Linking osteopetrosis end pycnodysostosis: Regulation of cathepsin K expression by the microphthalmia transcription factor family
Linking osteopetrosis end pycnodysostosis: Regulation of cathepsin K expression by the microphthalmia transcription factor family
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DOI：
10.1073/pnas.091479298
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发表时间：
2001-05-08
影响因子：
11.1
通讯作者：
Fisher, DE
中科院分区：
文献类型：
--
作者：
Motyckova, G;Weilbaecher, KN;Fisher, DE
各种遗传条件产生功能失调的破骨细胞，导致骨质疏松或骨硬化。这些包括人类垂体肥大症，由组织蛋白酶K突变引起的常染色体隐性综合征，组织蛋白酶K缺陷小鼠和miff突变啮齿动物菌株。Cathepsin K是一种在破骨细胞中高表达的半胱氨酸蛋白酶，在骨基质蛋白组分的降解中起重要作用。组织蛋白酶K在人类乳腺癌中也有显著的表达，它可能有助于肿瘤的侵袭性。Mitf是螺旋-环-螺旋转录因子亚家族的成员，该亚家族包含潜在的二聚化伙伴TFE3、TFEB和TFEC。在小鼠中，显性阴性而非隐性miff突变可产生骨质疏松症，这表明其他家族成员也有功能需求。Miff也被发现，TFE3也被认为可以调节破骨细胞功能的年龄依赖性变化。本研究通过组织蛋白酶K启动子中的三个共识元件确定了组织蛋白酶K是Miff和TFE3的转录靶点。此外，在mitf突变型破骨细胞中发现组织蛋白酶K mRNA和蛋白缺失，野生型mitf的过表达显著上调了培养的人破骨细胞中内源性组织蛋白酶K的表达。组织蛋白酶K启动子活性被mitf的显性阴性而非隐性小鼠等位基因破坏，其模式与它们的骨质疏松表型密切匹配。组织蛋白酶K和Mitf家族之间的这种关系有助于解释它们在骨质疏松症和骨质疏松症中相应缺陷的表型重叠，并确定组织蛋白酶K在骨稳态和人类恶性肿瘤中表达的可能调节因子。
Various genetic conditions produce dysfunctional osteoclasts resulting in osteopetrosis or osteosclerosis. These include human pycnodysostosis, an autosomal recessive syndrome caused by cathepsin K mutation, cathepsin K-deficient mice, and miff mutant rodent strains. Cathepsin K is a highly expressed cysteine protease in osteoclasts that plays an essential role in the degradation of protein components of bone matrix. Cathepsin K also is expressed in a significant fraction of human breast cancers where it could contribute to tumor invasiveness. Mitf is a member of a helix-loop-helix transcription factor subfamily, which contains the potential dimerization partners TFE3, TFEB, and TFEC. In mice, dominant negative, but not recessive, mutations of miff, produce osteopetrosis, suggesting a functional requirement for other family members. Miff also has been found-and TFE3 has been suggested-to modulate age-dependent changes in osteoclast function. This study identifies cathepsin K as a transcriptional target of Miff and TFE3 via three consensus elements in the cathepsin K promoter. Additionally, cathepsin K mRNA and protein were found to be deficient in mitf mutant osteoclasts, and overexpression of wild-type Mitf dramatically up-regulated expression of endogenous cathepsin K in cultured human osteoclasts. Cathepsin K promoter activity was disrupted by dominant negative, but not recessive, mouse alleles of mitf in a pattern that closely matches their osteopetrotic phenotypes. This relationship between cathepsin K and the Mitf family helps explain the phenotypic overlap of their corresponding deficiencies in pycnodysostosis and osteopetrosis and identifies likely regulators of cathepsin K expression in bone homeostasis and human malignancy.