Increased autophagy in EphrinB2-deficient osteocytes is associated with elevated secondary mineralization and brittle bone

Christina Vrahnas, Martha Blank, Toby A. Dite, Liliana Tatarczuch, Niloufar Ansari, Blessing Crimeen-Irwin, Huynh Nguyen, Mark R. Forwood, Yifang Hu, Mika Ikegame, Keith R. Bambery, Cyril Petibois, Eleanor J. Mackie, Mark J. Tobin, Gordon K. Smyth, Jonathan S. Oakhill, T. John Martin and Natalie A. Sims ()
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Christina Vrahnas: St. Vincent’s Institute of Medical Research
Martha Blank: St. Vincent’s Institute of Medical Research
Toby A. Dite: St. Vincent’s Hospital
Liliana Tatarczuch: The University of Melbourne
Niloufar Ansari: St. Vincent’s Institute of Medical Research
Blessing Crimeen-Irwin: St. Vincent’s Institute of Medical Research
Huynh Nguyen: Griffith University
Mark R. Forwood: Griffith University
Yifang Hu: The Walter and Eliza Hall Institute of Medical Research
Mika Ikegame: Okayama University
Keith R. Bambery: ANSTO Australian Synchrotron
Cyril Petibois: Allée Geoffroy Saint-Hilaire Bat. B2
Eleanor J. Mackie: The University of Melbourne
Mark J. Tobin: ANSTO Australian Synchrotron
Gordon K. Smyth: The Walter and Eliza Hall Institute of Medical Research
Jonathan S. Oakhill: St. Vincent’s Hospital
T. John Martin: St. Vincent’s Institute of Medical Research
Natalie A. Sims: St. Vincent’s Institute of Medical Research

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Mineralized bone forms when collagen-containing osteoid accrues mineral crystals. This is initiated rapidly (primary mineralization), and continues slowly (secondary mineralization) until bone is remodeled. The interconnected osteocyte network within the bone matrix differentiates from bone-forming osteoblasts; although osteoblast differentiation requires EphrinB2, osteocytes retain its expression. Here we report brittle bones in mice with osteocyte-targeted EphrinB2 deletion. This is not caused by low bone mass, but by defective bone material. While osteoid mineralization is initiated at normal rate, mineral accrual is accelerated, indicating that EphrinB2 in osteocytes limits mineral accumulation. No known regulators of mineralization are modified in the brittle cortical bone but a cluster of autophagy-associated genes are dysregulated. EphrinB2-deficient osteocytes displayed more autophagosomes in vivo and in vitro, and EphrinB2-Fc treatment suppresses autophagy in a RhoA-ROCK dependent manner. We conclude that secondary mineralization involves EphrinB2-RhoA-limited autophagy in osteocytes, and disruption leads to a bone fragility independent of bone mass.

Date: 2019
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DOI: 10.1038/s41467-019-11373-9

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