title: Mutation in Phex gene predisposes BALB/c-Phex(Hyp-Duk)/Y mice to otitis media.
abstract: Genetic susceptibility underlying otitis media (OM) remains to be understood. We show in this study that mutation in Phex gene predisposes the BALB/c-Phex(Hyp-Duk)/Y (abbreviated Hyp-Duk/Y) mice to OM, which occurs at post-natal day 21 (P21) with an average penetrance of 73%. The OM was identified by effusion in the middle ear cavity and/or thickening of middle ear mucosae, and was characterised by increase in goblet cells, deformity of epithelial cilia and higher expression of proliferating cell nuclear antigen (PCNA) in cells of the middle ear mucosae. Moreover, the transcription levels of Tlr2, Tlr4, Nfkb1, Ccl4, Il1b and Tnfα in the ears of the Hyp-Duk/Y mice at P35 were significantly upregulated, compared to those of the controls. Higher expression levels of TLR2, TLR4, NF-κB and TNF-α in the middle ears were demonstrated by immunohistochemistry (IHC). However, the OM in the mice was not prevented by azithromycin administration from gestational day 18 to P35. Further study showed that, in contrast to the low mRNA levels of Phex gene in the ears of the Hyp-Duk/Y mice, the mRNA level of Fgf23 was significantly elevated at P9, P14, P21 and P35. Meanwhile, mRNA levels of EP2 (PGE2 receptor), which expressed in the middle ear epithelia as demonstrated by IHC, were already increased at P14 even before the occurrence of OM, indicating that PGE2, an inflammatory mediator, is involved in the OM development in the mutants. Taking together, Phex mutation primarily up-regulates gene expression levels in FGF23 mediated pathways in the middle ears, resulting in cell proliferation and defence impairment at the mucosae and subsequently bacterial infection. The Hyp-Duk/Y mouse is a new genetic mouse model of OM.
authors.affiliation: The Transformative Otology and Neuroscience Center, Binzhou Medical University, Yantai, Shandong, People's Republic of China.
authors.forename: Fengchan
authors.initials: F
authors.lastname: Han
authors.forename: Heping
authors.initials: H
authors.lastname: Yu
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Jiangping
authors.initials: J
authors.lastname: Zhang
authors.forename: Cong
authors.initials: C
authors.lastname: Tian
authors.forename: Hongbo
authors.initials: H
authors.lastname: Li
authors.forename: Qing Yin
authors.initials: QY
authors.lastname: Zheng
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002923:Cilia / Q000648:ultrastructure; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005091:Exons; D000089703:Fibroblast Growth Factor-23; D005786:Gene Expression Regulation; D023061:Gene Order; D020022:Genetic Predisposition to Disease; D020397:Goblet Cells; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009154:Mutation; D010033:Otitis Media / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000235:genetics*
chemical_list: D016207:Cytokines; C000717428:Fgf23 protein, mouse; D018836:Inflammation Mediators; D000089703:Fibroblast Growth Factor-23; D053402:PHEX Phosphate Regulating Neutral Endopeptidase