title: Fkbp10 Deletion in Osteoblasts Leads to Qualitative Defects in Bone.
abstract: Osteogenesis imperfecta (OI), also known as brittle bone disease, displays a spectrum of clinical severity from mild (OI type I) to severe early lethality (OI type II), with clinical features including low bone mass, fractures, and deformities. Mutations in the FK506 Binding Protein 10 (FKBP10), gene encoding the 65-kDa protein FKBP65, cause a recessive form of OI and Bruck syndrome, the latter being characterized by joint contractures in addition to low bone mass. We previously showed that Fkbp10 expression is limited to bone, tendon, and ligaments in postnatal tissues. Furthermore, in both patients and Fkbp10 knockout mice, collagen telopeptide hydroxylysine crosslinking is dramatically reduced. To further characterize the bone specific contributions of Fkbp10, we conditionally ablated FKBP65 in Fkbp10fl/flmice (Mus musculus; C57BL/6) using the osteoblast-specific Col1a1 2.3-kb Cre recombinase. Using μCT, histomorphometry and quantitative backscattered electron imaging, we found minimal alterations in the quantity of bone and no differences in the degree of bone matrix mineralization in this model. However, mass spectroscopy (MS) of bone collagen demonstrated a decrease in mature, hydroxylysine-aldehyde crosslinking. Furthermore, bone of mutant mice exhibits a reduction in mineral-to-matrix ratio and in crystal size as shown by Raman spectroscopy and small-angle X-ray scattering, respectively. Importantly, abnormalities in bone quality were associated with impaired bone biomechanical strength in mutant femurs compared with those of wild-type littermates. Taken together, these data suggest that the altered collagen crosslinking through Fkbp10 ablation in osteoblasts primarily leads to a qualitative defect in the skeleton. © 2017 American Society for Bone and Mineral Research.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Caressa D
authors.initials: CD
authors.lastname: Lietman
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Joohyun
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Ingo
authors.initials: I
authors.lastname: Grafe
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Bi
authors.affiliation: Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Catherine G
authors.initials: CG
authors.lastname: Ambrose
authors.affiliation: Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling 1st Med. Dept. Hanusch Hospital, Vienna, Austria.
authors.forename: Nadja
authors.initials: N
authors.lastname: Fratzl-Zelman
authors.affiliation: Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling 1st Med. Dept. Hanusch Hospital, Vienna, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Roschger
authors.affiliation: Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling 1st Med. Dept. Hanusch Hospital, Vienna, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Klaushofer
authors.affiliation: Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Research Campus Golm, Potsdam, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wagermaier
authors.affiliation: Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Research Campus Golm, Potsdam, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Schmidt
authors.affiliation: Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Research Campus Golm, Potsdam, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Fratzl
authors.affiliation: Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Rai
authors.affiliation: Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA, USA.
authors.forename: MaryAnn
authors.initials: M
authors.lastname: Weis
authors.affiliation: Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Eyre
authors.affiliation: Micro-Imaging Center, Shriners Hospital for Children, Portland, OR, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Keene
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Brendan H
authors.initials: BH
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001696:Biomechanical Phenomena; D015519:Bone Density; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology*; D002113:Calcification, Physiologic; D003094:Collagen / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000378:metabolism; D003460:Crystallization; D005260:Female; D017353:Gene Deletion; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism*; D013059:Spectrum Analysis, Raman; D022021:Tacrolimus Binding Proteins / Q000172:deficiency* / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D003432:Cross-Linking Reagents; D003094:Collagen; D022021:Tacrolimus Binding Proteins; C491675:Fkbp10 protein, mouse
keywords: COLLAGEN; GENETIC ANIMAL MODELS; MATRIX MINERALIZATION; OSTEOBLASTS; OSTEOGENESIS IMPERFECTA