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Characterizing the Skeletal Phenotype of db/db Mice

Characterizing the Skeletal Phenotype of db/db Mice. Student: Bailey Lindenmaier Mentors: Dr. Russell Turner & Dr. Urszula Iwaniec Skeletal Biology Lab. Introduction. Age related Osteoporosis- Porous bone

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Characterizing the Skeletal Phenotype of db/db Mice

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  1. Characterizing the Skeletal Phenotype of db/db Mice Student: Bailey Lindenmaier Mentors: Dr. Russell Turner & Dr. Urszula Iwaniec Skeletal Biology Lab

  2. Introduction • Age related Osteoporosis- Porous bone • 1 in 3 women and 1 in 5 men over the age of 50 worldwide are estimated to have osteoporosis • In 2005, osteoporosis-related fractures were responsible for an estimated $19 billion in costs. • Health risks • Increases individuals risk of fractures • Following peak bone mass, lost bone mass is difficult to restore

  3. Leptin • Product of the OB gene • Primarily produced by adipose tissue. • Pleiotropic hormone • Appetite control • Energy regulation • Immune response • Cardiovascular and renal function • Essential for achieving optimal peak bone mass.

  4. Identifying the Mechanism of Leptin on Bone Remodeling • Leptin is a key hormone in regulating and maintaining healthy bones. • Early work suggests that s.c. leptin injection reduced bone loss following ovx. • Current data proposes that leptin functions via the CNS. • Osteoblast express leptin receptor. Possible peripheral affect? • Answers may lead to a generation of drugs to treat osteoporosis.

  5. Proposed Pathways of Leptin’s Effects on the Skeleton ObRb Receptor Leptin

  6. db/db mice • Loss of function in the leptin receptor • Mosaic skeletal type • Overall reduced bone mass • High cancellous bone mass of vertebrae. • Low bone mass in femur. • Decreased length of femoral bones. • Obese, hypogonadic, hyperinsulemic, hypercortisolic db/db Wild Type

  7. Goal Characterize skeletal growth of WT and leptin-deficient db/db mice.

  8. Study Design • A group of 10 WT and db/db mice sacrificed at 8 weeks for baseline. • A group of 7 WT and db/db mice sacrificed at 17 weeks. • Fed ad libitum, 12h light/dark cycle • Both femurs and LV 5 were excised at necropsy B6.BKS(D)-Leprdb

  9. µ CT Analysis • Micro - Computed Tomography • Fires an x-ray beam at a rotating specimen • Produces 3D images for structural measurements

  10. Bones Analyzed Vertebral Cancellous Bone Femoral cortex Femur Metaphysis (trabecular bone)

  11. Results Total Femur Bone Volume Femur Length ANOVA Effects Genotype: p<.001 Age: p<.001 Genotype x Age: p<.002 ANOVA Effects Genotype: p<.001 Age: p<.002 Genotype x Age: p<.004 0 0 db/db db/db 8 weeks 17 weeks 8 weeks 17 weeks

  12. Results Femur Cortical Thickness Diaphysis-Cortical Bone ANOVA Effects Genotype: p<.001 Age: p<.001 Genotype x Age: p<.001 0 db/db db/db 8 weeks 17 weeks

  13. Results Metaphysis Bone Volume/Tissue Volume ANOVA Effects Genotype: N.S Age: p<.001 Genotype x Age: p<.038 db/db db/db 8 weeks 17 weeks

  14. Results Lumbar Vertebrae 5 Bone Volume/Tissue Volume ANOVA Effects Genotype: p<.001 Age: p<.026 Genotype x Age: p<.007 0 db/db db/db 8 weeks 17 weeks

  15. Results Lumbar Vertebrae 5 Trabecular Thickness Lumbar Vertebrae 5 Trabecular Number ANOVA Effects Genotype: p<.001 Age: p<.001 Genotype x Age: p<.004 ANOVA Effects Genotype: N.S Age: p<.001 Genotype x Age: N.S 0 8 weeks 17 weeks 8 weeks 17 weeks

  16. Conclusions • Aging db/db mice have high bone mass in their lumbar vertebrae • Maintain trabecular number • Increase in trabecular thickness • Aging db/db mice have low bone mass in their femur. • Low cortical thickness • Reduced femoral length

  17. On the Horizon • Histomorphometric analysis of bone. • Bone marrow transplantation following irradiation to determine if leptin has a direct effect on bone remodeling.

  18. Acknowledgements • Dr. Russell Turner • Urszula Iwaniec • Dawn Olson • Kenneth Philbrick • Kevin Ahern • Howard Hughes Medical Institute

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