Fratzl-Zelman Nadja, Valenta Angelika, Roschger Paul, Nader Alexander, Gelb Bruce D, Fratzl Peter, Klaushofer Klaus
Ludwig Boltzmann Institute of Osteology, Fourth Medical Department, Hanusch Hospital and UKH-Meidling, A-1140 Vienna, Austria.
J Clin Endocrinol Metab. 2004 Apr;89(4):1538-47. doi: 10.1210/jc.2003-031055.
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.
致密性成骨不全症是一种罕见的人类遗传疾病，其特征为骨骼骨硬化、身材矮小和骨质脆弱。该疾病由组织蛋白酶K基因的突变引起，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，人们的兴趣集中在对组织蛋白酶K的药物抑制以预防骨质流失。然而，关于致密性成骨不全症中骨的细胞活性或材料质量知之甚少。在本研究中，对两名年龄分别为5岁和21岁的受影响个体的髂骨活检组织进行了光学显微镜检查、定量背散射电子成像和小角X射线散射研究。将结果与已发表的年龄匹配参考数据进行比较。确定了两名患者组织蛋白酶K基因的突变，包括一个新的缺陷。两名个体均患有严重的骨硬化症，他们的活检组织显示多核破骨细胞附着于脱矿基质区域以及与破骨细胞留下的未消化胶原蛋白相邻的骨衬细胞。由于矿化软骨残留物的大量夹杂，矿化基质的均匀性明显受到干扰。组织形态计量学评估显示骨形成的静态参数在数量上有所减少。相比之下，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，矿物颗粒的平均厚度显著增加，反映出骨重塑减少。对小梁结构的检查显示板层高度紊乱，这在沿胶原纤维纵轴定向的矿物晶体排列不佳中也很明显。综上所述，这些结果强烈表明功能性组织蛋白酶K对于平衡的骨转换很重要，酶缺乏会导致骨质量在小梁结构和板层排列方面严重恶化，这可能是致密性成骨不全症中骨质脆弱的原因。
