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.
Highlights
We were intrigued by the high level of EphrinB2 expression in fully embedded osteocytes[9], beyond the differentiation checkpoint
This work demonstrates that bone flexibility is maintained, and mineral accrual limited, by EphrinB2 signaling in osteocytes
The control mechanisms for primary and secondary mineralization are different, and osteocytes within the bone matrix contribute to secondary mineralization
Summary
We were intrigued by the high level of EphrinB2 expression in fully embedded osteocytes[9], beyond the differentiation checkpoint. Given the extensive connections between osteocytes[2] and the contact-dependent nature of EphrinB2:EphB4 signaling, we hypothesized that EphrinB2 might regulate osteocyte function in the bone matrix. We undertook the present work to determine the requirement for EphrinB2 expression in osteocytes. We found that EphrinB2 in osteocytes does not regulate initiation of bone mineralization, but limits secondary mineral accrual and retains bone matrix flexibility. We showed that osteocytes lacking EphrinB2 have modified genes associated with autophagy and increased autophagosomes, and that EphrinB2 suppresses autophagy in a RhoA-ROCK-dependent manner; this provides evidence that autophagic processes in osteocytes may directly control mineralization
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