Study for development of genetic therapy for keloid and hypertrophic scar.

疤痕疙瘩和增生性疤痕基因治疗开发的研究。

• 批准号: 14370570
• 负责人: YOSHIMURA Kotaro
• 金额: $ 7.68万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370570/
• 关键词: keloid; fibroblast; MMP; skin; retinoid; tretinoin; retinoic acid; レノイド; コラゲナーゼ; 繊維芽細胞; mRNA

Keloids are skin abnormalities that are characterized by excessive deposition of collagen bundles in the dennis. Patients with keloids complain not only about their cosmetic appearances, but also about continuous itching andlor tenderness associated with chronic inflammation. Degradation of extracellular matrix (ECM) may be upregulated associated with the expansion of keloids into circumferential skin, and high metabolic activity of keloid tissues may be due to increased matrix metalloproteinases (MMPs) activity. Based on these hypotheses, we examined differences in expressions of MMP-1, MMP-8, and MMP-13 between keloid-derived fibroblasts and normal dermal fibroblasts. Since retinoids are potent inhibitors of MMPs in the treatment of photoaged skin and cancers, we also examined whether or not tretinoin affects MMPs expressions of keloid-derived fibroblasts.The results of real-time PCR and ELISA demonstrated a significant upregulation of MMP-13 as well as significant downregulation of … More MMP-1 and MMP-8 in keloid-derived fibroblasts, both at mRNA and protein levels. MMP-1 mRNA expression in the control group was significantly upregulated after the addition of tretinoin, whereas no significant change was observed in the keloid group : MMP-8 mRNA expression in the control group was significantly upregulated with the peak at 12 hours by tretinoin, while no significant change was observed in the keloid-derived fibroblasts. In contrast, the remarkably elevated MMP-13 mRNA expression in the keloid group was significantly suppressed with the peak suppression at 12 hours after. addition of tretinoin, while MMP-13 mRNA expression in the control group was not significantly changed.The decrease in MMP-1 and MMP-8 may contribute to accumulation of type I and type III collagen in keloid tissues, and this mechanism may be modulated by molecular interaction with MMP-13. Tretinoin appeared to reverse the abnormal expression profile of MMPs in keloid-derived fibroblasts, such as markedly elevated expression of MMP-13, partly through inactivation of AP-1 pathway. The present results suggested that tretinoin may be clinically useful to improve chronic inflammation seen in keloids and prevent expansion of keloid tissues into circumferential normal skin. Less

瘢痕疙瘩是一种皮肤异常，其特征是丹尼斯的胶原束过度沉积。瘢痕疙瘩患者不仅抱怨他们的外表，还抱怨与慢性炎症相关的持续性瘙痒和/或压痛。细胞外基质(ECM)的降解可能随着瘢痕疙瘩向周围皮肤的扩张而上调，而瘢痕疙瘩组织的高代谢活性可能是由于基质金属蛋白酶(MMPs)活性增加所致。基于这些假设，我们检测了瘢痕疙瘩成纤维细胞和正常真皮成纤维细胞中基质金属蛋白酶-1、基质金属蛋白酶-8和基质金属蛋白酶-13的表达差异。由于在光老化皮肤和癌症的治疗中，维甲酸是MMPs的有效抑制剂，我们还检测了维甲酸是否影响瘢痕疙瘩成纤维细胞MMPs的表达。实时定量聚合酶链式反应和酶联免疫吸附试验的结果显示，MMP13的表达显著上调，…的表达显著下调瘢痕疙瘩成纤维细胞中的基质金属蛋白酶-1和基质金属蛋白酶-8在mRNA和蛋白水平均较高。对照组加入维甲酸后，基质金属蛋白酶-1mRNA表达显著上调，而瘢痕疙瘩组无明显变化：对照组基质金属蛋白酶-8mRNA表达显著上调，12h达高峰，而瘢痕疙瘩成纤维细胞则无明显变化。与之相反，瘢痕疙瘩组显著升高的基质金属蛋白酶-13mRNA的表达在瘢痕疙瘩组明显受到抑制，在12h达到高峰。MMP1和MMP8的表达减少可能与瘢痕疙瘩组织中I型和III型胶原的积聚有关，这一机制可能是通过与MMP13的分子相互作用来调控的。维甲酸可逆转瘢痕疙瘩成纤维细胞中MMPs的异常表达，如MMP13的表达显著增加，这部分是通过失活AP-1途径实现的。目前的结果提示，维甲酸可能在临床上用于改善瘢痕疙瘩的慢性炎症，防止瘢痕疙瘩组织扩张到周围正常皮肤。较少

项目成果

Okazaki M, Yoshimura K, Suzuki Y, Uchida G, Kitano Y, Harii K: "The mechanism of epidermal hyperpigmentation in cafe-au-lait macules of neurofibromatosis type 1 (von Recklinghausen's disease) may be associated with dermal fibroblast-derived stem cell fact

Okazaki M、Yoshimura K、Suzuki Y、Uchida G、Kitano Y、Harii K：“1 型神经纤维瘤病（冯·雷克林豪森病）的牛奶咖啡斑表皮色素沉着过度的机制可能与真皮成纤维细胞来源的干细胞有关

Okazaki M, Yoshimura K, Uchida a Harii K: "Elevated expression of Hepatocyte and Keratinocyte Growth Factor in cultured buccal-mucosa-derived fibroblasts compared with normal-skin-derived fibroblasts."Journal of Dermatological Science. 30. 108-115 (2002)

Okazaki M、Yoshimura K、Uchida a Harii K：“与正常皮肤来源的成纤维细胞相比，培养的颊粘膜来源的成纤维细胞中肝细胞和角质形成细胞生长因子的表达升高。”皮肤病学杂志。

Yoshimura K, et al.: "The Effect of two Episodes of denervation"Plast Reconstr. Surg. 109. 212-219 (2002)

Yoshimura K 等人：“两次去神经支配的效果”Plast Reconstr。

Yoshimura K.Uchida G.Okazaki M.Kitano Y.Harii K: "Differential expression of heparin-binding EGF-like growth factor (HB-EGF) mRNA in normal human keratinocytes induced by a variety of natural and synthetic retinoids."Experimental Dermatology. 12(Suppl.2).

Yoshimura K.Uchida G.Okazaki M.Kitano Y.Harii K：“由各种天然和合成类视黄醇诱导的正常人角质形成细胞中肝素结合 EGF 样生长因子 (HB-EGF) mRNA 的差异表达。”实验皮肤病学

Okazaki M, Yoshimura K, Uchida a Harii K.: "Correlation between age and the secretions of melanocyte-stimulating cytokines in cultured keratinocytes and fibroblasts."British Journal of Dermatology. (in press).

Okazaki M、Yoshimura K、Uchida a Harii K.：“年龄与培养的角质形成细胞和成纤维细胞中黑素细胞刺激细胞因子的分泌之间的相关性。”英国皮肤病学杂志。