Baroja-Mazo Alberto, Pelegrín Pablo
Inflammation and Experimental Surgery Unit, CIBERehd, University Hospital "Virgen de la Arrixaca" and Foundation for Healthcare Training and Research of The Region of Murcia (FFIS), Carretera Madrid-Cartagena s/n, 30120 Murcia, Spain.
J Osteoporos. 2012;2012:408242. doi: 10.1155/2012/408242. Epub 2012 Jul 8.
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.
P2X7受体介导的嘌呤能信号传导是一种参与骨重塑的知名机制。P2X7受体与包括类风湿性关节炎（RA）在内的各种骨和软骨疾病的病理生理学有关，RA是一种广泛且复杂的慢性炎症性疾病。P2X7受体诱导促炎因子（如白细胞介素-1β、前列腺素和蛋白酶）释放到滑液中，这些因子是RA临床症状的成因。因此，P2X7受体正成为一种新的抗炎治疗靶点，各种选择性P2X7受体拮抗剂正在进行临床试验。通过P2X7受体起作用的细胞外ATP信号传导是一个复杂且动态的过程，在炎症过程中会发生变化。这种信号传导部分受外核苷酸酶活性的调节，外核苷酸酶将细胞外ATP降解以产生其他活性分子，如腺苷或焦磷酸盐。最近的证据表明，在炎症消退过程中ATP的细胞外代谢存在差异，从而产生焦磷酸盐。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盐类似物，能够模拟焦磷酸盐的抗炎功能。双膦酸盐本身正成为治疗RA的有前景的抗炎药物，当与P2X7受体拮抗剂联合使用时，这种治疗方法可能会得到改善。
