ECTS2013 Poster Presentations Other diseases of bone and mineral metabolism (48 abstracts)
Long bone fragility in NF1 is due to deficiency of architecture, micro-structure and matrix mineralization
Jirko Kühnisch 1, , Jong Seto 3, , Claudia Lange 3, , Susanne Schrof 6 , Sabine Stumpp 1 , Karolina Kobus 2 , Julia Grohmann 2 , Nadine Kossler 2 , Peter Varga 6 , Monika Osswald 2 , Sigrid Tinschert 7 , Wenke Seifert 8 , Thaqif el Khassawna 6 , David Stevenson 9 , Florent Elefteriou 10 , Uwe Kornak 1, , Kay Raum 6 , Peter Fratzl 3, , Mateusz Kolanczyk 1, & Stefan Mundlos 1,
1Institute for Medical Genetics and Human Genetics, Charité, Universitätsmedizin Berlin, Berlin, Germany, 2FG Development & Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany, 3Department of Biomaterials, Max Planck Institute for Colloids and Interfaces, Potsdam, Germany, 4Institut für Physiologische Chemie, MTZ, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany, 5Department of Chemistry, Universität Konstanz, Konstanz, Germany, 6Julius Wolff Institute & Brandenburg School of Regenerative Therapies, Charité – Universitätsmedizin Berlin, Berlin, Germany, 7Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Dresden, Germany, 8Institute for Vegetative Anatomy, Charité, Universitätsmedizin Berlin, Berlin, Germany, 9Shriners Hospitals for Children Salt Lake City, Salt Lake City, Utah, Salt Lake City, USA, 10Center of Bone Biology, Vanderbilt University – Medical Center, Nashville, USA, 11Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany.
Neurofibromatosis type I (NF1) is a monogenetic disorder caused by mutations in the NF1 gene encoding for the Ras-GAP protein neurofibromin. Apart from benign tumour development NF1 is frequently associated with skeletal manifestations such as osteopenia or debilitating focal skeletal dysplasia. To assess a function of Nf1 in osteocytes we here apply a combinatorial approach of biophysical, histological and molecular techniques allowing differential analysis of two conditional mouse models, Nf1Prx1 and Nf1Col1, as well as cortical bone samples from NF1 patients.
Humeri of Nf1Prx1 mice appear dwarf, bowed and show severe disorganization at muscle to bone insertion sites suggesting diminished mechanical resistance. Within diaphysis Nf1Prx1 humeri demonstrate massive local defects of mineralization and organic matrix maturation. These changes were confirmed to a lesser degree also in Nf1Col1 humeri. Interestingly, mineralization lesions are associated with blood vessels that persist throughout postnatal bone development. Mechanical testing revealed severe impairment of Nf1Prx1 bone tissue strength. Reduced mechanical potency is partially caused by increased osteocyte volume in Nf1Prx1 and Nf1Col1 bone tissue. Osteocytes further show Ras hyperactivation inducing amplified pMEK1 and pERK1 signalling. Expression analysis detects increased levels of Tem7, Mgp and Phex. Importantly, Nf1Prx1 mice show only increased osteocalcin but normal Opg, Rankl and Fgf23 plasma levels suggesting increased osteoblast activity. Consistent with hypophosphatemia and urinary phosphate wasting cortical bone is hypomineralized. Human bone samples from NF1 patients show inhomogeneous mineralization, increased osteocyte volume and immature collagen maturation.
Thus, bone fragility in NF1 is determined by, first, overall diminished bone tissue quality due to increased micro-porosity, diminished organic matrix quality as well as hypomineralisation and, second, persistence of blood vessels leading to highly localized macro-porotic bone lesions at sites of torsional and bending force integration. Our results emphasize that exclusion of blood vessels from cortical bone during postnatal development is critically determining mechanointegrity.
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Bone Abstracts
ISSN 2052-1219 (online)
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