中耳胆脂瘤以骨质破坏为特征，发病机制不明。PTHrP及RANKL可诱导巨噬细胞向破骨细胞分化，激活破骨细胞活性，与溶骨性疾病发病密切相关。生物信息学分析发现miR-200b-3p序列存在PTHrP的结合位点，前期研究证实中耳胆脂瘤中存在miR-200b-3p低表达、PTHrP高表达、RANKL-RANK/OPG通路激活，且PTHrP、RANKL的表达及RANKL/OPG比值与骨质破坏程度呈正相关。然而miRNA-与PTHrP是否参与胆脂瘤骨质破坏及其机制尚不明确。据此我们提出：miR-200b-3p在胆脂瘤低表达，导致由胆脂瘤角质形成细胞分泌的靶基因PTHrP表达上调，进而激活RANKL-RANK/OPG信号通路，诱导巨噬细胞向破骨细胞分化，破坏骨质。本课题旨在揭示miR-200b-3p经PTHrP调控RANKL-RANK/OPG通路在中耳胆脂瘤骨质破坏的作用，为明确骨质破坏机制提供依据。

Middle ear cholesteatoma is a destructive squamous epithelial lesion of the temporal bone which gradually expands and leads to hearing loss by destruction of nearby bony structures. However, the exact molecular mechanism of bone resorption in cholesteatoma still remains controversial. PTHrP and RANKL-RANK/OPG signaling pathway is able to not only promote the differentiation and fusion of osteoclast precursors cells, but also activated the bone resorbing activity of mature osteoclasts. The abnormal expression of PTHrP is closely related to osteolytic diseases, including bone metastases resulting from tumors, rheumatoid arthritis, and so on. Bioinformatics analysis revealed a PTHrP binding site in the miRNA-200b-3p sequence. Meanwhile, our previous microRNA array analysis has demonstrated that miRNA-200b-3p is down-regulated in middle ear cholesteatoma, indicating that miRNA-200b-3p may play a crucial role in the pathogenesis of middle ear cholesteatoma. Furthermore, we have also demonstrated a high expression of PTHrP, RANKL and RANKL/OPG ratio in the epithelium of middle ear cholesteatoma, positively correlating with the degree of bone resorption. However, whether miRNA-200b-3p and PTHrP participant in the bone resorption process of middle ear cholesteatoma and the exactly intrinsic mechanism have been rarely reported. Accordingly, we firstly hypothesize that miRNA-200b-3p may be down-regulated in the cholesteatoma, and activate RANKL-RANK/OPG signaling pathway through upregulating PTHrP secreted by keratinocytes, resulting in inducing bone resorption by promoting macrophages differentiation into osteoclasts. In this topic, we will investigate the role of miRNA-200b-3p, PTHrP and RANKL-RANK/OPG signaling pathway in the bone resorption caused by cholesteatoma both in vivo and in vitro, in order to provide a basis for the molecular mechanism of bone resorption, and facilitate a new therapeutic target for the prevention and treatment of bone resorption in middle ear cholesteatoma.