Inner Ear

The middle ear contains the three auditory ossicles the malleus, incus, and stapes which sequentially conduct sound by transmitting sound vibrations from the tympanic membrane to the fluid in the cochlea via the oval window of the otic capsule, the bony case enclosing the cochlea and vestibular system.

In the otic capsule, the vibrations are converted into electrical signals and transduced to the brain via auditory nerves. Abnormal morphological changes of the bone structures in the auditory ossicles or the otic capsule may disturb sound transmission and cause conductive hearing loss and/or vestibular dysfunction.

Intra membranous ossification

The auditory ossicles and the otic capsule, unlike most bones in the skull; so that form through intramembranous ossification, develop like long bones through endochondral ossification. In this process an initial cartilage template is subsequently replace by bone while the terminally differentiate hypertrophic chondrocytes and the calcify cartilage matrix are remove by osteoclasts (bone modeling phase).

In humans, reduced OPG in the otic capsule is associate with otosclerosis; so a condition characterize by abnormal growth of bone at one or more foci within the middle ear or inner ear that often leads to hearing loss in patients. Otosclerosis develops initially through a first phase of bone resorption; so by activate osteoclasts and increase vascularization (the otospongiosis phase), follow by new bone deposition from osteoblasts and mineralization (the otosclerosis phase).

Family linkage analyses and candidate gene association studies; which have identify several loci associate with otosclerosis; so yet none of the otosclerosis causing genes within these regions has identify so far. Nevertheless, mutations in SERPINF1 or MEPE have been recently associate with familial otosclerosis.

Given that maintaining OPG level is fundamental to the prevention of bone turnover; so in the middle and inner ear and the consequent development of otosclerosis, a better understanding; so of the molecular mechanisms that regulates OPG expression will provide clues regarding the underlying biological basis of the disease.

Auditory ossicles and otic capsule

Here data demonstrate that Ca2+ influx through CaV1.2 regulates development of the auditory ossicles and otic capsule. Moreover, excessive Ca2+ influx through TS-causing mutant CaV1.2 channel causes deficits in both hearing and body balance. The abnormal bone growth of the auditory ossicles and the otic capsule in Col2a1-Cre; CaV1.2TS mice is likely due to both increase bone formation and decrease bone resorption.

Although this correlation has not been consistently observe; also the underlying mechanism of effect of fluoride on otosclerosis has not sufficiently establish, it is intriguing that fluoride; which plays an important role in both bone formation and homeostasis of bone mineral metabolism; so has show to affect Ca2+ homeostasis in many types of cells such as in proximal tubules, fibroblasts, cardiomyocytes, as well as osteoblasts.

Further, expression of CaV1.2 was stimulate by low-dose fluoride, inhibit by high-dose fluoride; also fluoride can stimulate cardiac L-type Ca2+ channel activity by increasing channel open probability or the duration of channel opening in a dose-dependent manner.