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。在兔股骨远端派-股关节表面形成全层软骨缺损(直径5 mm，深度5 mm)和表面性软骨缺损(直径5 mm)。手术后立即进行组织学检查，证实了为每个模型制造预期缺陷的手术方法。治疗采用EP2激动剂缓释材料(PLGA+明胶凝胶，直径5 mm，高度5 mm)，全层缺损组植入缺损区，表面缺损组置入靠近髌下脂肪垫。EP2激动剂用量分别为20 mg、80 mg、800 mg。术后4周处死动物，行组织学检查。在全厚模型中，缺损处充满了组织，这些组织主要由藏红花-O阴性梭形细胞组成。软骨细胞在残存的正常关节软骨交界处可见细胞增殖，其数量与EP2激动剂的剂量有关。在表面缺损模型中，缺损处被再生的软骨细胞填充，这些细胞呈藏红花素-O染色阳性。关节软骨细胞增殖活跃，有多个含有两个细胞的陷窝。这些结果表明，PGE2通过EP2信号刺激关节软骨细胞的增殖，EP2激动剂与合适的药物传递系统相结合，有望成为治疗关节软骨损伤的理想材料。

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.