustain a life-long osseus pathway for anti-resorptive signals even within a bone where a considerable loss of viable osteocytes must be expected, as demonstrated by a centripetal accumulation of dead osteocytes with age. The spatial distribution of dead osteocytes follows the same general pattern as otosclerosis. We suggest that clustering of dead osteocytes may impede the transmission of anti-resorptive signals locally, leaving such ghost regions susceptible to focal bone remodeling as in human otosclerosis. The preserved network of viable osteocytes around the depleted ghost regions may contain the process and distort the structure of bone remodeling into an abnormal otosclerotic pattern.

Conclusion: This study documents that otosclerotic bone remodeling is distributed centripetally around the inner ear space whereas normal bone remodeling is distributed centrifugally. We suggest that this inverse relation reflects the unique osteo-dynamic setting of the otic capsule: since perilabyrinthine bone remodeling is extremely low, osteocyte deficiency and microcracks accumulate in excess toward the inner ear space with age. This may disrupt the osseus functional network, impede propagation of anti-resorptive signals, and precipitate otosclerotic bone remodeling with a spatial preference for older bone., Objective: To quantify the spatial distribution of otosclerotic bone around the inner ear space in order to explore a possible spatial relation with normal capsular bone remodeling., Methods: Otosclerotic lesions in 53 undecalcified human temporal bones were identified and volume data were measured with the CAST-grid system and processed by dedicated software for advanced design-based stereology., Results: The maximum volume fraction of otosclerotic bone was observed in the innermost perilabyrinthine zones of the otic capsule. The volume fraction of otosclerotic bone declined gradually but significantly from the inner ear space towards the capsular periphery with a general perilabyrinthine centripetal distribution.

Conclusions: The location and three-dimensional (3D) shapes of the otosclerotic foci suggest a general centripetal distribution of otosclerotic bone remodeling around the inner ear space, whereas the normal bone remodeling is distributed centrifugally. The existence of an inverse spatial relation between normal and otosclerotic bone remodeling suggests that inner ear mechanisms in control of bone remodeling may have a pathogenetic role in otosclerosis., Objectives: To explore the 3D shape of otosclerotic lesions around the inner ear space by introducing the use of 3D reconstructions and to discuss the results in a new context of temporal bone dynamics and perilabyrinthine signaling pathways., Methods: Thirty-four otosclerotic lesions from 20 decalcified human temporal bones were rendered and visualized with the public 3D 'Reconstruct' software., Results: The majority of otosclerotic lesions were found close to the labyrinthine space at the well-established topographical sites of predilection with a smooth demarcation against the surrounding bone. However, in addition the virtual 3D technique revealed a new perilabyrinthine anisotropy of individual otosclerotic lesions, displaying a bulky end facing the inner ear space and a volumetric decline towards the capsular periphery.

The pathological perilabyrinthine bone remodelling of otosclerosis is associated with a genetic predisposition and triggered by mechanisms so far unknown. A proposed viral aetiology of otosclerosis originates from a similar concept of Paget's disease. However, at present, it is not clear why a virus should cause otosclerosis, confined to the bony otic capsule with no effects on the general skeleton in some patients, and systemic Paget's disease with only occasional involvement of the bony otic capsule in others. Moreover, the extent and distribution of pathological bone remodelling is different in Paget's disease of the temporal bone and in otosclerosis. Bone resorption and consequently bone remodelling which turns over the general skeleton at a rate of 10% per year is normally highly restricted in perilabyrinthine bone to a minimum of 0.13% per year except in otosclerosis, and systemic remodelling rates are normal even in otosclerotic patients. This suggests the existence of a local inner ear mechanism in control of capsular remodelling activity, which is either overruled, bypassed or most likely defective in otosclerosis, no matter what may have triggered the disease process. We present experimental data related to this mechanism, which may offer a truly local pathogenetic factor in otosclerosis.

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The otic capsule consists of dense highly mineralized compact bone. Inner ear osteoprotegerin (OPG) effectively inhibits perilabyrinthine remodeling and otic capsular bone turnover is very low compared to other bone. Consequently, degenerative changes like dead osteocytes and microcracks accumulate around the inner ear. Osteocytes are connected via canaliculi and need a certain connectivity to sustain life. Consequently, stochastic osteocyte apoptosis may disrupt the osteocytic network in unsustainable patterns leading to widespread cell death. When studying bulk-stained undecalcified human temporal bone, large clusters of dead osteocytes have been observed. Such "cellular voids" may disrupt the perilabyrinthine OPG mediated remodeling inhibition possibly leading to local remodeling. In the common ear disease otosclerosis pathological bone remodeling foci are found exclusively in the otic capsule. We believe the pathogenesis of otosclerosis is linked to the unique bony dynamics of perilabyrinthine bone and cellular voids may represent a starting point for otosclerotic remodeling. This study aims to identify and characterize cellular voids of the human otic capsule. This would allow future cellular void quantification and comparison of void and otosclerotic distribution to further elucidate the yet unknown pathogenesis of otosclerosis. [ABSTRACT FROM AUTHOR]

Copyright of Acta Oto-Laryngologica is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: Background: Bone remodeling is highly inhibited around the labyrinthine space, most likely by the action of the anti-resorptive cytokine osteoprotegerin (OPG). Inner ear OPG may enter the bony otic capsule through the lacuno-canalicular porosity (LCP). The aim of the study was to investigate the patency of this extracellular signaling pathway by exploring the viability, age dependency and spatial distribution of capsular osteocytes. Methods: Sixty-five bulk-stained undecalcified human temporal bones were selected to span the ages from 30th gestational week to 95 years. Osteocytes within 1000μm wide iso-concentric perilabyrinthine zones of bone were identified by 3-D vector calculations and the number of cells per unit of bone volume estimated within each zone by optical dissectors. Results: From a high initial numerical density and a centripetal distribution of viable osteocytes, the density declined over time. This effect was higher towards the inner ear space and shifted viable osteocytes into to a centrifugal distribution with age. Contrary to this, non-viable osteocytes accumulated centripetally around the inner ear space and accounted for 50% of all lacunae at 80 years of age. Non-viable osteocytes were heterogeneously distributed forming islets of varying size surrounded by the intact and viable parts of the LCP. Conclusion: The simultaneous presence of high numbers of non-viable osteocytes within a dense network of viable osteocytes is unique for the bony otic capsule. Viable osteocytes may sustain a life-long anti-resorptive signaling pathway for inner ear OPG. Clustering of non-viable osteocytes may locally impede the effect of OPG leaving the ghost regions unprotected against focal bone remodeling, as in human otosclerosis. [ABSTRACT FROM AUTHOR]

Using multiple fluorochrome tagging of eight mongrel dogs and a newly established methodology of measuring bone turnover (BTO) in the otic capsule, it has previously been demonstrated that BTO in the canine otic capsule is highly reduced close to the perilymphatic spaces (PLS) compared to the normal level of BTO in the periphery. Reanalysis of these data shows that this inhibition of BTO is far more pronounced around the cochlea and vestibule than around the semicircular canals. Similar tendencies are seen for the numerical density and mean label area of the bone remodelling units. With increasing distance to the PLS, these patterns are weakened, but still recognizable. In otosclerosis, foci of abnormal bone deposition are particularly frequent around the oval and round windows and in the cochlear capsule, i.e. where inhibition of bone remodelling is most prominent. A surpassing (or failure) of this pronounced inhibition must precede the tumultuous but delimited osteogenesis of otosclerosis. Otosclerosis may be a deviation of the normal BTO process in an osteometabolically abnormal site, perhaps initiated as an osteogenetic response to abnormal stress exposure. [ABSTRACT FROM AUTHOR]