Depletion of Protease-Activated Receptor 2 but Not Protease-Activated Receptor 1 May Confer Protection Against Osteoarthritis in Mice Through Extracartilaginous Mechanisms
Depletion of Protease-Activated Receptor 2 but Not Protease-Activated Receptor 1 May Confer Protection Against Osteoarthritis in Mice Through Extracartilaginous Mechanisms
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DOI：
10.1002/art.38876
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发表时间：
2014-12-01
影响因子：
13.3
通讯作者：
Little, Christopher B.
中科院分区：
文献类型：
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作者：
Jackson, Miriam T.;Moradi, Babak;Little, Christopher B.
Objective.目的探讨蛋白酶激活受体1（PAR-1）和PAR-2在小鼠骨关节炎（OA）病理过程中的作用，并鉴定PAR-1或PAR-2消融后主要受影响的细胞/组织。方法.通过内侧半月板（DMM）的不稳定性在野生型（WT）、PAR-1 /、PAR-1 /和PAR-2 /小鼠的关节中诱导OA，并在DMM后1、4和8周比较组织学特征（软骨聚集蛋白聚糖损失和侵蚀、软骨下骨硬化、骨赘和滑膜炎）的评分。在有或没有白细胞介素-1（IL-1）的小鼠股骨头组织培养物中研究PAR消融对软骨降解和软骨细胞金属蛋白酶表达/活性的影响。在DMM后1周，通过逆转录-聚合酶链反应测定滑膜细胞因子和金属蛋白酶基因的表达，并通过流式细胞术定量炎症细胞群。结果PAR-2的缺失，而不是PAR-1的缺失，在小鼠中显著延迟软骨损伤的进展，并抑制DMM后的软骨下骨硬化。PAR-1或PAR-2消融对IL-1诱导的软骨降解或软骨细胞金属蛋白酶表达/活化没有抑制作用。与接受假手术的对照小鼠相比，接受DMM的小鼠中持续存在较低但显着的滑膜炎水平，但在DMM后4或8周没有观察到基因型之间的差异。DMM后一周，在所有基因型中均观察到促炎细胞因子和金属蛋白酶基因的滑膜表达增加，沿着CD 4 T细胞、炎性单核细胞和活化巨噬细胞水平增加。然而，与PAR-1 /和WT小鼠相比，PAR-2 /小鼠中活化巨噬细胞的百分比显著降低。结论PAR-2的缺失，而不是PAR-1的缺失，导致DM引起的软骨损伤显著减少。PAR-2 /小鼠的软骨保护作用似乎是通过调节软骨外事件（如软骨下骨重塑和滑膜巨噬细胞活化）间接发生的，而不是通过改变软骨细胞分解代谢反应。
Objective. To explore the involvement of proteaseactivated receptor 1 (PAR-1) and PAR-2 in the pathologic processes of osteoarthritis (OA) and to identify the cells/tissues primarily affected by ablation of PAR-1 or PAR-2 in mice. Methods. OA was induced in the joints of wildtype (WT), PAR-1 /, PAR-1 /, and PAR-2 / mice by destabilization of the medial meniscus (DMM), and scores of histologic features (cartilage aggrecan loss and erosion, subchondral bone sclerosis, osteophytes, and synovitis) were compared at 1, 4, and 8 weeks postDMM. The effects of PAR ablation on cartilage degradation and chondrocyte metalloproteinase expression/ activity were studied in cultures of mouse femoral head tissue with or without interleukin-1 (IL-1 ). At 1 week post-DMM, synovial expression of cytokines and metalloproteinase genes was measured by reverse transcription-polymerase chain reaction, and populations of inflammatory cells were quantified by flow cytometry. Results. Deletion of PAR-2, but not that of PAR-1, in mice significantly delayed the progression of cartilage damage and inhibited subchondral bone sclerosis following DMM. There was no inhibitory effect of PAR-1 or PAR-2 ablation on IL-1 -induced cartilage degradation or chondrocyte metalloproteinase expression/activation. A low but significant level of synovitis persisted in mice subjected to DMM compared to that in control mice subjected to sham surgery, but no differences between the genotypes were seen 4 or 8 weeks post-DMM. One week after DMM, increased synovial expression of proinflammatory cytokines and metalloproteinase genes, along with increased levels of CD4 T cells, inflammatory monocytes, and activated macrophages, were seen in all genotypes. However, there was a significant reduction in the percentage of activated macrophages in PAR-2 / mice compared to PAR-1 / and WT mice. Conclusion. Deletion of PAR-2, but not that of PAR-1, results in a significant decrease in DMMinduced cartilage damage. The chondroprotection in PAR-2 / mice appears to occur indirectly through modulation of extracartilaginous events such as subchondral bone remodeling and synovial macrophage activation, rather than through alteration of chondrocyte catabolic responses.