Degeneration of the osteocyte network in the C57BL/6 mouse model of aging

Abstract

Age-related bone loss and associated fracture risk are major problems in musculoskeletal health. Osteocytes have emerged as key regulators of bone mass and as a therapeutic target for preventing bone loss. As aging is associated with changes in the osteocyte lacunocanalicular system, we focused on the responsible cellular mechanisms in osteocytes. Bone phenotypic analysis was performed in young-(5mo) and aged-(22mo) C57BL/6 mice and changes in bone structure/geometry correlated with alterations in osteocyte parameters determined using novel multiplexed-3D-confocal imaging techniques. Age-related bone changes analogous to those in humans were observed, including increased cortical diameter, decreased cortical thickness, reduced trabecular BV/TV and cortical porosities. This was associated with a dramatic reduction in osteocyte dendrite number and cell density, particularly in females, where osteocyte dendricity decreased linearly from 5, 12, 18 to 22mo and correlated significantly with cortical bone parameters. Reduced dendricity preceded decreased osteocyte number, suggesting dendrite loss may trigger loss of viability. Age-related degeneration of osteocyte networks may impair bone anabolic responses to loading and gender differences in osteocyte cell body and lacunar fluid volumes we observed in aged mice may lead to gender-related differences in mechanosensitivity. Therapies to preserve osteocyte dendricity and viability may be beneficial for bone health in aging.

Cx43 Overexpression in Osteocytes Prevents Osteocyte Apoptosis and Preserves Cortical Bone Quality in Aging Mice

“…Numerous studies have demonstrated the critical role that osteocytes play in sensing mechanical stimuli and coordinating targeted bone remodeling to repair damaged areas . Decreases in osteocyte viability have been observed in many conditions underlying bone loss . However, the specific mechanisms by which viable osteocytes prevent bone fragility in aging are not known.…”

“…Numerous studies suggest that the extensive osteocyte network within the mineralized bone matrix plays an essential role in orchestrating bone remodeling through cell‐cell communication among neighboring osteocytes and with cells on the bone surface . Consistent with this notion, old age and conditions of increased skeletal fragility are associated with reductions in osteocyte viability and increased prevalence of empty lacunae, and disruptions in the osteocyte network alter osteocytic regulation of bone remodeling . Osteocytes control intercellular signaling with distant cells both through the extracellular release of molecules and cytokines via hemichannels formed via connexins (Cx) and directly with adjacent cells through gap junction channels, formed by connexons present on the surface of neighboring cells .…”

Relative effects of age on implant integration in a rat model: A longitudinal in vivo microct study

“…Finally, there are intrinsic limitations to the animal model itself. The lifestyle associated with standard animal housing is sedentary: It was shown that old mice and rats with access to voluntary wheel running will use the option and show no age‐associated loss in osteocytes and overall better bones . In this regard, our findings are for sedentary elderly and may not be valid in a more physically active model.…”

The Spectrum of Fundamental Basic Science Discoveries Contributing to Organismal Aging

“…Taken together, these findings suggest that defective autophagy in osteoblast lineage cells prevents the proper transition of osteoblasts into osteocytes and causes degeneration of the osteocyte canalicular network . Interestingly, the latter phenomenon has recently been associated with natural chronological aging in mice . Given that impaired autophagy in osteoblast lineage cells and osteocytes appears to be a consequence of overwhelming stress that becomes intensified in bone over time, defective autophagy may have a causal role in skeletal aging.…”

“…(60) Interestingly, the latter phenomenon has recently been associated with natural chronological aging in mice. (61) Given that impaired autophagy in osteoblast lineage cells and osteocytes appears to be a consequence of overwhelming stress that becomes intensified in bone over time, defective autophagy may have a causal role in skeletal aging. However, direct evidence is lacking at this time.…”