RT Journal Article
SR Electronic
T1 Increased autophagy in ephrinB2 deficient osteocytes is associated with hypermineralized, brittle bones
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 260711
DO 10.1101/260711
A1 Christina Vrahnas
A1 Toby A Dite
A1 Niloufar Ansari
A1 Blessing Crimeen-Irwin
A1 Huynh Nguyen
A1 Mark R Forwood
A1 Yifang Hu
A1 Mika Ikegame
A1 Keith R Bambery
A1 Cyril Petibois
A1 Mark J Tobin
A1 Gordon K Smyth
A1 Jonathan S Oakhill
A1 T John Martin
A1 Natalie A Sims
YR 2018
UL http://biorxiv.org/content/early/2018/02/05/260711.abstract
AB 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. This cellular transition requires expression of ephrinB2, and we were intrigued about why ephrinB2 continues to be expressed at high levels 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.