Osteoprotegrin Knockout Mice Demonstrate Abnormal Remodeling of the Otic Capsule and Progressive Hearing Loss

Zehnder, Andreas; Kristiansen, Arthur G.; Adams, Joe C.; Kujawa, Sharon G.; Merchant, Saumil N.; McKenna, Michael J.

doi:10.1097/01.mlg.0000191466.09210.9a

Cited by 97 publications

(90 citation statements)

References 16 publications

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“…We recently found that expression of OPG also best characterizes the wild-type otic capsule (unpublished data). Our previous work showed that OPG plays an important role in the inhibition of otic capsule remod-eling [Zehnder et al, 2005], and that the otic capsule of the OPG knockout mice undergoes abnormal remodeling that closely resembles otosclerosis [Zehnder et al, 2006]. Because we did not observe active remodeling in the otic capsule of Mov13 mice, it is not surprising that expression levels of OPG remained high in the Mov13 otic capsule, thus contributing to the selection of OPG as a gene that is highly characteristic of the otic capsule.…”

Section: Discussionmentioning

confidence: 99%

Studies of Otic Capsule Morphology and Gene Expression in the Mov13 Mouse – An Animal Model of Type I Osteogenesis Imperfecta

Stanković

Kristiansen²,

Bizaki³

et al. 2007

Audiol Neurotol

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Type I osteogenesis imperfecta (OI) is a disorder of skeletal bones characterized by bone fragility and blue sclera, which can result from mutations in genes encoding for type I collagen – the COL1A1 and COL1A2 genes. Fifty percent of patients with type I OI develop hearing loss and associated histopathological changes in the otic capsule that are indistinguishable from otosclerosis, a major cause of acquired hearing loss. In an attempt to elucidate molecular and cellular mechanisms of hearing loss in type I OI, we have studied the Mov13 mouse, which has served as an animal model of type I OI by virtue of exhibiting variable transcriptional block of the COL1A1 gene. We studied the morphometry of the Mov13 otic capsule and compared expression levels of 60 genes in the otic capsule with those in the tibia and parietal bone of the Mov13 and wild-type mice. The degree of transcriptional block of the COL1A1 gene and its downstream effects differed significantly between the bones examined. We found that expression levels of bone morphogenetic protein 3 and nuclear factor ĸ-B1 best distinguished Mov13 otic capsule from wild-type otic capsule, and that osteoprotegerin, caspase recruitment domain containing protein 1, and partitioning defective protein 3 best distinguished Mov13 otic capsule from Mov13 tibia and parietal bone. Although the Mov13 mouse did not demonstrate evidence of active abnormal otic capsule remodeling as seen in type I OI and otosclerosis, studying gene expression in the Mov13 mouse has provided evidence that osteocytes of the otic capsule differ from osteocytes in other bones.

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Section: Discussionmentioning

confidence: 99%

Studies of Otic Capsule Morphology and Gene Expression in the Mov13 Mouse – An Animal Model of Type I Osteogenesis Imperfecta

Stanković

Kristiansen²,

Bizaki³

et al. 2007

Audiol Neurotol

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“…In nonoperated persons, (35,57) Bone morphogenetic protein 4 BMP4 Role in otic capsule chondrogenesis and bone formation (58,59) Involved in the generation of inner ear sensory epithelia (60) Noggin NOG Antagonist BMPs, with high affinity for BMP2 and 4 (61) Mutations in this gene cause syndromic stapes fixation (55,56) Fibroblast growth factor 2 FGF2 Role in otic capsule chondrogenesis (62) Synergistic interaction with TGF-␤1 is required for induction otic capsule formation (62) Localized in higher concentration lining the otic capsule in the Palmerston North autoimmune mouse, which develops otic capsule sclerotic lesions (63) Osteoprotegerin TNFRSF11B Primary regulator of bone metabolism (64) Abnormal bone remodeling within the otic capsule and progressive hearing loss in knockout mice (65) Retinoic acid receptor ␣ RARA Crucial role in initial differentiation of otic placode derivatives (66) Blocking of RARA in cultured periotic mesenchyme from otocysts reduces levels of TGF-␤1 and suppresses chondrogenesis (67) Otoraplin OTOR Role in initiation of periotic mesenchym chondrogenesis (68) Parathyroid hormone PTH Key regulator in bone turnover (69) Parathyroid hormone receptor 1 PTHR1 Receptor that binds PTH and PTHLH (70) Lower expression of mRNA in otosclerotic stapes (71) Diastrophic sulfate transporter SLC26A2 Acts as a sulphate exchanger in chondrocytes (72) Mutations in this gene cause diastrophic dysplasia, a systematic skeletal disorder (73) Has a higher activity in cells from stapes and the external auditory canal of otosclerosis patients (74) POU domain class 3, transcription factor 4 POU3F4 Mutations in this gene cause DFN3, characterized by a conductive hearing loss due to fixation of the stapes and progressive sensorineural hearing loss (75) Expressed in regions of the otic capsule that immediately surround the stapes during otic development (76) Membrane co-factor protein CD46 Receptor of measles virus (77) Signaling lymphocyte activation molecule SLAMF1 Receptor of measles virus (78) (21) Genomic DNA was isolated from either fresh or frozen blood, using standard techniques.…”

Section: Clinical Diagnosismentioning

confidence: 99%

Association of Bone Morphogenetic Proteins With Otosclerosis

Schrauwen

Thys

Vanderstraeten

et al. 2008

Journal of Bone and Mineral Research

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We studied the role of polymorphisms in 13 candidate genes on the risk of otosclerosis in two large independent case-control sets. We found significant association in both populations with BMP2 and BMP4, implicating these two genes in the pathogenesis of this disease.Introduction: Otosclerosis is a progressive disorder of the human temporal bone that leads to conductive hearing loss and in some cases sensorineural or mixed hearing loss. In a few families, it segregates as a monogenic disease with reduced penetrance, but in most patients, otosclerosis is more appropriately considered a complex disorder influenced by genetic and environmental factors. Materials and Methods: To identify major genetic factors in otosclerosis, we used a candidate gene approach to study two large independent case-control sets of Belgian-Dutch and French origin. Tag single nucleotide polymorphisms (SNPs) in 13 candidate susceptibility genes were studied in a stepwise strategy. Results: Two SNPs were identified that showed the same significant effect in both populations. The first SNP, rs3178250, is located in the 3Ј untranslated region of BMP2. Individuals homozygote for the C allele are protected against otosclerosis (combined populations: p ‫ס‬ 2.2 × 10

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“…OTSC and PDB are among the bony disorders that can affect the otic capsule of the middle ear (Hamed & Fayad, 2009). OPG knockout mice have shown abnormal bone remodeling in the otic capsule with many similarities to OTSC in human temporal bones (Zehnder et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Genetic Association and Altered Gene Expression of Osteoprotegerin in Otosclerosis Patients

Priyadarshi

Ray

Biswal

et al. 2015

Annals of Human Genetics

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SummaryOtosclerosis (OTSC) is a late-onset hearing disorder characterized by increased bone turnover in the otic capsule. Disturbed osteoprotegerin expression has been found in the otosclerotic foci which may have an important role in the pathogenesis of OTSC. To identify the genetic risk factors, we sequenced the coding region and exon-intron boundaries of the OPG gene in 254 OTSC patients and 262 controls. Sequence analysis identified five known polymorphisms c.9C>G, c.30+15C>T, c.400+4C>T, c.768A>G, and c.817+8A>C. Testing of these SNPs revealed sex specific association with c.9C>G in males and c.30+15C>T in females after multiple correction. Furthermore, meta-analysis provided evidence of association of the c.9C>G polymorphism with OTSC. In secondary analysis, we investigated the mRNA expression of OPG and associated genes RANK and RANKL in otosclerotic tissues compared to controls. Expression analysis revealed significantly missing/reduced OPG expression only in otosclerotic tissues. However, the signal sequence polymorphism c.9C>G has shown no effect on OPG mRNA expression. In conclusion, our results suggest that the risk of OTSC is influenced by variations in the OPG gene along with other factors which might regulate its altered expression in otosclerotic tissues. Further research is warranted to elucidate the mechanisms underlying these observations.

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Osteoprotegrin Knockout Mice Demonstrate Abnormal Remodeling of the Otic Capsule and Progressive Hearing Loss

Cited by 97 publications

References 16 publications

Studies of Otic Capsule Morphology and Gene Expression in the Mov13 Mouse – An Animal Model of Type I Osteogenesis Imperfecta

Studies of Otic Capsule Morphology and Gene Expression in the Mov13 Mouse – An Animal Model of Type I Osteogenesis Imperfecta

Association of Bone Morphogenetic Proteins With Otosclerosis

Genetic Association and Altered Gene Expression of Osteoprotegerin in Otosclerosis Patients

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