Adult Cartilage-Specific Peroxisonrie Proliferator-Activated Receptor Gamma Knockout Mice Exhibit the Spontaneous Osteoarthritis Phenotype
Adult Cartilage-Specific Peroxisonrie Proliferator-Activated Receptor Gamma Knockout Mice Exhibit the Spontaneous Osteoarthritis Phenotype
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DOI：
10.1016/j.ajpath.2012.12.012
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发表时间：
2013-04-01
影响因子：
6
通讯作者：
Kapoor, Mohit
中科院分区：
文献类型：
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作者：
Vasheghani, Faezeh;Monemdjou, Roxana;Kapoor, Mohit
骨关节炎（OA）是一种与年龄相关的进行性退行性关节疾病。过氧化物酶体促liferator激活受体γ (PPAR γ)是一种转录因子，被认为是对抗OA相关降解机制的有吸引力的治疗靶点。研究表明，通过其激动剂激活PPAR γ可以减少OA动物模型中OA分解代谢因子和炎症因子的合成以及软骨病变的发展。由于这些激动剂具有几种与PPAR γ无关的作用，因此PPAR γ在软骨稳态和OA中的具体体内功能在很大程度上仍然未知。本文中，我们使用使用Cre-Lox系统生成的软骨特异性PPAR γ敲除（KO）小鼠来描述PPAR γ在OA中的体内作用。成年PPAR γ KO小鼠表现出自发性OA表型，与软骨降解增强、细胞减少、滑膜和软骨纤维化、滑膜炎症、滑膜单核细胞内流、分解代谢因子（包括基质金属蛋白酶-13）表达增加以及基质金属蛋白酶生成的聚集蛋白和II型胶原新表位（VDIPEN和C1-2C）染色增加相关。我们证明PPAR γ缺乏的关节软骨表现出额外的分解代谢因子-缺氧诱导因子-2 α， syndecan-4和具有血栓反应蛋白基元5的崩解素和金属蛋白酶以及炎症因子环氧化酶-2和诱导型一氧化氮合酶的表达升高。总之，PPAR γ是软骨健康的关键调节因子，其缺乏会导致自发OA表型加速。
Osteoarthritis (OA) is an age-related progressive degenerative joint disease. Peroxisome pro-Liferator-activated receptor gamma (PPAR gamma), a transcription factor, is suggested as an attractive therapeutic target to counteract degradative mechanisms associated with OA. Studies suggest that activation of PPAR gamma by its agonists can reduce the synthesis of OA catabolic and inflammatory factors and the development of cartilage Lesions in OA animal models. Because these agonists impart several PPAR gamma-independent effects, the specific in vivo function of PPAR gamma in cartilage homeostasis and OA remains largely unknown. Herein, we describe the in vivo role of PPAR gamma in OA using cartilage-specific PPAR gamma knockout (KO) mice generated using the Cre-Lox system. Adult PPAR gamma KO mice exhibited a spontaneous OA phenotype associated with enhanced cartilage degradation, hypocellularity, synovial and cartilage fibrosis, synovial inflammation, mononuclear cell influx in the synovium, and increased expression of catabolic factors, including matrix metalloproteinase-13, accompanied by an increase in staining for matrix metalloproteinase-generated aggrecan and type II collagen neoepitopes (VDIPEN and C1-2C). We demonstrate that PPAR gamma-deficient articular cartilage exhibits elevated expression of the additional catabolic factors hypoxia-inducible factor-2 alpha, syndecan-4, and a disintegrin and metalloproteinase with thrombospondin motifs 5 and of the inflammatory factors cyclooxygenase-2 and inducible nitric oxide synthase. In conclusion, PPAR gamma is a critical regulator of cartilage health, the lack of which Leads to an accelerated spontaneous OA phenotype.