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, Natalie A Sims

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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.

Original languageEnglish
Article number3436
Number of pages16
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 31 Jul 2019

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Osteocytes
Physiologic Calcification
Autophagy
bones
Bone
Bone and Bones
Minerals
Osteoblasts
osteoblasts
minerals
Bone Matrix
deletion
Collagen
regulators
collagens
genes
mice
Genes

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Vrahnas, Christina ; Blank, Martha ; Dite, Toby A ; Tatarczuch, Liliana ; Ansari, Niloufar ; Crimeen-Irwin, Blessing ; Nguyen, Huynh ; 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. / Increased autophagy in EphrinB2-deficient osteocytes is associated with elevated secondary mineralization and brittle bone. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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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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Vrahnas, C, Blank, M, Dite, TA, Tatarczuch, L, Ansari, N, Crimeen-Irwin, 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 2019, 'Increased autophagy in EphrinB2-deficient osteocytes is associated with elevated secondary mineralization and brittle bone', Nature Communications, vol. 10, no. 1, 3436. https://doi.org/10.1038/s41467-019-11373-9

Increased autophagy in EphrinB2-deficient osteocytes is associated with elevated secondary mineralization and brittle bone. / Vrahnas, Christina; Blank, Martha; Dite, Toby A; Tatarczuch, Liliana; Ansari, Niloufar; Crimeen-Irwin, Blessing; Nguyen, Huynh; 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.

In: Nature Communications, Vol. 10, No. 1, 3436, 31.07.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Increased autophagy in EphrinB2-deficient osteocytes is associated with elevated secondary mineralization and brittle bone

AU - Vrahnas, Christina

AU - Blank, Martha

AU - Dite, Toby A

AU - Tatarczuch, Liliana

AU - Ansari, Niloufar

AU - Crimeen-Irwin, Blessing

AU - Nguyen, Huynh

AU - Forwood, Mark R

AU - Hu, Yifang

AU - Ikegame, Mika

AU - Bambery, Keith R

AU - Petibois, Cyril

AU - Mackie, Eleanor J

AU - Tobin, Mark J

AU - Smyth, Gordon K

AU - Oakhill, Jonathan S

AU - Martin, T John

AU - Sims, Natalie A

PY - 2019/7/31

Y1 - 2019/7/31

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-019-11373-9

DO - 10.1038/s41467-019-11373-9

M3 - Article

C2 - 31366886

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 3436

ER -