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首页> 外文期刊>The Laryngoscope: A Medical Journal for Clinical and Research Contributions in Otolaryngology, Head and Neck Medicine and Surgery, Facial Plastic and Reconstructive Surgery .. >Osteoprotegrin knockout mice demonstrate abnormal remodeling of the otic capsule and progressive hearing loss.
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Osteoprotegrin knockout mice demonstrate abnormal remodeling of the otic capsule and progressive hearing loss.

机译：骨保护素基因敲除小鼠表现出耳囊异常重塑和进行性听力丧失。

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OBJECTIVES: The otic capsule, when compared with other bones in the body, is unique in that it undergoes no significant remodeling of bone after development. We previously demonstrated that osteoprotegerin (OPG), which inhibits formation and function of osteoclasts, is produced at high levels in the inner ear of normal mice and secreted into the perilymph from where it diffuses into the surrounding otic capsule bone through a lacunocanalicular system. To test our hypothesis that the high level of OPG may be important in the inhibition of otic capsule remodeling, we studied the light microscopic histology of the otic capsule in OPG knockout mice for evidence of abnormal remodeling of bone. We also tested the hearing in OPG knockout mice to determine whether OPG and its influence on surrounding bone is important for auditory function. METHODS: Temporal bone histopathology and pathophysiology were compared in homozygous OPG knockout mice and C57BL/6 (B6) mice, the background strain for the knockouts. Auditory function in age-matched animals from each group was evaluated at approximately 4-week intervals from 8 to 21 weeks using frequency-specific auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE). After each of the last three evaluations, the cochleae from one mouse of each group were harvested, processed, and examined by light microscopy. RESULTS: Osteoprotegerin knockout mice demonstrated abnormal remodeling of bone within the otic capsule with multiple foci showing osteoclastic bone resorption and formation of new bone. Such changes were not seen in the age-matched B6 controls. The active bone remodeling process in the knockout animals showed many similarities to otosclerosis seen in human temporal bones. Over the time period that we monitored, auditory function was significantly and progressively compromised in the knockout animals relative to B6 controls. At the earliest age of test (8 wk), the loss was apparent as a mild, high-frequency reduction in sensitivity by ABR. In contrast, DPOAE losses in the knockouts were substantial even at 8 weeks, and by 21 weeks, these losses exceeded our equipment limits. Results of ABR testing showed hearing sensitivity changes in the animals of the background strain were confined largely to the high frequencies, whereas OPG knockouts demonstrated substantial low-frequency shifts in addition to those at high frequencies. CONCLUSIONS: The histopathological and pathophysiological findings in OPG knockout mice support the hypothesis that OPG is important in the inhibition of bone remodeling within the otic capsule and the maintenance of normal auditory function. This mouse may provide a valuable animal model of human otosclerosis.
机译：目的：与体内其他骨骼相比，耳囊具有独特性，因为它在发育后不会发生明显的骨骼重塑。我们先前证明，抑制破骨细胞形成和功能的骨保护素（OPG）是在正常小鼠的内耳中高水平产生的，并分泌到周围淋巴中，并从那里通过耳鼻腔系统扩散到周围的耳capsule囊骨中。为了检验我们的假设，即高水平的OPG可能在抑制耳囊重塑中起重要作用，我们研究了OPG基因敲除小鼠耳囊的光学显微组织学，以证明骨骼异常重塑。我们还测试了OPG基因敲除小鼠的听力，以确定OPG及其对周围骨骼的影响是否对听觉功能很重要。方法：比较纯合OPG基因敲除小鼠和C57BL / 6（B6）小鼠（其基因敲除的背景菌株）的颞骨组织病理学和病理生理。使用频率特异性听觉脑干反应（ABR）和畸变产物耳声发射（DPOAE），在大约8周至21周的4周间隔内，评估每组年龄匹配的动物的听觉功能。在最后三个评估中的每一个之后，收获，处理并通过光学显微镜检查来自每组一只小鼠的耳蜗。结果：骨保护素基因敲除小鼠表现出耳囊内的骨骼异常重塑，并有多个病灶，显示破骨细胞吸收并形成新骨。在年龄匹配的B6对照中未发现此类变化。剔除动物中活跃的骨骼重塑过程显示出与人类颞骨中耳硬化症的许多相似之处。在我们监测的时间内，相对于B6对照，基因敲除动物的听觉功能明显且逐渐受到损害。在最早的测试年龄（8周），通过ABR灵敏度的轻度，高频降低就明显消失了。相比之下，淘汰赛中的DPOAE损失甚至在8周时还是相当可观的，到21周时，这些损失已经超过了我们的设备极限。 ABR测试的结果表明，背景菌株的动物的听觉敏感性变化主要局限于高频，而OPG敲除除高频外，还表现出明显的低频偏移。结论：OPG基因敲除小鼠的组织病理学和病理生理学发现支持以下假设，即OPG对抑制耳囊内的骨重塑和维持正常的听觉功能很重要。该小鼠可以提供人耳硬化症的有价值的动物模型。

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