Peroxisome Proliferator-Activated Receptor δ Promotes the Progression of Posttraumatic Osteoarthritis in a Mouse Model
Peroxisome Proliferator-Activated Receptor δ Promotes the Progression of Posttraumatic Osteoarthritis in a Mouse Model
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DOI：
10.1002/art.38915
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发表时间：
2015-02-01
影响因子：
13.3
通讯作者：
Beier, F.
中科院分区：
文献类型：
--
作者：
Ratneswaran, A.;LeBlanc, E. A.;Beier, F.
目标。骨关节炎（OA）是一种严重的全关节疾病，以关节软骨退行性变、软骨下骨改变、骨赘形成和滑膜增生为特征。目前，没有药物治疗可以减缓疾病的进展，导致患者的生活质量大大降低，在许多情况下需要进行关节置换手术。OA缺乏有效治疗的部分原因是我们对促进疾病发生和进展的分子机制了解不完全。本研究的目的是研究核受体过氧化物酶体增殖激活受体δ (PPAR δ)在创伤后软骨变性小鼠模型中的促进作用。用药理激动剂PPAR delta （GW501516）处理小鼠软骨细胞和膝关节外植体，以评估基因表达、组织学特征和基质糖胺聚糖分解的变化。在体内，PPAR δ被特异性地从小鼠软骨中删除。根据国际骨关节炎研究协会（OARSI）系统的组织病理学评分和免疫组织化学分析来比较手术破坏内侧半月板（DMM）的突变小鼠和对照组。在体外，GW501516激活PPAR δ导致软骨细胞中几种蛋白酶的表达增加，并导致膝关节外植体中聚集蛋白降解和糖胺聚糖释放。在体内，软骨特异性PPAR δ敲除小鼠没有表现出骨骼发育的任何异常，但在创伤后OA的DMM模型中表现出明显的保护作用（与对照组相比）。OARSI评分和免疫组织化学分析证实突变小鼠对dmm诱导的软骨变性有较强的保护作用。这些数据证明了内源性PPAR δ在创伤后OA中的分解代谢作用，并表明药物抑制PPAR δ是一种很有前途的治疗策略。
Objective. Osteoarthritis (OA) is a serious disease of the entire joint, characterized by articular cartilage degeneration, subchondral bone changes, osteophyte formation, and synovial hyperplasia. Currently, there are no pharmaceutical treatments that can slow the disease progression, resulting in greatly reduced quality of life for patients and the need for joint replacement surgeries in many cases. The lack of available treatments for OA is partly due to our incomplete understanding of the molecular mechanisms that promote disease initiation and progression. The purpose of the present study was to examine the role of the nuclear receptor peroxisome proliferator-activated receptor delta (PPAR delta) as a promoter of cartilage degeneration in a mouse model of posttraumatic OA.Methods. Mouse chondrocytes and knee explants were treated with a pharmacologic agonist of PPAR delta (GW501516) to evaluate changes in gene expression, histologic features, and matrix glycosaminoglycan breakdown. In vivo, PPAR delta was specifically deleted from the cartilage of mice. Histopathologic scoring according to the Osteoarthritis Research Society International (OARSI) system and immunohistochemical analysis were used to compare mutant and control mice subjected to surgical destabilization of the medial meniscus (DMM).Results. In vitro, PPAR delta activation by GW501516 resulted in increased expression of several proteases in chondrocytes, as well as aggrecan degradation and glycosaminoglycan release in knee joint explants. In vivo, cartilage-specific PPAR delta-knockout mice did not display any abnormalities of skeletal development but showed marked protection in the DMM model of posttraumatic OA (as compared to control littermates). OARSI scoring and immunohistochemical analyses confirmed strong protection of mutant mice from DMM-induced cartilage degeneration.Conclusion. These data demonstrate a catabolic role of endogenous PPAR delta in posttraumatic OA and suggest that pharmacologic inhibition of PPAR delta is a promising therapeutic strategy.