Sclerostin Deficiency Is Linked to Altered Bone Composition

Authors

  • Norbert Hassler,

    1. Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Viennese sickness insurance funds (WGKK) and Research funds of the Austrian workers compensation board (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital Vienna, Austria
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    • NH and AR contributed equally to this work and are listed in alphabetical order.
  • Andreas Roschger,

    1. Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Viennese sickness insurance funds (WGKK) and Research funds of the Austrian workers compensation board (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital Vienna, Austria
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    • NH and AR contributed equally to this work and are listed in alphabetical order.
  • Sonja Gamsjaeger,

    1. Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Viennese sickness insurance funds (WGKK) and Research funds of the Austrian workers compensation board (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital Vienna, Austria
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  • Ina Kramer,

    1. Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
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  • Sonja Lueger,

    1. Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Viennese sickness insurance funds (WGKK) and Research funds of the Austrian workers compensation board (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital Vienna, Austria
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  • Antoon van Lierop,

    1. Leiden Center of Bone Quality, Leiden University Medical Center, Leiden, the Netherlands
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  • Paul Roschger,

    1. Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Viennese sickness insurance funds (WGKK) and Research funds of the Austrian workers compensation board (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital Vienna, Austria
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  • Klaus Klaushofer,

    1. Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Viennese sickness insurance funds (WGKK) and Research funds of the Austrian workers compensation board (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital Vienna, Austria
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  • Eleftherios P Paschalis,

    Corresponding author
    1. Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Viennese sickness insurance funds (WGKK) and Research funds of the Austrian workers compensation board (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital Vienna, Austria
    • Address correspondence to: Eleftherios P Paschalis, PhD, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria. E-mail: lpaschalis@gmx.net

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  • Michaela Kneissel,

    1. Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
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  • Socrates Papapoulos

    1. Leiden Center of Bone Quality, Leiden University Medical Center, Leiden, the Netherlands
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  • For a Commentary on this article, please see Eriksen (J Bone Miner Res. 2014;29:2141–2143. DOI: 10.1002/jbmr.2346).

ABSTRACT

High bone mass in animals and humans with sclerostin deficiency is associated with increased bone strength, which is not the case for all disorders with high bone mineral density, some of which are even associated with fragility fractures owing to unfavorable bone composition. In the current study we investigated whether alterations in bone composition may contribute to the bone strength characteristics associated with lack of sclerostin. We examined cortical bone of Sost-knockout (KO) mice (n = 9, 16 weeks old) and sclerosteosis patients (young [4 to 14 years], n = 4 and adults [24 and 43 years], n = 2) by quantitative backscattered electron imaging and Raman microspectroscopy and compared it to bone from wild-type mice and healthy subjects, respectively. In Sost-KO mice endocortical bone exhibited altered bone composition, whereas subperiosteal bone was unchanged. When comparing endocortical bone tissue of identical tissue age as defined by sequential dual fluorochrome labeling the average bone matrix mineralization was reduced −1.9% (p < 0.0001, younger tissue age) and −1.5% (p < 0.05, older tissue age), and the relative proteoglycan content was significantly increased. Similarly, bone matrix mineralization density distribution was also shifted toward lower matrix mineralization in surgical samples of compact bone of sclerosteosis patients. This was associated with an increase in mineralization heterogeneity in the young population. In addition, and consistently, the relative proteoglycan content was increased. In conclusion, we observed decreased matrix mineralization and increased relative proteoglycan content in bone subcompartments of Sost-KO mice—a finding that translated into sclerosteosis patients. We hypothesize that the altered bone composition contributes to the increased bone strength of patients with sclerostin deficiency. © 2014 American Society for Bone and Mineral Research.

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