Increased autophagy in EphrinB2-deficient osteocytes is associated with elevated secondary mineralization and brittle bone
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Blank, Martha
Dite, Toby A
Tatarczuch, Liliana
Ansari, Niloufar
Crimeen-Irwinl, Blessing
Huynh, Nguyen
Forwood, Mark R
Hu, Yifang
Ikegame, Mika
Bambery, Keith R
Petibois, Cyril
Mackie, Eleanor J
Tobin, Mark J
Smyth, Gordon K
Oakhill, Jonathan S
Martin, T John
Sims, Natalie A
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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.
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Nature Communications
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10
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1
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© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Clinical sciences
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Multidisciplinary Sciences
Science & Technology - Other Topics
AGE-RELATED-CHANGES
ENDOPLASMIC-RETICULUM
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Vrahnas, C; Blank, M; Dite, TA; Tatarczuch, L; Ansari, N; Crimeen-Irwinl, B; Nguyen, H; Forwood, MR; Hu, Y; Ikegame, M; Bambery, KR; Petibois, C; Mackie, EJ; Tobin, MJ; Smyth, GK; Oakhill, JS; Martin, TJ; Sims, NA, Increased autophagy in EphrinB2-deficient osteocytes is associated with elevated secondary mineralization and brittle bone, Nature Communications, 2019, 10 (1), pp. 3436: 1-3436: 1