Bone biology: insights from osteogenesis imperfecta and related rare fragility syndromes.
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TLDR
The most recent advances in the understanding of processes involved in abnormal bone mineralization, collagen processing and osteoblast function are described, as illustrated by the characterization of new causative genes for OI and OI‐related fragility syndromes.Abstract:
The limited accessibility of bone and its mineralized nature have restricted deep investigation of its biology. Recent breakthroughs in identification of mutant proteins affecting bone tissue homeostasis in rare skeletal diseases have revealed novel pathways involved in skeletal development and maintenance. The characterization of new dominant, recessive and X-linked forms of the rare brittle bone disease osteogenesis imperfecta (OI) and other OI-related bone fragility disorders was a key player in this advance. The development of in vitro models for these diseases along with the generation and characterization of murine and zebrafish models contributed to dissecting previously unknown pathways. Here, we describe the most recent advances in the understanding of processes involved in abnormal bone mineralization, collagen processing and osteoblast function, as illustrated by the characterization of new causative genes for OI and OI-related fragility syndromes. The coordinated role of the integral membrane protein BRIL and of the secreted protein PEDF in modulating bone mineralization as well as the function and cross-talk of the collagen-specific chaperones HSP47 and FKBP65 in collagen processing and secretion are discussed. We address the significance of WNT ligand, the importance of maintaining endoplasmic reticulum membrane potential and of regulating intramembrane proteolysis in osteoblast homeostasis. Moreover, we also examine the relevance of the cytoskeletal protein plastin-3 and of the nucleotidyltransferase FAM46A. Thanks to these advances, new targets for the development of novel therapies for currently incurable rare bone diseases have been and, likely, will be identified, supporting the important role of basic science for translational approaches.read more
Citations
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Zebrafish: A Resourceful Vertebrate Model to Investigate Skeletal Disorders.
Francesca Tonelli,Jan Willem Bek,Roberta Besio,Adelbert De Clercq,Laura Leoni,Phil Salmon,Paul Coucke,Andy Willaert,Antonella Forlino +8 more
TL;DR: The techniques that make zebrafish a powerful model to investigate the molecular and physiological basis of skeletal disorders are discussed.
Journal ArticleDOI
Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2.
Fleur S van Dijk,Oliver Semler,Julia Etich,Anna Köhler,Juan A. Jimenez-Estrada,Nathalie Bravenboer,Lauria Claeys,Elise Riesebos,Sejla Gegic,Sander R. Piersma,Connie R. Jimenez,Quinten Waisfisz,Carmen-Lisset Flores,Julián Nevado,Arjan G. J. Harsevoort,Guus J. M. Janus,A.A. Franken,Astrid M. van der Sar,Hanne Meijers-Heijboer,Karen E. Heath,Pablo Lapunzina,Peter G. J. Nikkels,Gijs W. E. Santen,Julian Nüchel,Markus Plomann,Raimund Wagener,Mirko Rehberg,Heike Hoyer-Kuhn,Elisabeth M.W. Eekhoff,Gerard Pals,Matthias Mörgelin,Simon Newstead,Brian T. Wilson,Brian T. Wilson,Victor L. Ruiz-Perez,Victor L. Ruiz-Perez,Alessandra Maugeri,Christian Netzer,Frank Zaucke,Dimitra Micha +39 more
TL;DR: The identification of bi-allelic pathogenic KDELR2 variants as a cause of OI in four families highlights the importance of intracellular recycling of ER-resident molecular chaperones for collagen type I and bone metabolism and a crucial role of HSP47 in the KD ELR2-associated pathogenic mechanism leading to OI.
Journal ArticleDOI
Plastin 3 in health and disease: a matter of balance
Lisa Wolff,Eike A. Strathmann,Ilka Müller,Daniela Mählich,Charlotte Veltman,Anja Niehoff,Anja Niehoff,Brunhilde Wirth +7 more
TL;DR: In this article, a plethora of discoveries have turned Plastin 3 into a highly interesting protein involved in many cellular processes, signaling pathways, and diseases, such as endocytosis, cell migration, axonal growth, neurotransmission, translation, and others.
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New perspectives on the treatment of skeletal dysplasia.
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Early-Onset Osteoporosis.
Outi Mäkitie,M. Carola Zillikens +1 more
TL;DR: Osteoporosis is a skeletal disorder with enhanced bone fragility, usually affecting the elderly as mentioned in this paper, which is very rare in children and young adults and the definition is not only based on a low BMD (a Z-score < − 2.0 in growing children and a T-score ≥ 0.5 in young adults) but also on the occurrence of fragility fractures and/or the existence of underlying chronic diseases or secondary factors such as use of glucocorticoids.
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