Everts V, Hou W S, Rialland X, Tigchelaar W, Saftig P, Brömme D, Gelb B D, Beertsen W
Department of Cell Biology and Histology, Academic Medical Centre, University of Amsterdam, 1100 DE Amsterdam, The Netherlands.
Calcif Tissue Int. 2003 Oct;73(4):380-6. doi: 10.1007/s00223-002-2092-4. Epub 2003 Jul 24.
The rare osteosclerotic disease, pycnodysostosis, is characterized by decreased osteoclastic bone collagen degradation due to the absence of active cathepsin K. Although this enzyme is primarily expressed by osteoclasts, there is increasing evidence that it may also be present in other cells, including fibroblasts. Since fibroblasts are known to degrade collagen intracellularly following phagocytosis, we analyzed various soft connective tissues (periosteum, perichondrium, tendon, and synovial membrane) from a 13-week-old human fetus with pycnodysostosis for changes in this collagen digestion pathway. In addition, the same tissues from cathepsin K-deficient and control mice were analyzed. Microscopic examination of the human fetal tissues showed that cross-banded collagen fibrils had accumulated in lysosomal vacuoles of fibroblasts. Morphometric analysis of periosteal fibroblasts revealed that the volume density of collagen-containing vacuoles was 18 times higher than in fibroblasts of control patients. A similar accumulation was seen in periosteal fibroblasts of three children with pycnodysostosis. In contrast to the findings in humans, an accumulation of internalized collagen was not apparent in fibroblasts of mice with cathepsin K deficiency. Our observations indicate that the intracellular digestion of phagocytosed collagen by fibroblasts is inhibited in humans with pycnodysostosis, but probably not in the mouse model mimicking this disease. The data strongly suggest that cathepsin K is a crucial protease for this process in human fibroblasts. Murine fibroblasts may have other proteolytic activities that are expressed constitutively or up regulated in response to a deficiency of cathepsin K. This may explain why cathepsin K-deficient mice lack the dysostotic features that are prominent in patients with pycnodysostosis.
罕见的骨硬化性疾病——致密性成骨不全症，其特征是由于缺乏活性组织蛋白酶K，破骨细胞对骨胶原的降解减少。尽管这种酶主要由破骨细胞表达，但越来越多的证据表明它也可能存在于其他细胞中，包括成纤维细胞。由于已知成纤维细胞在吞噬后会在细胞内降解胶原，我们分析了一名13周大患有致密性成骨不全症的人类胎儿的各种软结缔组织（骨膜、软骨膜、肌腱和滑膜）中这种胶原消化途径的变化。此外，还分析了组织蛋白酶K缺陷小鼠和对照小鼠的相同组织。对人类胎儿组织的显微镜检查显示，交叉带状胶原纤维在成纤维细胞的溶酶体空泡中积累。骨膜成纤维细胞的形态计量分析表明，含胶原空泡的体积密度比对照患者的成纤维细胞高18倍。在三名患有致密性成骨不全症的儿童的骨膜成纤维细胞中也观察到了类似的积累。与人类的发现相反，在组织蛋白酶K缺陷的小鼠的成纤维细胞中，内化胶原的积累并不明显。我们的观察表明，在患有致密性成骨不全症的人类中，成纤维细胞对吞噬胶原的细胞内消化受到抑制，但在模拟这种疾病的小鼠模型中可能没有。数据强烈表明，组织蛋白酶K是人类成纤维细胞中这一过程的关键蛋白酶。小鼠成纤维细胞可能具有其他组成性表达或在组织蛋白酶K缺乏时上调的蛋白水解活性。这可能解释了为什么组织蛋白酶K缺陷的小鼠缺乏致密性成骨不全症患者中突出的骨发育异常特征。
