Development of the treatment for cartilage regeneration by a prostanoid signal-acting material

通过体内实验研究EP2激动剂对关节软骨缺损的治疗作用。兔股骨远端髌骨-股骨关节表面形成全层软骨缺损（直径5mm，深度5mm）和表面软骨缺损（直径5mm）。手术后立即进行组织学检查，确定了为每个模型创建预期缺陷的适当程序。采用EP2激动剂缓释材料（PLGA+明胶凝胶，直径5mm，高度5mm）进行治疗，全层缺损模型放置于缺损处，表面缺损模型放置于髌下脂肪垫附近。EP2激动剂的剂量分别为20mg、80mg、800mg。术后4周处死动物，对缺损进行组织学检查。在全层模型中，缺损被组织填充，主要由safranion-O阴性纺锤细胞组成。观察到与正常残余关节软骨交界处的软骨细胞增殖，其数量与EP2激动剂的剂量有关。在表面缺陷模型中，缺损被再生软骨细胞填充，safaranin-O染色呈阳性。可见多腔隙含2个细胞，提示关节软骨细胞增生活跃。这些结果表明，PGE2信号通过EP2刺激了关节软骨细胞的增殖，并且结合适当的药物递送系统，EP2激动剂将成为治疗损伤关节软骨的有希望的材料，这些损伤一直被认为没有再生能力。

The effects of EP2 agonists for the treatment of articular cartilage defects were investigated by in vivo experiments. Full thickness cartilage defects (5mm in diameter and 5mm depth) and surface cartilage defects (5mm in dianeter) were created in the patello-femoral joint surface of the distal portion of femurs of rabbits. Histological examination was performed immediately after the operation, which confirmed the porper procedure to creat intended defects for each model. Treatment was carried out using EP2 agonists slow-releasing materials (PLGA+gelatin gel, 5mm in diameter and 5mm height), which was placed in the defect in the case of full thickness defect model and adjacet to infrapatellar fat pad in the case of surface defect model. The amount of EP2 agonist were either 20mg, 80mg, or 800mg. Animals were sacrified at four weeks after operation, and the defects were examined histologically. In the case of full thickness model, the defect was filled with tissues, which mainly composed of safranion-O negative spindel cells. The proliferation of cartilage cells were observed at the junction facing to residual normal articular cartialge, the amount of which depended on the dose of EP2 agonists. In the surface defect model, the defect was filled with regenerated chondrocytes, which were positive for safaranin-O staining. There were many lacunae containing two cells, indicating the active proliferation of articular chondrocytes. These resultis suggested that PGE2 signal through EP2 stimulated proliferation of articular cartilage cells, and that combined with a proper drug-delivery system, EP2 agonists will be promising therapeutic materials for damaged articular cartilages, which have been regarded not to have a regenerative potency.