Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization
Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization
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DOI：
10.1359/jbmr.1999.14.10.1654
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发表时间：
1999-10-01
影响因子：
6.2
通讯作者：
Kola, I
中科院分区：
文献类型：
--
作者：
Gowen, M;Lazner, F;Kola, I
Cathepsin K是一种主要在破骨细胞中表达的半胱氨酸蛋白酶，活化的Cathepsin K切割关键的骨基质蛋白，并被认为在骨吸收过程中降解骨的有机相中起重要作用，人类Cathepsin K基因的突变已被证明与罕见的骨骼发育不良有关。这些个体中组织蛋白酶K突变形式的功能活性程度尚未被阐明，但预计其功能活性较低或不存在。为了研究组织蛋白酶K在骨吸收中的作用，我们产生了组织蛋白酶K基因缺失的小鼠，对小鼠的组织学和放射学分析显示长骨和椎骨骨质疏松，关节形态异常，x射线微电脑断层扫描图像允许定量骨体积的增加。原发性海绵膜和胫骨近端干骺端骨小梁的厚度和数量，并不是所有的骨骼都受到类似的影响。软骨细胞分化正常。小鼠的造血区室也出现异常，特别是骨髓细胞减少和脾肿大，杂合动物表现正常。对骨组织进行仔细的组织学检查，发现完全分化的破骨细胞位于脱矿骨的小区域。这强烈表明，缺乏组织蛋白酶k的破骨细胞能够使细胞外基质脱矿，但不能充分去除脱矿的骨。这与组织蛋白酶K作为基质降解蛋白酶在骨吸收中的作用完全一致。
Cathepsin K is a cysteine protease expressed predominantly in osteoclasts, Activated cathepsin K cleaves key bone matrix proteins and is believed to play an important role in degrading the organic phase of bone during bone resorption, Mutations in the human cathepsin K gene have been demonstrated to be associated with a rare skeletal dysplasia, pycnodysostosis. The degree of functional activity of the mutated forms of cathepsin K in these individuals has not been elucidated, but is predicted to be low or absent, To study the role of cathepsin K in bone resorption, we have generated mice deficient in the cathepsin K gene, Histologic and radiographic analysis of the mice revealed osteopetrosis of the long bones and vertebrae, and abnormal joint morphology, X-ray microcomputerized tomography images allowed quantitation of the increase in bone volume, trabecular thickness, and trabecular number in both the primary spongiosa and the metaphysis of the proximal tibiae, Not all bones were similarly affected. Chondrocyte differentiation was normal. The mice also had abnormalities in hematopoietic compartments, particularly decreased bone marrow cellularity and splenomegaly, The heterozygous animals appeared normal. Close histologic examination of bone histology revealed fully differentiated osteoclasts apposed to small regions of demineralized bone. This strongly suggests that cathepsin K-deficient osteoclasts are capable of demineralizing the extracellular matrix but are unable to adequately remove the demineralized bone. This is entirely consistent,vith the proposed function of cathepsin K as a matrix-degrading proteinase in bone resorption.