Does aging decrease osteocyte lacunar-canalicular bone quality?

项目总结

Project Summary Bone fracture is common in aging, yet therapies for maintaining bone quality in aging are limited. The osteocyte participates in bone quality maintenance and may be a promising therapeutic target for bone fragility in aging. Osteocytes reside within bone in lacunae that are connected by canaliculi. The osteocyte can both resorb and deposit bone tissue adjacent to the immense lacunar-canalicular system (LCS). Aging diminishes the number and size of lacunae and canaliculi and also changes several aspects of osteocyte behavior. However, these changes in lacunar and canalicular morphologies do not reveal how the fraction of osteocytes engaged in bone resorption or deposition change in aging. Likewise, changes to the amount of remodeled bone near lacunae and canaliculi due to aging are not known. Thus, there are critical gaps in the understanding of how aging impacts osteocyte-mediated bone quality. The overarching hypothesis of this work is that LCS remodeling increases bone quality by decreasing bone mineral and matrix maturity near osteocytes, and that with increased age, less osteocytes participate in LCS remodeling. One Aim is proposed to investigate this hypothesis. Femurs from skeletally-mature young adult (6 mo), middle-age (18 mo), and aged (24 mo) female and male C57Bl/6 mice will be studied for lacunar-canalicular remodeling characteristics. The fraction of osteocytes participating in bone mineral and matrix resorption will be evaluated from histology and immunohistochemistry, while the fraction of bone-forming osteocytes will be assessed by measuring lacunae positive for fluorochrome labels. For each age, mineral and matrix will be mapped for bone-forming and non-bone-forming osteocyte lacunae using Auger Electron Spectroscopy (AES) at submicron resolution. Complementary submicroscale-resolution Atomic Force Microscopy (AFM) maps of the same lacunae will identify the impact of osteocyte remodeling on bone tissue modulus. AES and AFM maps will also be generated for canaliculi. Osteocyte lacunar and canalicular morphologies will be measured for the same femurs. Completion of this project will significantly advance the understanding of how osteocytes remodel bone across the lifespan. The project will also answer the question of whether changes to osteocyte lacunar and canalicular geometries in aging is associated with loss of bone quality near the osteocyte. The innovative use of Auger Electron Spectroscopy and complementary Atomic Force Microscopy will provide new insights into how aging changes bone quality at physiologically-relevant resolution adjacent to the lacunar-canalicular system. This approach is expected to have broad utility for evaluating the impacts of disease, injury, and therapeutics on osteocyte-mediated bone quality. The long-term goal of this research is to investigate whether osteocyte behavior can be changed through therapeutic interventions to influence LCS remodeling and improve skeletal fracture resistance.