Development of therapy for malignant tumors and inflammatory diseases employing midkine as a molecular target

Midkine在缺血或化疗药物引起的肾损伤中起重要作用。促进炎性白细胞的迁移是midkine作用的主要机制。我们在小鼠尾静脉注射midkine反义寡核苷酸抑制midkine的表达。寡核苷酸DNA被肾小管上皮细胞积极摄取。在缺血或给药前注射寡核苷酸，炎症性白细胞向肾小管的迁移明显受到抑制。义寡核苷酸DNA没有表现出这种效应。此外，低聚DNA治疗确实减轻了缺血肾损害。损伤后新生内膜的形成也被先前的反义寡核苷酸治疗所减少。midkine参与手术后粘连和注射抗II型胶原后关节炎，类风湿关节炎模型。用缺乏midkine基因的小鼠来证明。在这两种情况下，促进炎性白细胞的迁移；此外，在关节炎的情况下，midkine促进破骨细胞的分化。我们开发了反义寡核苷酸DNA和siRNA来抑制人midkine的表达。我们还发现，间胶原有助于siRNA的稳定和结合，并通过抑制VBGF的表达来验证其作用，从而抑制了生长人类肿瘤的裸鼠的生长。利用midkine基因缺失的小鼠，证实了midkine在宿主血管中参与肿瘤转移。

Midkine played important roles in renal injury caused by ischemia or chemotherapeutic reagent. Promotion of migration of inflammatory leukocytes was the primary mechanism of midkine action. We injected midkine antisense oligo DNA to tail vein of mice to suppress midkine expression. The oligo DNA was actively taken up by renal tubular epithelial cells. When oligo DNA was injected before ischemia or drug administration, migration of inflammatory leukocytes to renal tubules was significantly suppressed. Sense oligo DNA did not exhibited the effects. Furthermore, renal damage by ischemia was indeed lessened by the oligo DNA treatment. Neointima formation after injury was also lessened by prior treatment with the antisense oligo DNA.The involvement of midkine in adhesions after surgery and arthritis after injection of anti-type II collagen, a model of rheumatoid arthritis. was shown by using mice deficient in the midkine gene. In both cases, promotion of migration of inflammatory leukocytes is involved ; in addition midkine promoted differentiation of osteoclasts in the case of arthritis.We developed antisense oligo DNA and siRNA to suppress the expression of human midkine. We also found that atelocollagen helped both stabilization and incorporation of siRNA, and verified the effects by suppressing VBGF expression leading to the growth suppression of nude-mice grown human tumors. The involvement of midkine in host blood vessels in tumor metastasis was demonstrated by using mice deficient in the midkine gene.