title: Unique micro- and nano-scale mineralization pattern of human osteogenesis imperfecta type VI bone.
abstract: 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.
authors.affiliation: Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept. Hanusch Hospital, 1140 Vienna, Austria. Electronic address: nadja.fratzl-zelman@osteologie.at.
authors.forename: Nadja
authors.initials: N
authors.lastname: Fratzl-Zelman
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Dept. of Biomaterials, 14424 Potsdam, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Schmidt
authors.affiliation: Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept. Hanusch Hospital, 1140 Vienna, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Roschger
authors.affiliation: 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.
authors.forename: Andreas
authors.initials: A
authors.lastname: Roschger
authors.affiliation: Genetics Unit, Shriners Hospital for Children, McGill University, Montreal H3G 1A6, Canada.
authors.forename: Francis H
authors.initials: FH
authors.lastname: Glorieux
authors.affiliation: Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept. Hanusch Hospital, 1140 Vienna, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Klaushofer
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Dept. of Biomaterials, 14424 Potsdam, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wagermaier
authors.affiliation: Genetics Unit, Shriners Hospital for Children, McGill University, Montreal H3G 1A6, Canada.
authors.forename: Frank
authors.initials: F
authors.lastname: Rauch
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Dept. of Biomaterials, 14424 Potsdam, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Fratzl
mesh_terms: D000293:Adolescent; D001842:Bone and Bones / Q000503:physiopathology*; D002113:Calcification, Physiologic; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D010013:Osteogenesis Imperfecta / Q000503:physiopathology*
keywords: High-resolution backscattered electron imaging; Matrix mineralization; Osteogenesis imperfecta type VI; Pediatric bone biopsies; Quantitative backscattered electron imaging; Synchrotron small angle X-ray scattering