A novel model of spontaneous otitis media with effusion (OME) in the Oxgr1 knock-out mouse

Abstract

Objective A novel mouse model with a specific genetic mutation in a G protein coupled receptor (GPCR) encoded by the oxgr1 gene results in a predisposition to spontaneous otitis media with effusion. As a primary component of interest in OME, mucin expression was examined in this model to assess expression as compared to wild type animals and suitability as a murine model of OME. Method Mutant (oxgr1−/−) and wild-type (oxgr1+/+) mice between ages of 2–5 months were examined by otoscopy and auditory brainstem response (ABR). Histology changes in the middle ear were evaluated. Expression of mucin genes in the middle ear epithelium was determined using RT-PCR and quantitative PCR. Result Otoscopic exam showed signs of inflammation in 82% of mutant mice. Significant elevated ABR thresholds were detected in mutant mice indicating hearing loss. Histology analysis of the middle ears demonstrated the presence of inflammatory cells, changes in the mucosal epithelium, and middle ear fluid. RT PCR using universal primers for bacterial 18s rRNA suggested the absence of bacteria in the middle ear. The knockout mice demonstrated expression of muc1, muc2, muc3, muc4, muc5AC, muc5B, muc9, muc10, muc13, muc15, muc16, muc18, muc19 and muc20. There was a trend of increase in muc5B and muc19 expression in the middle ear of the knockout mice compared to that of wild-type. There was no significant change in the level of muc2, and muc5AC was expressed at a level below the detection limit of quantification. Conclusion Development of a murine model with genetic defect has several attractive features. The rate of OME in these animals is high at 82%. It is clear that this OME is related to histopathologic changes in the middle ear epithelium of these knock-out mice. Induction of mucus effusion is evident though the viation in dysregulation of GFM does exist in this non-challenge study condition. The underlying cause of these differences between individual animal requires further investigation. Given this, the oxgr1−/− model is likely to be an ideal model to examine mucin regulation in MEE and potentially develop novel GPCR-specific targeted interventions to regulate these processes.

Exercise‐induced α‐ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1‐dependent adrenal activation

“…Notably, both wheel-running and ladder-climbing significantly increase circulating AKG (91.3 AE 3.7 lM versus 112.2 AE 3.2 lM; Fig 1I), indicating an enhanced OXGR1 activation induced by exercise. Previous studies have indicated that OXGR1 plays an important role in mucin regulation in otitis (Kerschner et al, 2013) and cardiac hypertrophy (Omede et al, 2016). However, there is no known role of OXGR1's effects on fat thermogenesis and lipolysis.…”

Salivary Mucin 19 Glycoproteins

“…Recent genome-wide association studies identified MUC19 as a susceptibility gene of Crohn disease (119 -121). Muc19 expression is absent in the gastrointestinal tract of mice (21,122), as well as in cattle except for inconsistent and sparse expression in jejunum (123). MUC19 expression in the human gastrointestinal tract has not been studied extensively.…”

Ectopic Mineralization and Conductive Hearing Loss in Enpp1asj Mutant Mice, a New Model for Otitis Media and Tympanosclerosis

“…Heritability studies have shown that genetic factors can play an important role in otitis media susceptibility, but few contributing genes have been identified in human populations [1]. In contrast to human studies, a growing number of mouse mutations have been identified that manifest a high incidence of otitis media, including Eya4 , Tlr4 , p73 , MyD88 , Fas , E2f4 , Plg , Fbxo11 , Evi1 [1,2], Sh3pxd2b [3], Rpl38 [4], Isl1 [5], Chd7 [6], Lmna1 [7], Phex [8], Oxgr1 [9], Tgif1 [10], and Mcph1 [11]. The wide diversity of these genes and their mutant pathologies, including craniofacial abnormalities with Eustachian tube malformations and innate immune response defects, underscores the complex nature of otitis media.…”