Evaluation of the relationship between lacunar wall strain and osteocyte β-catenin signaling pathway activation using finite element methods and confocal fluorescence imaging.
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Abstract
Mechanical loading of bone has been shown to result in activation of Wnt/β-catenin signaling in osteocytes, leading to increased bone formation, but the mechanism of mechanotransduction is still unknown. It has been observed that following cyclic compression loading, osteocytes in murine cortical bone have heterogeneous levels of Wnt/β-catenin signaling. This led us to investigate whether the heterogeneity of bone strain at the lacunocanalicular walls might directly affect the level of Wnt/β-catenin signaling activity in an enclosed osteocyte. The right ulna of an anesthetized 5-mo male TOPGAL transgenic mouse was subjected to cyclic compression loading at 2.25 N at 2 Hz for 100 cycles and for control the left ulna was not loaded. After 1 hour both ulnae were harvested. Bone slices from the ulnae, were stained with the β-galactosidase (β-gal) substrate DDAOG to create a fluorescent stain that indicates the level of Wnt/β-catenin signaling activity in osteocytes. We labeled the lacunocanalicular network in the same samples with the fluorescent dye FITC. Multiplexed 3D confocal fluorescence images were collected, and the computational finite element modeling software, Materialise® Innovation Suites (MIMICs and 3-Matic modules), was used to assess the level of Wnt/β-catenin signaling in the osteocytes and generate finite element models of the bone with its lacunocanalicular network. The finite element analysis software FEBio was used to perform strain analysis on the models and predict bone strain in the bone matrix of the samples. The levels of Wnt/β-catenin signaling in the loaded bone were significantly higher than in the non-loaded bone. In the non-loaded bone, every osteocyte showed small amounts of activity, possibly a basal level of signaling or the result of prior cage activity. The levels of β-catenin signaling pathway activation were heterogeneous, and robust linear regression analysis reported correlation between activation and the average strain in regions representing bone surrounding the osteocytes. When only high strain elements were considered, however, the significance level of the correlation between osteocyte activation and strain was reduced. This suggests that in addition to bone strains, there may be other factors that are critical in determining osteocyte activation levels.
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Introduction -- Literature Review -- Methods -- Results -- Discussion -- Conclusion
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Ph.D. (Doctor of Philosophy)