Adenosine A2A receptor activation prevents wear particle-induced osteolysis.
Adenosine A2A receptor activation prevents wear particle-induced osteolysis.
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DOI：
10.1126/scitranslmed.3003393
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发表时间：
2012-05-23
影响因子：
17.1
通讯作者：
Cronstein BN
中科院分区：
文献类型：
--
作者：
Mediero A;Frenkel SR;Wilder T;He W;Mazumder A;Cronstein BN
假体松动与磨损颗粒诱导的炎症和破骨细胞介导的骨破坏有关，是导致关节假体失败的常见原因，导致翻修手术。腺苷A2A受体（A2AR）在许多组织中介导有效的抗炎作用并阻止破骨细胞分化。我们在磨损颗粒诱导骨吸收的小鼠颅骨模型中验证了A2AR激动剂可以减少破骨细胞介导的骨吸收的假设。C57Bl/6和A2A敲除（A2ARKO）小鼠接受超高分子量聚乙烯颗粒（UHMWPE）治疗，每天用生理盐水或A2AR激动剂CGS21680治疗。2周后，颅骨显微计算机断层扫描显示，与对照组小鼠相比，CGS21680以剂量依赖的方式减少了颗粒诱导的骨凹陷和孔隙度，增加了皮质骨和骨体积。组织学检查显示CGS21680治疗后炎症减轻。在A2AKO小鼠中，CGS21680不影响破骨细胞介导的骨吸收或炎症。在CGS21680治疗后，骨吸收标志物核因子kb受体激活因子（RANK）、RANK配体（RANKL）、组织蛋白酶K、CD163和骨桥蛋白水平降低，同时破骨细胞减少。CGS21680显著降低骨组织中白细胞介素1β (IL-1β)和TNFα的分泌，而显著增加IL-10的分泌。这些小鼠实验结果表明，特定部位递送腺苷A2AR激动剂可以提高植入物的存活率，延迟或消除翻修性关节整形手术的需要。
Prosthesis loosening, associated with wear-particle–induced inflammation and osteoclast-mediated bone destruction, is a common cause for joint implant failure, leading to revision surgery. Adenosine A2A receptors (A2AR) mediate potent anti-inflammatory effects in many tissues and prevent osteoclast differentiation. We tested the hypothesis that an A2AR agonist could reduce osteoclast-mediated bone resorption in a murine calvaria model of wear-particle–induced bone resorption. C57Bl/6 and A2A knockout (A2ARKO) mice received ultrahigh-molecular weight polyethylene particles (UHMWPE) and were treated daily with either saline or the A2AR agonist CGS21680. After 2 weeks, micro-computed tomography of calvaria demonstrated that CGS21680 reduced particle-induced bone pitting and porosity in a dose-dependent manner, increasing cortical bone and bone volume compared to control mice. Histological examination demonstrated diminished inflammation after treatment with CGS21680. In A2AKO mice, CGS21680 did not affect osteoclast-mediated bone resorption or inflammation. Levels of bone-resorption markers receptor activator of nuclear factor-kB (RANK), RANK ligand (RANKL), cathepsin K, CD163, and osteopontin were reduced following CGS21680 treatment, together with a reduction in osteoclasts. Secretion of interleukin 1β (IL-1β) and TNFα was significantly decreased, whereas IL-10 was markedly increased in bone by CGS21680. These results in mice suggest that site-specific delivery of an adenosine A2AR agonist could enhance implant survival, delaying or eliminating the need for revision arthroplastic surgery.
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影响因子：
33.7
作者：
Chan, Edwin S. L.;Cronstein, Bruce N.
通讯作者：
Cronstein, Bruce N.
影响因子：
6.2
作者：
Gharibi, Borzo;Abraham, Anju A.;Evans, Bronwen A. J.
通讯作者：
Evans, Bronwen A. J.
影响因子：
5.3
作者：
Bozic, Kevin J.;Kurtz, Steven M.;Berry, Daniel J.
通讯作者：
Berry, Daniel J.
影响因子：
4.4
作者：
Lemaire, Irma;Falzoni, Simonetta;Di Virgilio, Francesco
通讯作者：
Di Virgilio, Francesco
影响因子：
4.8
作者：
Kara, Firas M.;Chitu, Violeta;Cronstein, Bruce N.
通讯作者：
Cronstein, Bruce N.