Fratzl-Zelman Nadja, Schmidt Ingo, Roschger Paul, Roschger Andreas, Glorieux Francis H, Klaushofer Klaus, Wagermaier Wolfgang, Rauch Frank, Fratzl Peter
Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept. Hanusch Hospital, 1140 Vienna, Austria.
Max Planck Institute of Colloids and Interfaces, Dept. of Biomaterials, 14424 Potsdam, Germany.
Bone. 2015 Apr;73:233-41. doi: 10.1016/j.bone.2014.12.023. Epub 2014 Dec 29.
Osteogenesis imperfecta (OI) is a heterogeneous group of inheritable connective tissue disorders characterized by mutation in genes involved in collagen synthesis and leading to increased bone fragility, low bone mass, impaired bone material properties and abnormally high bone matrix mineralization. Recessive OI type VI is caused by mutation in SERPINF1 leading to a loss-of-function of pigment epithelium-derived factor (PEDF) a collagen-binding protein with potent antiangiogenic activity. Affected patients develop a severe OI phenotype with a striking histological characteristic, rare in other OI types, of an excess of osteoid tissue and prolonged mineralization lag time. To get insights into matrix mineralization, we evaluated biopsies from 9 affected children by quantitative and by high-resolution backscattered electron imaging and assessed bone mineralization density distribution. Thickness, shape and arrangement of mineral particles were measured in a subset of 4 patients by synchrotron small angle X-ray scattering. Typical calcium content in the bone matrix was found to be increased compared to controls, even exceeding values found previously in OI patients with collagen-gene mutations. A main characteristic however, is the coexistence of this highly mineralized bone matrix with seams showing abnormally low mineral content. Atypical collagen fibril organization was found in the perilacunar region of young osteocytes, suggesting a disturbance in the early steps of mineralization. These observations are consistent with the presence of a heterogeneous population of mineral particles with unusual size, shape and arrangement, especially in the region with lower mineral content. The majority of the particles in the highly mineralized bone areas were less disorganized, but smaller and more densely packed than in controls and in previously measured OI patients. These data suggest that the lack of PEDF impairs a proper osteoblast-osteocyte transition and consequently affects the early steps of mineralization, downstream collagen assembly making OI type VI different from "classical" OI with mutations in collagen-type I encoding genes, despite the typical hypermineralization of the bone matrix.
成骨不全症（OI）是一组遗传性结缔组织疾病，具有异质性，其特征是参与胶原蛋白合成的基因突变，导致骨脆性增加、骨量量减少、骨材料性能受损以及骨基质矿化异常增高。隐性VI型OI是由SERPINF1基因突变引起的，导致色素上皮衍生因子（PEDF）功能丧失，PEDF是一种具有强大抗血管生成活性的胶原结合蛋白。受影响的患者会出现严重的OI表型，具有显著的组织学特征，即在其他OI类型中罕见的类骨质组织过多和矿化延迟时间延长。为了深入了解基质矿化情况，我们通过定量分析和高分辨率背散射电子成像对9名受影响儿童的活检样本进行了评估，并评估了骨矿化密度分布。通过同步加速器小角X射线散射对4名患者的子集测量了矿物颗粒的厚度、形状和排列。与对照组相比，发现骨基质中的典型钙含量增加，甚至超过了先前在患有胶原基因突变的OI患者中发现的值。然而，一个主要特征是这种高度矿化的骨基质与矿化含量异常低的骨缝共存。在年轻骨细胞的陷窝周围区域发现了非典型的胶原纤维组织，这表明矿化早期步骤受到干扰。这些观察结果与存在大小、形状和排列异常的异质性矿物颗粒群体一致，特别是在矿化含量较低的区域。高度矿化骨区域中的大多数颗粒比对照组和先前测量的OI患者中的颗粒排列更有序，但更小且堆积更密集。这些数据表明，PEDF的缺乏会损害成骨细胞向骨细胞的正常转变，从而影响矿化的早期步骤，下游的胶原组装使得VI型OI不同于具有I型胶原编码基因突变的“经典”OI，尽管骨基质存在典型的矿化过度。
