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  Multiscale, converging defects of macro-porosity, microstructure and matrix mineralization impact long bone fragility in NF1

Kühnisch, J., Seto, J., Lange, C., Schrof, S., Stumpp, S., Kobus, K., et al. (2014). Multiscale, converging defects of macro-porosity, microstructure and matrix mineralization impact long bone fragility in NF1. PLoS One, 9(1): e86115. doi:10.1371/journal.pone.0086115.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-B382-4 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-B3A7-0
Genre: Journal Article

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 Creators:
Kühnisch, Jirko1, Author
Seto, Jong, Author
Lange, Claudia, Author
Schrof, Susanne, Author
Stumpp, Sabine, Author
Kobus, Karolina1, Author
Grohmann, Julia1, Author
Kossler, Nadine2, Author              
Varga, Peter, Author
Oßwald, Monika2, Author              
Emmerich, Denise1, Author
Tinschert, Sigrid, Author
Thielemann, Falk, Author
Duda, Georg, Author
Seifert, Wenke, Author
El Khassawna, Thaqif, Author
Stevenson, David A., Author
Elefteriou, Florent, Author
Kornak, Uwe2, Author              
Raum, Kay, Author
Fratzl, Peter, AuthorMundlos, Stefan2, Author              Kolanczyk, Mateusz2, Author               more..
Affiliations:
1Max Planck Society, ou_persistent13              
2Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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Free keywords: Animals Biomechanical Phenomena Blood Vessels/pathology Bone Density Bone Matrix/*pathology/*physiopathology Bone and Bones/blood supply/*pathology/*physiopathology *Calcification, Physiologic Collagen/metabolism Diaphyses/blood supply/metabolism/pathology Homeodomain Proteins/metabolism Mice Mice, Knockout Neurofibromatosis 1/*pathology/*physiopathology Neurofibromin 1/deficiency/metabolism Osteocytes/metabolism/pathology Porosity Tibia/pathology/physiopathology
 Abstract: Bone fragility due to osteopenia, osteoporosis or debilitating focal skeletal dysplasias is a frequent observation in the Mendelian disease Neurofibromatosis type 1 (NF1). To determine the mechanisms underlying bone fragility in NF1 we analyzed two conditional mouse models, Nf1Prx1 (limb knock-out) and Nf1Col1 (osteoblast specific knock-out), as well as cortical bone samples from individuals with NF1. We examined mouse bone tissue with micro-computed tomography, qualitative and quantitative histology, mechanical tensile analysis, small-angle X-ray scattering (SAXS), energy dispersive X-ray spectroscopy (EDX), and scanning acoustic microscopy (SAM). In cortical bone of Nf1Prx1 mice we detected ectopic blood vessels that were associated with diaphyseal mineralization defects. Defective mineral binding in the proximity of blood vessels was most likely due to impaired bone collagen formation, as these areas were completely devoid of acidic matrix proteins and contained thin collagen fibers. Additionally, we found significantly reduced mechanical strength of the bone material, which was partially caused by increased osteocyte volume. Consistent with these observations, bone samples from individuals with NF1 and tibial dysplasia showed increased osteocyte lacuna volume. Reduced mechanical properties were associated with diminished matrix stiffness, as determined by SAM. In line with these observations, bone tissue from individuals with NF1 and tibial dysplasia showed heterogeneous mineralization and reduced collagen fiber thickness and packaging. Collectively, the data indicate that bone fragility in NF1 tibial dysplasia is partly due to an increased osteocyte-related micro-porosity, hypomineralization, a generalized defect of organic matrix formation, exacerbated in the regions of tensional and bending force integration, and finally persistence of ectopic blood vessels associated with localized macro-porotic bone lesions.

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Language(s): eng - English
 Dates: 2014-01-21
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1371/journal.pone.0086115
ISSN: 1932-6203 (Electronic)
 Degree: -

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Title: PLoS One
Source Genre: Journal
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Publ. Info: San Francisco, CA : Public Library of Science
Pages: - Volume / Issue: 9 (1) Sequence Number: e86115 Start / End Page: - Identifier: ISSN: 1932-6203
CoNE: /journals/resource/1000000000277850