Genetic ablation of adenosine receptor A3 results in articular cartilage degeneration.
Genetic ablation of adenosine receptor A3 results in articular cartilage degeneration.
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DOI：
10.1007/s00109-018-1680-3
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Evseenko D
中科院分区：
文献类型：
--
作者：
Shkhyan R;Lee S;Gullo F;Li L;Peleli M;Carlstrom M;Chagin AS;Banks NW;Limfat S;Liu NQ;Evseenko D
骨关节炎（OA）是关节炎的最常见形式，其特征在于关节炎症和软骨退化，导致关节残疾、不适、剧烈疼痛、炎症和僵硬。已经表明，腺苷是由腺嘌呤连接到呋喃核糖组成的嘌呤核苷，由人滑膜酶促产生。然而，腺苷信号转导在滑膜关节的稳态和病理学中的功能意义仍不清楚。腺苷通过四种细胞表面受体起作用，即，A1、A2 A、A2 B和A3，在这里，我们系统地分析了A3受体缺乏的小鼠以及用特定类似物对该受体进行的药理学调节。数据显示，腺苷受体信号传导在下调分解代谢机制中起重要作用，从而防止软骨退化。A3的消融导致老年小鼠中OA的发展。从机制上讲，A3信号抑制软骨细胞中的细胞分解代谢过程，包括下调Ca 2 +/钙调蛋白依赖性蛋白激酶（CaMKII）（一种促进基质降解和炎症的酶）以及Runt相关转录因子2（RUNX 2）。此外，选择性A3激动剂保护软骨细胞免受促炎细胞因子或低渗应激引起的细胞凋亡。这些新的数据阐明了A3的保护作用，A3通过抑制细胞内CaMKII激酶和RUNX 2转录因子（关节软骨中的两种主要促分解代谢调节因子）介导。
Osteoarthritis (OA), the most common form of arthritis, is characterized by inflammation of joints and cartilage degradation leading to disability, discomfort, severe pain, inflammation, and stiffness of the joint. It has been shown that adenosine, a purine nucleoside composed of adenine attached to ribofuranose, is enzymatically produced by the human synovium. However, the functional significance of adenosine signaling in homeostasis and pathology of synovial joints remains unclear. Adenosine acts through four cell surface receptors, i.e., A1, A2A, A2B, and A3, and here, we have systematically analyzed mice with a deficiency for A3 receptor as well as pharmacological modulations of this receptor with specific analogs. The data show that adenosine receptor signaling plays an essential role in downregulating catabolic mechanisms resulting in prevention of cartilage degeneration. Ablation of A3 resulted in development of OA in aged mice. Mechanistically, A3 signaling inhibited cellular catabolic processes in chondrocytes including downregulation of Ca2+/calmodulin-dependent protein kinase (CaMKII), an enzyme that promotes matrix degradation and inflammation, as well as Runt-related transcription factor 2 (RUNX2). Additionally, selective A3 agonists protected chondrocytes from cell apoptosis caused by pro-inflammatory cytokines or hypo-osmotic stress. These novel data illuminate the protective role of A3, which is mediated via inhibition of intracellular CaMKII kinase and RUNX2 transcription factor, the two major pro-catabolic regulators in articular cartilage.
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影响因子：
7
作者：
Muller-Fassbender, H;Bach, G L;Setnikar, I
通讯作者：
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影响因子：
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作者：
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DOI：
10.1186/1757-7241-21-86
发表时间：
2013-12-11
影响因子：
3.3
作者：
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5.5
作者：
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De Bari, Cosimo
影响因子：
4.9
作者：
Dreier R
通讯作者：
Dreier R