REGULATING OSTEOCLASTS FOR THE MAINTENANCE OF AUDITORY OSSICULAR MORPHOLOGY, THE MIDDLE EAR AND HEARING
Abstract
Currently little is known about whether and how osteoclasts play a role in the vibration of auditory ossicles. This review focuses on morphological change of auditory ossicles and hearing function when osteoclasts increase or decrease.
Prevention of bone resorption may be implicated with clinical application of several middle-ear diseases.
Introduction
Bone remodeling may be important for auditory ossicular structure. Osteoclasts are specialized multinuclear macrophages that secrete HCL and hydrolases causing bone resorption. Osteoclasts are upregulated after inflammation, and ossicles are eroded by repeated otitis media. Therefore, regulating of the number of os-teoclasts is critical for maintaining the shape and size of auditory ossicles. For bone remodeling to occur, receptor activator of nuclear factor-kB (NF-kB) ligand (RANKL) must bind with its receptor (RANK), located on osteoclasts. The potentially continuous bone loss is mitigated by the decoy receptor osteoprotegerin (OPG) which competitively binds RANKL and blocks the interaction of RANKL-RANK. The osteoclastic bone resorption in adults is balanced by osteoblastic bone formation through ‘coupling’ mechanisms, which maintain bone integrity (bone remodeling )(Fig.1). 1
We reviewed the role of osteoclasts in the maintenance of the ossicular structure and how hearing function is impaired in knock-out mice with increased or decreased osteoclast numbers.
Auditory ossicles in osteopetrotic mice
Conductive and/or sensorineural hearing loss is frequently seen in humans with ostepetrosis.2–5 We analyzed hearing function and the morphology of the auditory ossicles in osteopetrotic mice, which lack osteoclasts due to either a c-Fos or RANKL deficiency. The auditory brainstem response showed that mice of both genotypes had hearing loss, and that the mobility of the malleus was dramatically reduced as revealed by laser Dop-pler vibrometry.6 Although involvement of the nervous system cannot be excluded, impaired vibration of the malleus is the most plausible explanation for the hearing loss of osteopetrotic mice.6 The impaired vibration was apparently due to contact of the malleus with the promontory, the reduced volume of the tympanic cavity and the increased volume of auditory ossicles in comparion to control animals.6
Fig. 1. Summary of osteoclast differentiation and bone resorption – RANK-RANKL lignad Osteoprotegerin osteoclast differentiation. RANKL: receptor activator of nuclear factor-kappa B ligand. Osteoclasts differentiate from precursors of the monocyte macrophage lineage in the presence of the cytokine RANKL.
Excessive numbers of osteoclasts in ossicles
However, too much of a ‘good thing’ also leads to hearing loss. The shape of ossicles and hearing were also degraded when the numbers of osteoclasts were increased. Mice lacking OPG (Opg-/-mice), also known as a model for juvenile Paget’s disease, exhibited excessive numbers of osteoclasts resulting in abnormal bone remodeling of the otic capsule.7,8 Auditory ossicles in Opg-/-mice are massively resorbed by the abundant osteoclasts which may also result in impaired hearing function.7,8 In Opg-/-mice, the ligament at the junction of the stapes and the otic capsule is lost by bony ankylosis (fusion).7,8
Osteoclasts in cholesteatoma
We counted the number of Cathepsin K positive cells which are markers of osteoclasts. There are significant differences of the number of cathepsin K cells between normal people and patients with cholesteatoma.
Bisphosphonate therapy in otosclerosis
Opg -/-mice were intra-peritonally injected with risedronate, one of the widely-used bisphosphonates, for five days/week over nine weeks. The treatment significantly inhibited bone loss in auditory ossicles as well as in long bones of Opg-/-mice compared to untreated control mice.9 Thinning of malleus handle and bony fusion of the junction between the stapes and the otic capsule were reduced by the treatment. In addition, hearing loss in Opg-/-mice was significantly reduced by risedronate treatment.9
The clinical controlled trial is ongoing. We investigate whether bisphophonate can prevent progressive hearing loss in Pts with otosclerosis or not.
Conclusion
We have shown that both osteopetrosis and osteoporosis impacts the structure of the middle-ear ossicles and impairs hearing function. The modification of the ossicles provides an explanation for the impaired vibration of auditory ossicles seen in both osteoporotic and osteopetrotic mouse models. Anti-bone-resorptive therapy can prevent osteoclastic bone resorption of ossicles and progressive hearing loss. The number of Cathepsin K positive cells and/or osteoclasts are significantly increased in the ossicles in cases of cholesteatoma. The anti-bone-resorptive medication may prevent bone resorption of cholesteatoma.
Acknowledgements
This work was supported by Grants-in-Aid for Young Scientists B (17791198, 21791643 to S.K.), for Scientific Research C (23592495 to S.K.), and Grants-in-Aid for Scientific Research B (17390420 and 21390425 to K.M.) from JSPS; and a Keio University Special Grant-in-Aid for Innovative Collaborative Research Projects.
References
1.Zhao C, Irie N, Takada Y et al. Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab 4:111–121, 2006
2.Hawke M, Jahn AF, Bailey D. Osteopetrosis of the temporal bone. Arch Otolaryngol 107:278–282, 1981
3.Stocks RM, Wang WC, Thompson JW, Stocks MC 2nd, Horwitz EM. Malignant infantile osteopetrosis: otolaryngological complications and management. Arch Otolaryngol Head Neck Surg 124:689–694, 1998
4.Benichou OD, Laredo JD, de Vernejoul MC. Type II autosomal dominant osteopetrosis (Albers-Schonberg disease): clinical and radiological manifestations in 42 patients. Bone 26:87–93, 2000
5.Maranda B, Chabot G, Decarie JC et al. Clinical and cellular manifestations of OSTM1-related infantile osteopetrosis. J Bone Miner Res 23:296–300, 2008
6.Kanzaki S, Takada Y, Niida S et al. Impaired vibration of auditory ossicles in osteopetrotic mice. Am J Pathol 178:1270–1278, 2011
7.Zehnder AF, Kristiansen AG, Adams JC, Kujawa SG, Merchant SN, McKenna MJ. Osteoprotegrin knockout mice demonstrate abnormal remodeling of the otic capsule and progressive hearing loss. Laryngoscope 116:201–206, 2006
8.Kanzaki S, Ito M, Takada Y, Ogawa K, Matsuo K. Resorption of auditory ossicles and hearing loss in mice lacking osteopro-tegerin. Bone 39:414–419, 2006
9.Kanzaki S, Takada Y, Ogawa K, Matsuo K. Bisphosphonate therapy ameliorates hearing loss in mice lacking osteoprotegerin. J Bone Miner Res 24:43–49, 2009
10.Boyle WJ, Simonet W, Lacey DL. Osteoclast differentiation and activation. Nature 423, 337–342, 2003
Address for correspondence: Sho Kanzaki, MD, PhD, Department of Otolaryngology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160–8582, Japan. skan@a7.keio.jp
Cholesteatoma and Ear Surgery – An Update, pp. 33–35
Edited by Haruo Takahashi
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