Hearing Research xxx (2015) 1e6

Contents lists available at ScienceDirect

Hearing Research
journal homepage: www.elsevier.com/locate/heares

Review

The pathophysiology of otosclerosis: Review of current research

M. Rudic a, *, I. Keogh a, R. Wagner b, E. Wilkinson b, c, N. Kiros d, E. Ferrary e, f,
O. Sterkers e, f, A. Bozorg Grayeli e, 1, K. Zarkovic g, N. Zarkovic h
a

Discipline of Otorhinolaryngology, National University of Ireland, Galway, Ireland

Global ENT Outreach, USA
c
House Ear Clinic, LA, USA
d
Megbare Senayi General Hospital, Addis Ababa, Ethiopia
e
UMR-S 1159 Inserm, University Paris 6, France
f
AP-HP, La Piti

e Salp^
etri
ere Hospital, University Paris 6, France
g
University Medical School, Clinical Hospital Centre Zagreb Division of Pathology, Croatia
h
Institute RuCer Boskovi
c, Zagreb, Croatia
b

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 4 March 2015
Received in revised form
10 July 2015
Accepted 20 July 2015
Available online xxx

Otosclerosis is a complex disease of the human otic capsule with highest incidence in adult Caucasians.
So far, many possible etiological factors like genetics, HLA, autoimmunity, viruses, inammation, and
hormones have been investigated but still the development of the disease remains unclear. Currently, the
surgical replacement of stapes (stapedotomy) remains the best possible treatment option. In this review,
we analyze different etiological factors studied so far in otosclerosis pathophysiology and discuss most
recent ndings and possible new research pathways.
2015 Elsevier B.V. All rights reserved.

Keywords:
Otosclerosis
Pathophysiology
Hearing loss
Stapes

Contents
1.
2.
3.

Otosclerosis: definitions and epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Otosclerosis pathophysiology: literature study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Different genes involved . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Collagens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
TGF-b superfamily . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Angiotensin II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
Autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5.
HLA system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.6.
Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.7.
Measles virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.8.
Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.9.
Parathyroid hormone and parathyroid hormone-related peptides receptor expression in otosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.10.
Oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: HLA, Human Leukocyte Antigen; TGF-b, Transgrowing Growth Factor-b; BMP2/4, Bone Morphogenetic Proteins 2 and 4; SNP, Single Nucleotide Polymorphism; CD46/ CD150, Signaling lymphocytic activation molecules; IL1/6, Interleukin 1 and 6; TNF-a, Tumor Necrosis Factor-a; PTH, Parathyroid Hormone; C3a/C3b/C5a,
Complement fragments 3a, 3b and 5a; RASS, Renin Angiotensin Aldosterone System; AGTM235 and ACE I/D, Genetic polymorphisms of Renin Angiotensin Aldosterone
System; ROS, Reactive Oxygen Species; HNE, 4-hydoxynonenal
* Corresponding author. Academic Department of Otorhinolaryngology, University College Hospital Galway, c/o ENT OutPatientsDepartment, Ireland.
E-mail address: [email protected] (M. Rudic).
1
Present address: ENT Department of Dijon, Bourgogne University, France.
http://dx.doi.org/10.1016/j.heares.2015.07.014
0378-5955/ 2015 Elsevier B.V. All rights reserved.

Please cite this article in press as: Rudic, M., et al., The pathophysiology of otosclerosis: Review of current research, Hearing Research (2015),
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M. Rudic et al. / Hearing Research xxx (2015) 1e6

4.

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Otosclerosis: denitions and epidemiology

Otosclerosis (localized bone dysplasia) is a primary disease of
the human otic (labyrinthine) capsule and stapes footplate.
Depending on the site, size, and histologic features of the pathologic involved area hearing and balance are affected. When
describing otosclerosis, it is important to distinguish between the
histological and the clinical form of the disease (Declau et al.,
2007). Clinical/radiological otosclerosis refers to the presence of
otosclerotic foci at the site where it causes conductive hearing
loss by interfering with the motion of the stapes or of the round
window membrane (Guild, 1944; Shambaugh, 1994; Arnold and
Friedmann, 1987). Otosclerotic plaques are mainly localized
anterior to the oval window (ssula ante fenestram region), and
on the stapes footplate (80%), at the round window (30%), pericochlear region (21%) and the anterior part of the internal auditory canal (19%), Arnold, 2007. Other localizations although very
rare have also been described: malleus, incus, facial canal, semicircular canals and endolymphatic duct (Guild, 1944). Histological otosclerosis refers to a disease process without clinical
symptoms, discovered only on routine sectioning of the temporal
bone. There are three forms of histologic lesions of otosclerosis:
otospongiosis (early phase), transitional phase and otosclerosis
(nal phase). The early, active phase lesions consist of the presence of histiocytes, osteoblasts, and the most active cell group
osteocytes (Fraysse et al., 1994). They absorb the bone around
pre-existing blood vessels that causes higher and better microcirculation. As osteoblast becomes more involved, these areas
grow rich in amorphous ground substance and decient in
mature collagen, resulting in formation of new spongy bone. With
hematoxylin and eosin staining, this new bone appears densely
blue known as mantles of Manasse (1912). The late phase is
characterized with the formation of sclerotic, dense bone in areas
of the previous bony resorption. The vascular spaces, previously
dilated, are narrowed due to bony deposits. Otosclerosis begins in
endochondral bone, as the spongious and sclerosis continue the
endosteal and periosteal layers also become involved (Roland and

Samy, 2006).
The clinical presentation of otosclerosis is mainly a conductive
hearing loss, although sensorineural hearing loss, and mixed
hearing loss may also occur. Symptom onset usually occurs by the
early third decade of life, but onset is not unusual later in life.
Bilateral form of disease is present in almost 80% of cases (Roland
and Samy, 2006). The course of otosclerosis is very variable and so
far there are no known factors that could suggest the progression
of the disease. However, there are evidence showing that puberty,
pregnancy, and menopause hormonal factors could inuence the
disease progression (Glasscock and Shambaugh, 1990; Donaldson
and Snyder, 1993). The otosclerosis is predominantly a Caucasian
disease correlating well with their geographic distribution
throughout the world and with the mean prevalence estimated at
3/1000 (Karosi et al., 2009). Clinical otosclerosis is very rare
among black (1%), oriental and American Indian populations
(Guild, 1944). The Japanese and South American populations have
half the incidence of that of Caucasians S (Tato and Tato, 1967;
Thys et al., 2009). About 60% of the patients with clinical
otosclerosis report a family history of the disease. The remaining
40% of cases are either autosomal dominant inherited cases with
failure of penetrance in other family members, phenocopies, new
mutations or rare cases transmitted with alternate model of inheritance (Thys et al., 2009).
Several medical treatment options have been suggested for
otosclerosis, sodium uoride, NaF (Causse et al., 1982; Bozorg
Grayeli et al., 2003), biphosphonates (Keneddy et al., 1993;
Quesnel et al., 2012), and bioavonoids-antioxidants (Sziklai and
Rib

ari, 1995). Nevertheless, the best possible treatment option
still remains stapedotomy (Gjuri
c, 2007).
Despite intensive research the pathophysiology of otosclerosis it
still poorly understood. It is current understanding that otosclerosis
is a complex disease with different environmental and genetic
etiological factors involved. The aim of this paper is to provide a
systematic review of the literature concerning the pathophysiology
of otosclerosis. Fig. 1.

Fig. 1. Schematic diagram showing possible correlation of various etiological factors in otosclerosis. TGF-b (Transgrowing growth factor-b), AGTM235 and ACE I/D (Genetic
polymorphisms of Renin Angiotensin Aldosterone System), BMP2/4 (Bone morphogenetic proteins 2 and 4), TNF-a (Tumor necrosis factor-a), IL1/6 (Interleukin 1 and 6), C3a/C3b/
C5a (Complement fragments 3a, 3b and 5a), CD46/CD150 (Signaling lymphocytic activation molecules), PTH (Parathyroid hormone), ROS (Reactive oxygen species).

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M. Rudic et al. / Hearing Research xxx (2015) 1e6

2. Otosclerosis pathophysiology: literature study

2.1. Genetics
In 1861, the rst report on a familiar pattern of hearing loss due
to otosclerosis was presented by Toynbee. Later, Magnus, in 1876,
documented another family case of hearing loss. In 1922, Albrecht
was rst to conclude that otosclerosis could be inherited as an
autosomal dominant disease in certain families. In 1960, Larson
supported this hypothesis, and found that in most autosomal
dominant families, the penetrance is incomplete and lies between
25 and 40%. Fowler, in 1966, conducted a twin study and found
concordance for clinical otosclerosis in nearly all 40 pairs of
monozygotic twins that supported the initial theory that otosclerosis has a genetic basis. He further concluded that due to the lack
of evidence on the genetic transmission of histologic otosclerosis, it
is not known whether the genetic basis of inheritance is related to
the formation of the otosclerotic focus within the temporal bone or
the tendency for a lesion to progress once it has already started, or
both. Further studies showed that the genetic background facilitates the progression of the disease, but a triggering factor is
probably needed. Morrison and Bundy (1970), in a detailed genetic
study in larger otosclerotic families, concluded that otosclerosis is
an autosomal dominant disease with a 40% penetrance. The results
of that study were conrmed in 1975 (Gapany-Gapanavicus et al.)
and 1982 (Causse et al.). Although a strong familial background
exists, 40e50% of all clinical cases have been reported to be sporadic, by reduced penetrance, and characterized by other model of
inheritance besides autosomal dominant. Today, several known loci
have been localized (OTSC1, OTSC2, OTSC3, OTSC4, OTSC5, OTSC6,
OTSC7, OTSC8, and OTSC10) on chromosomes 15 q, 7 q, 6 p, 16 q, 3 q,
6 q, 9 p, and 1 q (Tomek et al., 1998; Van Den Bogaert et al., 2001,
2002, 2004; Chen et al., 2002; Brownstein et al., 2006; Thys et al.,
2007; Bel Hadj et al., 2009; Schrauwen et al., 2008). However, to
date none of the otosclerosis causing genes have been identied
despite the known chromosomal localization. Recently, a new locus
on chromosome 7q22.1, found in the gene RELN (reelin protein that
has a crucial role in the regulation of neuronal migration and
positioning in the brain development) has been associated with
otosclerosis. What is known today of RELN function has not an
evident link with otosclerosis pathogenesis, but this nding could
offer a new insight in the molecular mechanism related to the
development of the disease (Schrauwen et al., 2010). Still, many
otosclerosis patients do not have a family history of otosclerosis or
do not follow a clear Mendelian segregation of disease, and they
represent the so-called complex form of otosclerosis, caused by
environmental and genetic factors.
3. Different genes involved
3.1. Collagens
Mc Kenna et al., in 1998 showed a signicant association between clinical otosclerosis and the type I collagen COL1A1 gene
using three different polymorphic markers within the gene. More
recent studies on association of COL1A1 and otosclerosis have
demonstrated even more signicant association between clinical
otosclerosis, both familial and sporadic, and an Sp1 binding site
polymorphism in the rst intron of the COL1A1 gene (McKenna
et al., 2004). In 2007, Chen et al. further conrmed the correlation between the COL1A1 expression and otosclerosis.
3.2. TGF-b superfamily
The transforming growth factor-b1 (TGF-b1) is a member of the

TGF-b superfamily and plays an important role in the embryonic

development and maintenance of both cartilage and bone. In human otosclerotic bone cell cultures, TGF-b1 can modify the
phenotypic expression of glycosamynoglycans, bronectin and
collagen of the extracellular matrix (Bodo et al., 1995). In two large
independent population studies (Janssens et al., 2005; Thys et al.,
2009), TGF-b1 has been associated with otosclerosis. Based on the
association with the TGF-b1 family, 13 new candidate genes were
selected and further analyzed, relating to the metabolism of the otic
capsule, the involvement in the syndromic or non-syndromic forms
of stapes xation, and other hypothesis related to the development
of the otosclerosis. Two genes, bone morphogenetic proteins 2 and
4 (BMP2 and BMP4), showed a signicant association. Results
showed that the individuals who possess the T allele of a single
nucleotide polymorphism (SNP) in the 30 untranslated region of
BMP2 have a higher risk of developing otosclerosis. The other single
nucleotide polymorphism (SNP) association was an amino acidchanging SNP lying on exon 4 of BMP4 (Schrauwen et al., 2008).
3.3. Angiotensin II
Angiotensin II is implicated in the key events of inammation
and bone turnover via various growth factors and cytokines
(Lamperter et al., 1998; Asaba et al., 2009). Previous studies showed
that two genetic polymorphisms of the renin-angiotensinaldosterone system linked to higher plasmatic angiotensin II concentrations (AGT M235T and ACE I/D) were also associated with a
higher relative risk of otosclerosis occurrence in a French Caucasian
population (Imauchi et al., 2008). A replicate study performed in
larger Belgian-Dutch population was unable to duplicate these
ndings. However, it is possible that other variants in AGT and ACE
could be associated with otosclerosis (Schrauwen et al., 2009).
In vitro studies, angiotensin II receptors and angiotensinogen
mRNA were expressed in bone cell cultures obtained from otosclerotic and control stapes (Imauchi et al., 2008). Moreover,
in vitro, angiotensin II stimulated the production of the proinammatory cytokine IL-6, and reduced the alkaline phosphatase
activity in otosclerotic osteoblast-like cell cultures. These effects
appeared to be specic to otosclerosis since they were not observed
in control cell cultures (Imauchi et al., 2008). However, further
research is necessary to better clarify the inuence of Angiotensin II
in otosclerosis pathophysiology particularly its effects on inammation pathways in primary bone otosclerotic cultures.
3.4. Autoimmunity
Autoimmune reaction against the otic capsule has been suggested as a possible etiologic factor in otosclerosis, and autoantibodies against type II collagen have been detected in the sera of
patients with otosclerosis. The COL2A1 gene was rst analyzed, due
to its connection with the globuli interossei, and the hypothesis
that an autoimmune reaction to type II collagen could be involved
in otosclerosis (Yoo, 1984). However, later study by Sorensen et al.,
in 1988 did not support autoreactivity to type II collagen as an
etiopathogenetic factor in otosclerosis.
3.5. HLA system
Like in many other diseases, associations with the human
leukocyte antigen (HLA) have been investigated for otosclerosis.
HLA is an important factor associated with many diseases, especially those with an immunological component. The HLA system
represents the major histocompatibility complex in humans, and is
encoded by a complex DNA segment on chromosome 6. Study by
Miyazawa et al., in 1996, showed an association between HLA

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M. Rudic et al. / Hearing Research xxx (2015) 1e6

system and otosclerosis whereas in study by Nibu et al., 1990, no

association could be determined.
3.6. Inammation
Previous studies have demonstrated the possible role of inammatory and regulatory cytokines in the etiopathogenesis of
otosclerosis (Karosi et al., 2006). TNF-a is an inammatory cytokine
produced by monocyte-macrophage system which regulates the
differentiation and activation of bone-derived mesenchymal cells.
Its increased expression in otosclerotic bone could result in an
extensive osteoclast activation cascade and pathologic boneturnover (Stankovic and McKenna, 2006). Cytokines such as
osteoprotegerin (OPG), receptor activator of nuclear factor-kappa B
(RANK), and RANK ligand (RANK-L) play a major role in the system
that directly controls bone turnover (Zehnder et al., 2005). RANK-L
is expressed by many cells including osteoblasts that are directly
involved in bone turnover. It also regulates the differentiation,
activation, and survival of osteoclasts by its specic RANK receptor.
Osteoprotegerin or TNF-a super family member 11b (TNFaSF11b) is
the main inhibitor of the tumor necrosis factor alpha and an
antagonist of the RANK-L. It blocks the osteolysis and osteoclast
formation and induces the osteoclast apoptosis. Its main function is
to maintain and secure the normal bone turnover (Boyce and Xing,
2007). Cytotoxic enzymes (elastase, collagenase, cathepsin-D/B),
inammatory cytokine mediators such as TNF-a, IL-1, IL-6, and
complement fragments (C3a, C3b, C5a), are released from otosclerotic foci in the early stages of the disease. It is possible that
these molecules ow into the perilymph and interfere with the
electromotility of outer hair cells, causing sensorineural hearing
loss (Karosi et al., 2006). In a recent study in 2009, Sziklai et al.
showed that short-term effects of the TNF-a will not induce hearing loss, but its long-term effects might lead to sensorineural
hearing loss associated with changes in the gene expression of the
sensory epithelium. The increased TNF-a production could trigger
the focal bone resorption, thus the administration of monoclonal
anti TNF-a antibody could be considered as a potential medical
treatment option in types of cochlear otosclerosis with sensorineural hearing loss (Sziklai et al., 2009).
3.7. Measles virus
Over the past 20 years, many authors studied the potential role
of measles virus infection in the pathophysiology of otosclerosis. In
1986, McKenna et al. reported for the rst time the presence of
paramyxoviral nucleocapsids resembling structures in the osteoblastelike cells of the otosclerosis origin. Later, several studies
supported this hypothesis based on electron microscopy observations, immunohistologic studies, and RNA detection in the otosclerotic tissue (Arnold and Friedmann, 1987; McKenna and Mills,
1990; Niedermayer et al., 1994; Arnold et al., 1996). On the contrary, a study reported by Grayeli et al., in 2000 could not conrm
these results. The study was carried out on a large number of otosclerotic samples (35 patients), and measles virus could not be
detected in any of the analyzed samples by multiple highly sensitive detection methods. They concluded that high incidence of
acute infections by viruses such as herpes simplex virus and measles virus in the general population, and the presence of these viruses in different organs including the inner ear in normal
individuals challenge the possible causal relationship between the
measles virus and the chronic disease. In 2007, Arnold et al. suggested the decrease in otosclerosis incidence due to a measles
vaccination in the early 1970s. However, since otosclerosis develops
mostly between the 3rd and 5th decade of life, it is too early to draw
a denitive conclusion. The measles virus shows certain

organotropism to the otic capsule and only human and primates are
host of the measles virus due to their complementary cell surface
structures CD46 and CD150 (Dorig et al., 1993; Tatsuo et al., 2000). A
study undertaken by Karosi et al., in 2006 showed the existence of 4
new novel splice variants of the measles virus receptor CD46 only
present in the otosclerotic stapes footplate. Study of Sizklai et al., in
2009 analyzed stapes footplates (n 248) by hematoxylin-eosin
staining and corresponding MV-, OPG- and TNF-alpha-specic
RT-PCR. Results conrmed presence of measles virus in stapes
footplate of patients with histologically diagnosed otosclerosis.
Measles virus may be a triggering factor in the inammatory events
that occur during the active phase of otosclerosis in a subpopulation of patients. However, the exact role of measles virus in the
pathogenesis of otosclerosis remains to be further analyzed.
3.8. Hormones
Estrogen deciency is considered to be a cause of osteoporosis in
menopause women, and estrogen substitute therapy has shown
benecial effect in those cases. Although, it is well established that
estrogen inhibits bone resorption (Pacici, 1996), its effect on osteoblasts is still unclear. In otosclerosis, hearing deterioration has
been associated with pregnancy, and thus sex hormones were
believed to be involved in the progression of the disease (Menger
and Tange, 2003). Study of Lippy et al., in 2005 compared female
patients with (n 47) and without (n 47) children. Many women
had bilateral form of otosclerosis so total number of ears studied
was 128. This retrospective comparison did not show a difference of
hearing loss between the two groups. However, considering the
methodological limitations of such a study, denitive conclusions
cannot be drawn. Estrogen has an inhibitory effect on bone
resorption by directly inhibiting osteoclast activity as well as
decreasing auto and paracrine production of cytokines such as
interleukin (IL) 1 and IL-6, and tumor necrosis factor, TNF (Pacici,
1996). Contradictory observations were published concerning the
estrogenic effect in osteoblasts, depending on the model and
experimental protocol. Both decrease and increase of alkaline
phosphatase activity, and osteoblastic proliferation have been reported. This variability might be explained by the predominant
type of estrogen receptor present in the target tissue (Bord et al.,
2000). Imauchi et al. (2004) investigated the effect of 17b-Estradiol on bone remodeling via diastrophic dysplasia sulphate transporter (DTDST) in otosclerosis and in a human osteoblast-like cell
line (SaOS-2). 17b-Estradiol inhibited DTDST in SaOS-2 that
expressed type a- and b-receptors mRNAs. In otosclerotic cell cultures that expressed only type a receptors, no effect could be
observed. Authors concluded that the response to estrogens in
terms of DTDST activity might be related to the expressed receptor
type. It is possible that exacerbating effects of estrogens in patients
with otosclerosis may be mediated by peculiar proles of estrogen
receptor in otosclerotic cells and therefore regulatory mechanisms
related to the estrogen receptor prole in the otosclerotic cells need
to be further analyzed.
3.9. Parathyroid hormone and parathyroid hormone-related
peptides receptor expression in otosclerosis
Considering the major role of parathyroid hormone (PTH) in the
physiology of bone metabolism mediated via osteoblasts (Aurbach
et al., 1992) and the histological aspect of otosclerosis, the role of
this hormone in the etiology of the disease has been investigated.
Fano et al. (1993) showed that higher PTH concentration was
required to stimulate the adenylate cyclase activity in stapes cells.
The study conducted by Grayeli et al. (1999) showed a lower PTHPTHrP receptor mRNA expression in the otosclerotic samples

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M. Rudic et al. / Hearing Research xxx (2015) 1e6

associated with a lower cyclic AMP response. This difference supports the hypothesis that abnormal cellular response to PTH may
contribute to the abnormal turnover in otosclerosis.
3.10. Oxidative stress
Oxidative stress and ROS have been so far linked with many
types of hearing loss like age-related, noise-induced, drug ototoxicity. Major ROS production pathways include OXPHOS dysfunction,
increased pro-ROS enzyme activity, and decreased anti ROS activity
(Kamogashira et al., 2015). One of the signaling pathways of
Angiotensin II is also via reactive oxygen species (ROS). Furthermore, ROS secondary messenger HNE (4-hydroxynonenal) act as a
signaling molecule regulating TGF autocrine and paracrine function
achieving differential effects on bone cells, often in dependence to
their differentiation, proliferation as well as their antioxidant capacities (Biasi et al., 2006; Zarkovic, 2003, Negre-Salvayre et al.,
2010). Potentially ROS could be produced in otosclerotic foci and
diffuse into inner ear compartment through the cochlear endosteum, causing cochlear damage and sensorineural hearing loss.
Thus it would be interesting to further investigate their possible
role in the sensorineural hearing loss in otosclerosis.
4. Summary
Despite intensive research, pathophysiology of otosclerosis still
remains unclear. Studies have suggested different etiological factors
(autoimmunity, genetics, inammation, viruses, and hormonal inuences) but all still with no denitive conclusions. Further studies
(both population and in vitro) are needed in order to better clarify
the pathophysiology of this complex disease.
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Please cite this article in press as: Rudic, M., et al., The pathophysiology of otosclerosis: Review of current research, Hearing Research (2015),
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