Abstract
PURPOSE: The molecular mechanism of bone strengthening with exercise remains unclear. We have identified a molecule, follistatin-like 3 (FSTL3), that may drive mechanical load-dependent bone remodeling. METHODS: Female Sprague Dawley rats (12-14 wks, n=10), wild-type (Fstl3+/+, 10-12 wks, n=10) or homozygous Fstl3-/- C57Bl/6 mice (10-12 wks, n=10) were subjected to treadmill walking (EX) for 45 min/day. After 0, 2, 5 or 15 days of EX, gene expression was analyzed by quantitative real time polymerase chain reaction, Western blots, or immunohistochemistry of the trabecular bone/bone marrow at distal femur ends. Bone mineral apposition rates were assessed by administration of Calcein and Alizarin complexones on day 3 and 12. Statistical analysis was performed by one-way ANOVA with Tukey’s post hoc or T-test. RESULTS: Gene expression analysis revealed that EX stimulated Fstl3 mRNA expression by 6 fold on day 2, and mRNA declined to basal levels by day 5. Minimal FSTL3 protein expression was exhibited in the control non-EX trabecular bone, but a robust increase in FSTL3 expression was observed in EX rat femurs at days 2 and 5. Non-EX mice exhibited a significantly narrow distance between the Calcein and Alizarin incorporation and limited bone deposition. EX Fstl3+/+ and Fstl3+/- mice demonstrated a significant increase in bone deposition on the endosteal surface of the femurs not observed in Fstl3-/- mice. Representative stress-strain curves of the cortical bone of the Fstl3+/+ and Fstl3 -/- femurs revealed that strain at ultimate strength of femurs from Fstl3+/+ mice was approximately 25% > than that of Fstl3 -/- mice. Furthermore, the yield strain and yield energy were significantly upregulated by EX in Fstl3+/+, but not in Fstl3-/- mice. CONCLUSION: FSTL3 is a mechanoresponsive protein that may provide a new paradigm for investigating EX-driven bone formation as well as a marker to monitor the effects of EX on bone in health and disease.
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