Role of Cysteine Cathepsins in Extracellular Proteolysis
Role of Cysteine Cathepsins in Extracellular Proteolysis
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DOI：
10.1007/978-3-642-16861-1_2
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发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Wilson, Susan
中科院分区：
文献类型：
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作者：
Broemme, Dieter;Wilson, Susan
半胱氨酸组织蛋白酶是溶酶体蛋白酶，具有管家功能和高度特化的功能。虽然它们的活性在溶酶体酸性和还原条件下是最佳的，但组织蛋白酶可以显著促进细胞外基质的降解。这可能发生在生理条件下，如组织蛋白酶K介导的骨吸收或病理条件下。细胞外基质降解可通过组织蛋白酶的分泌在细胞外发生，或在基质物质的内吞作用后在细胞内发生。在生理条件下，细胞外基质通过其中性pH、氧化环境和高水平的有效内源性组织蛋白酶抑制剂来保护免受组织蛋白酶活性的影响。然而，这些障碍可以通过细胞周围酸化和病理生理降低的抗组织蛋白酶浓度来克服。尽管基质金属蛋白酶主要负责细胞外基质的稳态，但半胱氨酸蛋白酶有助于其在疾病条件下的破坏。开发组织蛋白酶抑制剂作为抗基质降解药物似乎是一个成功的策略。
Cysteine cathepsins are lysosomal proteases with housekeeping as well as highly specialized functions. Although their activities are optimal at lysosomal acidic and reducing conditions, cathepsins can significantly contribute to the degradation of the extracellular matrix. This may happen under physiological conditions as in cathepsin K-mediated bone resorption or under pathological conditions. Extracellular matrix degradation can occur extracellularly by the secretion of cathepsins or intracellularly following the endocytosis of matrix material. Under physiological conditions, the extracellular matrix is safeguarded against cathepsin activities by its neutral pH, oxidative environment, and high levels of potent endogenous cathepsin inhibitors. However, these barriers can be overcome by pericellular acidification and pathophysiologically reduced anticathepsin concentrations. Whereas matrix metalloproteases are primarily responsible for the homeostasis of the extracellular matrix, cysteine proteases contribute to its destruction under disease conditions. The development of cathepsin inhibitors as anti matrix-degrading drugs appears to be a successful strategy.