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.
N1 - Funding Information:
We thank the staff of the St. Vincent’s Health Bioresources Center for excellent animal care and assistance, Mr Joshua Johnson and Mrs Ingrid Poulton for technical assistance with histology, Dr. Roger Curtain (Bio21) for technical assistance with BSEM, Dr. Paul Roschger for advice on BSEM analysis, Dr. Eleftherios Paschalis for advice on collagen crosslinking analysis, and Dr. Elizabeth Allan for work on the Kusa 4b10 cells. This work was supported by NHMRC Grants 1042129 and 1081242 to N.A.S. and T.J.M., Program Grant 1054618 to G.K.S., and a Brockhoff Foundation Grant to C.V. J.S.O. was supported by an ARC Future Fellowship. N.A.S. was supported by an NHMRC Senior Research Fellowship and by the SVI Brenda Shanahan Fellowship. Part of this work was untaken at the Infrared Microspectroscopy Beamline at the Australian Synchrotron, part of ANSTO. C.V. also thanks the Australia and New Zealand Bone and Mineral Society for the award of the Christine & T.J. Martin Travel Award, which allowed the laboratory visit to C.P. St. Vincent’s Institute acknowledges the support of the Victorian State Government OIS program.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
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.
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U2 - 10.1038/s41467-019-11373-9
DO - 10.1038/s41467-019-11373-9
M3 - Article
C2 - 31366886
AN - SCOPUS:85070418614
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3436
ER -