1. Anabolic Response to Skeletal Loading in Mice with Targeted Disruption of Pleiotrophin Gene C. Kesavan and S. Mohan JLP VA Medical Center, Loma Linda Univ Loma Linda, CA, 92357 ASBMR 2008

3. Load Load Good Responder Poor Responder Skeletal Response to Loading Differs in Different Individuals

4. Variation in skeletal response to loading is genetically determined 0.00 5.00 10.00 15.00 20.00 6 7 8 9 Load (N) % Increase in vBMD vs unloaded bone Four point bending device C57BL/6J C3H/HeJ Four point bending Increases BMD in C57BL but not in C3H mice P<0.001 Kesavan et al., 2005 P<0.01

5. ML increases pleiotrophin (PTN) expression-Whole genome microarray analysis PTN signals through β -catenin and PI3K PTN expression level ( arbitrary units) p<0.0001 Xing et al., 2005 PTN/HB-GAM/OSF Syndecan Rprp ζ β -catenin PI3K Proliferation/survival/Migration

6. Time course changes in PTN expression in the loaded bones of C57BL Mice A p<0.05 vs. 2- and 4- days of loading (One-way ANOVA) p<0.05 p<0.001 p<0.0001 Days (Duration) Fold increase in PTN vs. unloaded bones A

7. Greater PTN expression in response to ML in good responder C57BL versus poor responder C3H mice Mean ± SD; N = 6 0 2 4 6 8 10 C57BL C3H Fold increase in PTN vs. unloaded bones P<0.0001 P<0.05 P<0.05

10. Skeletal changes in response to loading in PTN KO and control mice *p<0.05 vs. unloaded bones, N = 7 Percent increase vs. unloaded bones * * * * * *

11. Micro-CT analysis of skeletal response to loading Control PTN KO Unloaded Loaded Mean ± SD, N = 7 BV/TV (%) 3.88 ± 2.6 Tb.N (1/mm) 1.56 ± 0.76 Tb.Th (mm) 0.037 ± 0.0.01 Tb.S (mm) 0.76 ± 0.28 BV/TV (%) 2.81 ± 1.5 Tb.N (1/mm) 1.61 ± 0.36 Tb.Th (mm) 0.036 ± 0.0.01 Tb.S (mm) 0.57 ± 0.21

12. Greater midkine expression in response to ML in PTN KO and Control mice N=6 Fold increase vs. unloaded bones P<0.05 P<0.05 P<0.001

15. Thank you Skeletal Un loading Skeletal Loading