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Increased autophagy in ephrinB2 deficient osteocytes is associated with hypermineralized, brittle bones

Christina Vrahnas, Toby A Dite, Niloufar Ansari, Blessing Crimeen-Irwin, Huynh Nguyen, Mark R Forwood, Yifang Hu, Mika Ikegame, Keith R Bambery, Cyril Petibois, Mark J Tobin, Gordon K Smyth, Jonathan S Oakhill, T John Martin, Natalie A Sims
doi: https://doi.org/10.1101/260711
Christina Vrahnas
1Bone Biology and Disease Unit, St. Vincent’s Institute of Medical Research, Melbourne, Victoria, 3065, Australia
2Department of Medicine, The University of Melbourne, St. Vincent’s Hospital, Melbourne, Victoria, 3065, Australia
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Toby A Dite
2Department of Medicine, The University of Melbourne, St. Vincent’s Hospital, Melbourne, Victoria, 3065, Australia
3Metabolic Signalling Laboratory, St. Vincent’s Institute of Medical Research, Melbourne, Victoria, 3065, Australia
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Niloufar Ansari
1Bone Biology and Disease Unit, St. Vincent’s Institute of Medical Research, Melbourne, Victoria, 3065, Australia
2Department of Medicine, The University of Melbourne, St. Vincent’s Hospital, Melbourne, Victoria, 3065, Australia
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Blessing Crimeen-Irwin
1Bone Biology and Disease Unit, St. Vincent’s Institute of Medical Research, Melbourne, Victoria, 3065, Australia
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Huynh Nguyen
4School of Medical Science and Menzies Health Institute Queensland, Griffith University, Gold Coast, 4222, Queensland, Australia
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Mark R Forwood
4School of Medical Science and Menzies Health Institute Queensland, Griffith University, Gold Coast, 4222, Queensland, Australia
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Yifang Hu
5Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3010, Australia
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Mika Ikegame
6Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8525, Japan
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Keith R Bambery
7Infrared Microspectroscopy (IRM) Beamline, Australian Synchrotron, Clayton, Victoria, 3168, Australia
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Cyril Petibois
8University of Bordeaux, Inserm U1029 LAMC, Allée Geoffroy Saint-Hilaire Bat. B2, F33600, Pessac, France
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Mark J Tobin
7Infrared Microspectroscopy (IRM) Beamline, Australian Synchrotron, Clayton, Victoria, 3168, Australia
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Gordon K Smyth
5Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3010, Australia
9School of Mathematics and Statistics, The University of Melbourne, Melbourne, Victoria, 3010, Australia
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Jonathan S Oakhill
2Department of Medicine, The University of Melbourne, St. Vincent’s Hospital, Melbourne, Victoria, 3065, Australia
3Metabolic Signalling Laboratory, St. Vincent’s Institute of Medical Research, Melbourne, Victoria, 3065, Australia
10Mary MacKillop Institute for Health Research, Australian Catholic University, Victoria, 3065, Australia
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T John Martin
1Bone Biology and Disease Unit, St. Vincent’s Institute of Medical Research, Melbourne, Victoria, 3065, Australia
2Department of Medicine, The University of Melbourne, St. Vincent’s Hospital, Melbourne, Victoria, 3065, Australia
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Natalie A Sims
1Bone Biology and Disease Unit, St. Vincent’s Institute of Medical Research, Melbourne, Victoria, 3065, Australia
2Department of Medicine, The University of Melbourne, St. Vincent’s Hospital, Melbourne, Victoria, 3065, Australia
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  • For correspondence: nsims@svi.edu.au
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Summary

Mineralized bone forms when collagen-containing osteoid accrues hydroxyapatite crystals. This process has two phases: a rapid initiation (primary mineralization), followed by slower accrual of mineral (secondary mineralization) that continues until that portion of bone is renewed by remodelling. Within the bone matrix is an interconnected network of cells termed osteocytes. These cells are derived from bone-forming osteoblasts. Osteoblast differentiation requires expression of ephrinB2, and we were intrigued about why ephrinB2 continues to be expressed in mature osteocytes. To determine its function in osteocytes, we developed an osteocyte-specific ephrinB2 null mouse and found they exhibited a brittle bone phenotype. This was not caused by a change in bone mass, but by an intrinsic defect in the strength of the bone material. Although the initiation of osteoid mineralization occurred at a normal rate, the process of secondary mineralization was accelerated in these mice. The maturing mineralized bone matrix incorporated mineral and carbonate more rapidly than controls, indicating that osteocytic ephrinB2 suppresses mineral accumulation in bone. No known regulators of mineralization were modified in the bone of these mice. However, RNA sequencing showed differential expression of a group of autophagy-associated genes, and increased autophagic flux was confirmed in ephrinB2 knockdown osteocytes. This indicates that the process of secondary mineralization in bone makes use of autophagic machinery in a manner that is limited by ephrinB2 in osteocytes, and that this process may be disrupted in conditions of bone fragility.

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Posted March 01, 2018.
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Increased autophagy in ephrinB2 deficient osteocytes is associated with hypermineralized, brittle bones
Christina Vrahnas, Toby A Dite, Niloufar Ansari, Blessing Crimeen-Irwin, Huynh Nguyen, Mark R Forwood, Yifang Hu, Mika Ikegame, Keith R Bambery, Cyril Petibois, Mark J Tobin, Gordon K Smyth, Jonathan S Oakhill, T John Martin, Natalie A Sims
bioRxiv 260711; doi: https://doi.org/10.1101/260711
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Increased autophagy in ephrinB2 deficient osteocytes is associated with hypermineralized, brittle bones
Christina Vrahnas, Toby A Dite, Niloufar Ansari, Blessing Crimeen-Irwin, Huynh Nguyen, Mark R Forwood, Yifang Hu, Mika Ikegame, Keith R Bambery, Cyril Petibois, Mark J Tobin, Gordon K Smyth, Jonathan S Oakhill, T John Martin, Natalie A Sims
bioRxiv 260711; doi: https://doi.org/10.1101/260711

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