骨关节炎（osteoarthritis，OA）是最常见且严重危害人类健康的关节疾患之一，但OA发生的分子机制尚未明确，遗传小鼠模型也十分有限。已有的体外研究关于PI3K/Akt信号通路在OA发生中的作用一直存在争议。本研究利用组织特异性条件基因敲除技术，在小鼠关节软骨细胞中特异性地敲除Pten基因或Akt1基因，在体内过度激活或阻断PI3K/Akt信号通路，从正反两方面直接明确该信号通路与OA发生之间的因果联系。综合利用各种分子生物学技术手段，我们将深入探索PTEN调节的PI3K/Akt信号通路维持关节软骨完整性的分子机制，并在人类OA标本中验证这些分子机制的变化。更重要的是，我们将利用本OA小鼠模型，探索以PI3K/Akt信号通路为靶标防治OA的可能性。本研究将有助于我们更全面的认识骨关节疾病发生的分子机制，为研究相关疾病提供新颖的实验动物模型和新的治疗思路。

Osteoarthritis (OA) is the most common articular disease that greatly compromise human health. The molecular mechanisms underlying the initiation and progression of OA still remain unclear, partially due to the lack of genetic mice models of OA. Existing in vitro studies regarding whether PI3K/Akt signaling is beneficial or harmful to OA are still under controversial. In this study, we will clarify the causal relationship between PI3K/Akt signaling and OA by tissue-specific gene knockout experiments in which PI3K/Akt signaling is activated within the articular chondrocytes of Col2a1-Cre;Ptenfl/fl mice, or inhibited within the Col2a1-Cre;Akt1fl/fl mice, respectively. The detailed molecular mechanisms how PTEN-regulated PI3K/Akt signaling maintains articular cartilage intact will be uncovered by a compound application of molecular biology technologies, and will be verified within human samples as well. More importantly, therapeutic strategies targeting PI3K/Akt pathway will be practically tested and verified via employing these genetic mice models. Our studies can provide us with novel OA animal models and help us gain a profound understanding of osteoarticular diseases.