Research Day

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The Wnt signaling pathway has been shown to play a role in bone homeostasis and carcinogenesis. On the one hand, a decrease in signaling has been associated with a decrease in bone mass, on the other, an increase in signaling with cancer development. LGK974 is a Wnt signaling inhibitor currently being investigated as a potential cancer therapeutic agent. This molecule inhibits Porcupine, a transmembrane protein necessary for Wnt ligand secretion. In light of the above and based on our preliminary data, treatment with LGK974 leads to bone mass loss. Our investigation aims to address whether such bone loss can be prevented by mechanically inducing stress to the bone during the treatment. We treated twelve 16-week old C57Bl/6J male mice with LGK974 (chemical Porcupine inhibitor) and twelve with a vehicle (0.5% Methyl Cellulose, 0.5% Tween-80 in water) on weekdays for two weeks. During that time, under isoflurane-induced anesthesia, all animals underwent right forearm mechanical loading at 60 cycles per day for 3 consecutive days using a 2-Hz haversine waveform at a peak force of 2.4 N. The non-loaded left forearm served as an internal control. Both loaded and control limbs were harvested 15 days post first loading day and processed for micro-computed tomography (microCT). Also, for dynamic histomorphometry (quantitative study of the microscopic organization and structure of the bone), we injected a small group of animals with two doses of 1% calcein solution on two different days to allow for measurement of bone formation rate and matrix apposition rate (a measure of the amount of bone matrix deposited per osteoblast cluster). All procedures performed in this experiment were in accordance with the Van Andel Research Institute Institutional Animal Care and Use Committee guidelines. So far, we have analyzed half of the collected ulnas, and even though, at this point, our results have not reached statistical significance, we see a trend of increased bone area, as well as cross sectional thickness in the loaded ulnas. We are currently in the process of analyzing the rest of the samples in order to determine if, all combined, our results reach statistical significance. If not, the next step would be processing the samples for histomorphometry. In conclusion, we have successfully established a mechanical ulnar loading model in order to study if mechanical loading can offset drug induced bone loss.



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