Cathepsin L in bone marrow-derived cells is required for retinal and choroidal neovascularization.
Cathepsin L in bone marrow-derived cells is required for retinal and choroidal neovascularization.
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DOI：
10.2353/ajpath.2010.091027
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发表时间：
2010-05
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通讯作者：
N. Shimada;K. Ohno-Matsui;S. Iseki;M. Koike;Y. Uchiyama;Jiying Wang;Takeshi Yoshida;Tetsuji Sato-Tetsuji
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作者：
N. Shimada;K. Ohno-Matsui;S. Iseki;M. Koike;Y. Uchiyama;Jiying Wang;Takeshi Yoshida;Tetsuji Sato-Tetsuji
许多威胁视力的疾病的特征在于眼内新血管形成（例如，增殖性糖尿病视网膜病变和年龄相关性黄斑变性）。虽然抗VEGF抗体的新疗法被用于治疗这些眼内新生血管性疾病，但视力恢复有限，主要是因为纤维血管组织的残留。治疗的理想目标是防止新血管通过基质屏障侵入无血管组织。本研究的目的是确定组织蛋白酶L，基质降解酶，眼内血管生成中发挥的作用。使用已建立的视网膜和脉络膜新生血管动物模型，我们证明特异性抑制剂对组织蛋白酶L的抑制导致眼内新生血管的显着减少。在组织蛋白酶L缺陷小鼠中发现了类似的新生血管减少。将组织蛋白酶L缺陷小鼠的骨髓移植到野生型小鼠中，可显著降低眼内新生血管的程度。此外，免疫细胞化学分析表明，VE钙粘蛋白阳性的内皮祖细胞，而不是CD43阳性或Iba-1阳性细胞，是主要的细胞有助于产生组织蛋白酶L。这些数据表明，内皮祖细胞中表达的组织蛋白酶L在眼内血管生成中发挥关键作用，并提出了靶向组织蛋白酶L治疗新生血管性眼部疾病的潜在治疗方法。
Many vision-threatening diseases are characterized by intraocular neovascularization, (e.g., proliferative diabetic retinopathy and age-related macular degeneration). Although a new therapy with anti-VEGF antibodies is being used to treat these intraocular neovascular disorders, the visual recovery is limited, mainly because of the remnants of fibrovascular tissues. The ideal goal of the treatment is to prevent the invasion of new vessels into the avascular tissue through a matrix barrier. The purpose of this study was to determine the role played by cathepsin L, a matrix degrading enzyme, on intraocular angiogenesis. Used established animal models of retinal and choroidal neovascularization, we demonstrated that an inhibition of cathepsin L by specific inhibitors resulted in a significant decrease of intraocular neovascularization. A similar decrease of neovascularization was found in cathepsin L-deficient mice. Transplantation of bone marrow from cathepsin L-deficient mice into wild-type mice significantly reduced the degree of intraocular neovascularization. In addition, immunocytochemical analyses demonstrated that VE cadherin-positive endothelial progenitor cells, but not CD43-positive or Iba-1-positive cells, were the major cells contributing to the production of cathepsin L. These data indicate that cathepsin L expressed in endothelial progenitor cells plays a critical role in intraocular angiogenesis and suggest a potential therapeutic approach of targeting cathepsin L for neovascular ocular diseases.