Clinical case seminar - Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis
Clinical case seminar - Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis
复制标题
DOI：
10.1210/jc.2003-031055
复制
发表时间：
2004-04-01
影响因子：
5.8
通讯作者：
Klaushofer, K
中科院分区：
文献类型：
--
作者：
Fratzl-Zelman, N;Valenta, A;Klaushofer, K
骨质疏松症是一种罕见的人类遗传性疾病，以骨骼骨硬化、身材矮小和骨脆性为特征。这种疾病是由组织蛋白酶K基因突变引起的，组织蛋白酶K是一种溶酶体半胱氨酸蛋白酶，在破骨细胞中高度表达，对矿化骨中有机基质的降解至关重要。最近，人们的兴趣集中在抑制组织蛋白酶K以防止骨丢失的药物上。然而，关于骨质疏松症中的细胞活性或骨的材料质量，人们知之甚少。在本研究中，使用光学显微镜、定量背向散射电子成像和小角x射线散射法对两个年龄分别为5岁和21岁的患者的移行骨活检进行了研究。将结果与已发表的年龄匹配的参考数据进行比较。对两例患者的组织蛋白酶K基因突变进行了鉴定，其中包括一种新的缺陷。这两个人都有严重的骨硬化，活组织检查显示与脱钙基质区域相对的多核破骨细胞，以及与破骨细胞遗留的未消化的胶原蛋白相邻的骨衬细胞。由于矿化软骨残留物的大量包裹体，矿化基质的均质性明显受到干扰。组织形态计量学评价显示，骨形成的静态参数定量减少。相反，尽管组织蛋白酶K活性不足，但破骨细胞参数接近正常范围。在纳米结构水平上，矿物质颗粒的平均厚度显著增加，反映了骨改建的减少。对骨小梁结构的检查显示，板层高度无序，这一点也从沿胶原纤维纵轴定向的矿物晶体排列不良而明显。综上所述，这些结果有力地表明，功能性组织蛋白酶K对平衡的骨转换是重要的，而酶缺乏导致骨小梁结构和板层排列方面的骨质量严重恶化，这可能是骨质疏松症骨脆性的原因。
Pycnodysostosis is an uncommon human genetic disorder characterized by osteosclerosis of the skeleton, short stature, and bone fragility. The disease results from mutations in the cathepsin K gene, a lysosomal cysteine protease highly expressed in osteoclasts and crucial for the degradation of organic matrix from mineralized bone. Recently, interest has focused on a pharmaceutical inhibition of cathepsin K to prevent bone loss. However, little is known about the cellular activity or material quality of bone in pycnodysostosis. In the present study, transiliac bone biopsies from two affected individuals, aged 5 and 21 yr, were investigated using light microscopy, quantitative backscattered electron imaging, and small angle x-ray scattering. Results were compared with published age-matched reference data. The mutations in the cathepsin K gene of both patients were identified, including one novel defect. Both individuals had severe osteosclerosis, and their biopsies displayed multinucleated osteoclasts apposed to areas of demineralized matrix as well as bone-lining cells adjacent to this undigested collagen left over by osteoclasts. The homogeneity of the mineralized matrix was markedly disturbed due to large inclusions of mineralized cartilage residues. Histomorphometric evaluation showed a quantitative decrease in static parameters of bone formation. In contrast and despite deficient cathepsin K activity, osteoclastic parameters were close to normal range. At the nanostructural level, there was a marked increase in the mean thickness of the mineral particles, reflecting decreased bone remodeling. Examination of the trabecular structure revealed that the lamellae were highly disordered, which was also apparent from a poor alignment of mineral crystals oriented along the longitudinal axis of collagen fibrils. Taken together, these results strongly suggest that functional cathepsin K is important for balanced bone turnover, and enzyme deficiency results in a profound deterioration of bone quality with respect to trabecular architecture and lamellar arrangement, which is presumably the reason for bone fragility in pycnodysostosis.