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theses

Current trends in the Western-pattern diet are replacing bone-fortifying, calcium-rich beverages, and foods with sweetened artificial alternatives. High-fructose corn syrup has only been used as a popular sweetener since 1970. Diet may impact growth by limiting the bioavailability of nutrients required for bone to reach its full genetic potential. The effects of reduced calcium, in animal models and man, have been studied extensively and in the work to be presented, I uncovered that low calcium diet results in lower bone cellularity, i.e., fewer incorporating osteocytes per bone tissue volume. However, the current understanding of fructose and its effects on bone growth are varied, due to the absence of a standardized model and standard fructose administration regimen. Fructose is metabolized in the cytoplasm by the enzyme ketohexokinase (KHK), and excessive consumption may affect bone health. Specifically, previous work in calcium-restricted, growing mice demonstrated that fructose disrupted intestinal calcium transport. I hypothesized that the observed effects on bone were KHK-dependent and examined the effects of fructose on the long bones of growing mice in a series of studies. Congenic mice with intact KHK (wild-type, WT) or global knockout of both isoforms of KHK A/C (KHK-KO), were fed control diets or administered fructose either through diet or implanted osmotic pumps for 8 weeks. I found that dietary fructose increased by 40-fold plasma fructose in KHK-KO compared to controls (p < 0.05). Plasma fructose was less effected due to pump administration. Obesity (no differences in epidydimal fat or body weight) or altered insulin, was not observed due to the fructose levels introduced. Longitudinal growth of the femur long-bone was inhibited in the KHK-KO mice fed 20% fructose. Unexpectedly, fructose feeding resulted in greater bone mineral density, percent volume and number of trabeculae in the distal femur of KHK-KO. Moreover, higher plasma fructose concentrations correlated with greater trabecular bone volume, greater work-to-fracture in three-point bending of the femur mid-shaft, and greater plasma sclerostin. Since the metabolism of fructose is severely inhibited in the KHK-KO condition, the new results combined with additional data generated during the completion of this dissertation suggests that fructose reaching the lower intestine may affect bone growth through an interaction with the microbiota. Future pursuit of this line of research is important as the effects of increased fructose consumption on bone during growth may influence the future risk for osteoporotic fracture.

ETD_9884

Ph.D.

Includes bibliographical references

doi:10.7282/t3-gg6e-4682

ETD doctoral

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