Nociceptive tolerance is improved by bradykinin receptor B1 antagonism and joint morphology is protected by both endothelin type A and bradykinin receptor B1 antagonism in a surgical model of osteoarthritis.
Nociceptive tolerance is improved by bradykinin receptor B1 antagonism and joint morphology is protected by both endothelin type A and bradykinin receptor B1 antagonism in a surgical model of osteoarthritis.
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DOI：
10.1186/ar3338
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发表时间：
2011-05-16
影响因子：
4.9
通讯作者：
Moldovan F
中科院分区：
文献类型：
--
作者：
Kaufman GN;Zaouter C;Valteau B;Sirois P;Moldovan F
Endothelin-1 是一种血管收缩肽，主要通过 A 型内皮素受体 (ETA) 影响软骨代谢。与在慢性炎症条件下通过缓激肽受体 B1 (BKB1) 发挥作用的炎症九肽血管扩张剂缓激肽 (BK) 一起，这些血管活性因子会加剧关节疼痛和炎症。我们描述了一项关于使用 ETA 和/或 BKB1 特异性肽拮抗剂治疗手术诱发的骨关节炎疗效的临床前研究。我们假设两种受体的拮抗作用将以协同方式减少骨关节炎的进展和关节伤害感受。通过横断右前十字韧带在雄性大鼠中手术诱导骨关节炎。随后每周对动物进行关节内注射ETA和/或BKB1的特定肽拮抗剂进行治疗。术后两个月，每两周通过静态负重测量后肢伤害感受。尸检后，通过 X 射线和磁共振对右膝关节进行放射学分析，并通过 OARSI 组织病理学评估系统进行组织学分析。单一局部 BKB1 拮抗剂治疗可减少整体后肢伤害感受，并加速疾病诱发后的术后恢复。 ETA 和/或 BKB1 拮抗剂治疗均可保护关节放射形态学和组织形态学。根据放射学和组织学的测量，双重 ETA/BKB1 拮抗作用稍微更具保护性。 BKB1 拮抗作用可改善伤害性耐受性，ETA 和/或 BKB1 拮抗作用可防止骨关节炎手术模型中的关节软骨退化。因此，它们代表了一种新的治疗策略：特异性受体拮抗作用可能对疾病管理有益。
Endothelin-1, a vasoconstrictor peptide, influences cartilage metabolism mainly via endothelin receptor type A (ETA). Along with the inflammatory nonapeptide vasodilator bradykinin (BK), which acts via bradykinin receptor B1 (BKB1) in chronic inflammatory conditions, these vasoactive factors potentiate joint pain and inflammation. We describe a preclinical study of the efficacy of treatment of surgically induced osteoarthritis with ETA and/or BKB1 specific peptide antagonists. We hypothesize that antagonism of both receptors will diminish osteoarthritis progress and articular nociception in a synergistic manner. Osteoarthritis was surgically induced in male rats by transection of the right anterior cruciate ligament. Animals were subsequently treated with weekly intra-articular injections of specific peptide antagonists of ETA and/or BKB1. Hind limb nociception was measured by static weight bearing biweekly for two months post-operatively. Post-mortem, right knee joints were analyzed radiologically by X-ray and magnetic resonance, and histologically by the OARSI histopathology assessment system. Single local BKB1 antagonist treatment diminished overall hind limb nociception, and accelerated post-operative recovery after disease induction. Both ETA and/or BKB1 antagonist treatments protected joint radiomorphology and histomorphology. Dual ETA/BKB1 antagonism was slightly more protective, as measured by radiology and histology. BKB1 antagonism improves nociceptive tolerance, and both ETA and/or BKB1 antagonism prevents joint cartilage degradation in a surgical model of osteoarthritis. Therefore, they represent a novel therapeutic strategy: specific receptor antagonism may prove beneficial in disease management.
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影响因子：
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