Modulating P2X7 Receptor Signaling during Rheumatoid Arthritis: New Therapeutic Approaches for Bisphosphonates.
Modulating P2X7 Receptor Signaling during Rheumatoid Arthritis: New Therapeutic Approaches for Bisphosphonates.
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DOI：
10.1155/2012/408242
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发表时间：
2012
影响因子：
1.9
通讯作者：
Pelegrín P
中科院分区：
文献类型：
--
作者：
Baroja-Mazo A;Pelegrín P
P2 X7受体介导的嘌呤能信号传导是参与骨重建的众所周知的机制。P2 X7受体与各种骨和软骨疾病的病理生理学有关，包括类风湿性关节炎（RA），一种广泛而复杂的慢性炎症性疾病。P2 X7受体诱导促炎因子（例如，白细胞介素-1 β、白细胞介素和蛋白酶）导致RA的临床症状。因此，P2 X7受体正在成为一种新的抗炎治疗靶点，各种选择性P2 X7受体拮抗剂正在进行临床试验。 通过P2 X7受体作用的细胞外ATP信号传导是一种复杂且动态的情况，其在炎症过程中变化。这种信号传导部分由胞外核苷酸酶的活性调节，胞外核苷酸酶降解胞外ATP以产生其他活性分子，如腺苷或焦磷酸。最近的证据表明，在炎症消退期间ATP的细胞外代谢差异产生焦磷酸盐。细胞外焦磷酸盐通过促进替代性巨噬细胞活化来抑制促炎信号传导。 我们的论文表明，双膦酸盐是代谢稳定的焦磷酸类似物，能够模拟焦磷酸盐的抗炎功能。双膦酸盐本身是治疗RA的有前途的抗炎药物，当与P2 X7受体拮抗剂联合给药时，这种治疗可以得到改善。
P2X7 receptor-mediated purinergic signaling is a well-known mechanism involved in bone remodeling. The P2X7 receptor has been implicated in the pathophysiology of various bone and cartilage diseases, including rheumatoid arthritis (RA), a widespread and complex chronic inflammatory disorder. The P2X7 receptor induces the release into the synovial fluid of the proinflammatory factors (e.g., interleukin-1β, prostaglandins, and proteases) responsible for the clinical symptoms of RA. Thus, the P2X7 receptor is emerging as a novel anti-inflammatory therapeutic target, and various selective P2X7 receptor antagonists are under clinical trials. Extracellular ATP signaling acting through the P2X7 receptor is a complex and dynamic scenario, which varies over the course of inflammation. This signaling is partially modulated by the activity of ectonucleotidases, which degrade extracellular ATP to generate other active molecules such as adenosine or pyrophosphates. Recent evidence suggests differential extracellular metabolism of ATP during the resolution of inflammation to generate pyrophosphates. Extracellular pyrophosphate dampens proinflammatory signaling by promoting alternative macrophage activation. Our paper shows that bisphosphonates are metabolically stable pyrophosphate analogues that are able to mimic the anti-inflammatory function of pyrophosphates. Bisphosphonates are arising per se as promising anti-inflammatory drugs to treat RA, and this therapy could be improved when administrated in combination with P2X7 receptor antagonists.