title: CRTAP deficiency leads to abnormally high bone matrix mineralization in a murine model and in children with osteogenesis imperfecta type VII.
abstract: Cartilage-associated protein (CRTAP) is an essential cofactor for the proper post-translational chain modification and collagen folding. CRTAP mutations lead mice (Crtap-/- mice) and humans (OI type VII) to a severe/lethal osteochondrodystrophy; patients have fractures at birth, deformities of the lower extremities and impaired growth. The consequences of CRTAP deficiency on intrinsic bone material properties are still unknown. In the present study we evaluated bone quality based on quantitative backscattered electron imaging (qBEI) to assess bone mineralization density distribution (BMDD) in femurs from 12 weeks old Crtap-/- mice and transiliac bone biopsies from 4 children with hypomorphic mutations and having residual CRTAP expression. The analyses revealed in the bone matrix of Crtap-/- animals and OI type VII patients a significant increase in mean (CaMean) and most frequent mineral concentration (CaPeak) compared to wild-type littermates and control children, respectively. The heterogeneity of mineralization (CaWidth) was reduced in Crtap-/- mice but normal in OI type VII patients. The fraction of highly mineralized bone matrix (CaHigh) was remarkably increased in the patients: cancellous bone from 2.1 to 3.7 times and cortical bone from 7.6 to 25.5 times, associated with an increased persistence of primary bone. In conclusion, the BMDD data show that CRTAP deficiency results in a shift towards higher mineral content of the bone matrix similar to classical OI with collagen gene mutations. Our data further suggest altered mineralization kinetics resulting ultimately in an overall elevated tissue mineralization density. Finally, in OI type VII patients the increased portion of primary bone is most likely reflecting a disturbed bone development.
authors.affiliation: Ludwig Boltzmann Institute of Osteology, Hanusch Hospital, Vienna, Austria. nadja.fratzl-zelman@osteologie.at
authors.forename: N
authors.initials: N
authors.lastname: Fratzl-Zelman
authors.forename: R
authors.initials: R
authors.lastname: Morello
authors.forename: B
authors.initials: B
authors.lastname: Lee
authors.forename: F
authors.initials: F
authors.lastname: Rauch
authors.forename: F H
authors.initials: FH
authors.lastname: Glorieux
authors.forename: B M
authors.initials: BM
authors.lastname: Misof
authors.forename: K
authors.initials: K
authors.lastname: Klaushofer
authors.forename: P
authors.initials: P
authors.lastname: Roschger
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics; D001857:Bone Matrix / Q000378:metabolism* / Q000503:physiopathology; D002113:Calcification, Physiologic / Q000235:genetics / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005269:Femur / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D010013:Osteogenesis Imperfecta / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
chemical_list: C108053:CRTAP protein, human; C486354:Crtap protein, mouse; D016326:Extracellular Matrix Proteins; D018832:Molecular Chaperones; D011506:Proteins