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Introduction:Orthopedic surgeons are challenged by impaired or delayed fracture repair in osteoporotic bone, which requires either prolongation of rehabilitation process or salvage procedures to avoid delay in returning to work and /or even permanent care. Therapeutic stratagem should be defined according to identified molecular target. However,molecular mechanism of osteoporotic fracture repair remains poorly understood. In terms of histopathology, callus hardening is an important stage during fracture repair, which forms through two processes, the direct periosteam-dependent bone formation (intramembranous ossification) and the formation of bone through a cartilage intermediate (endochondral ossification). It has been reported that estrogen receptor beta (ERbeta) signaling participates in inhibiting angiogenesis in breast cancer cells in vitro using transient transfection assay. On the other hand, evidence from ERbeta gene knockout female mouse has demonstrated that, during bone development, ERbeta signaling participates in inhibiting both intramembranous and endochondral ossification.
Material and Methods:30 ERbeta knockout (KO) and 30 wild type female mice (WT, C57BL/6) aged 3 months were used in this study. All mice were ovariectomised first. After 6 weeks, bilateral 0.8mm-diamter drill holes were made from the posterior to the anterior of the diaphysis of the femur. High resolution micro-CT (VivaCT 40 Scanco) was employed to in-vivo monitoring the repair process at day 0,3,7,10,14 and 21. Bone volume fraction (BV/TV) and bone mineral density (BMD) in defect region and marrow region were analyzed separately to evaluate the healing process. Serum samples were collect at each time point, bone formation marker PINP and bone resorption marker CTX were employed to describe bone turnover. Repeat measure ANOVA and Independent t-test was performed to analyze the data.
Results and Discussion:Micro-CT 2D and 3D images showed larger callus size and better mineralization status in KO mice group compare to its wild type. The BV/TV and BMD in defect region increased from day 0 to 7, and rapidly reached the peak at day 14, and then dropped at day 21 in WT group, the values in KO group were significantly higher at day 7, 10, 14 and 21. The BV/TV and BMD in marrow region showed similar pattern with defect region in WT group while those in KO group were significantly higher at day 7, 10 and 14. Bone formation marker PINP reached the peak at day 10 in KO group while that reached the peak at day 14 in WT group. Bone resorption markers CTX, do not show significant difference between two groups. The results suggest blockade ERbeta could promote osteoporotic fracture repair without affect the remodeling phase.
Conclusion:This is the first study employing high resolution micro-CT to in-vivo monitoring the fracture repair. ERbeta pathway is a potential therapeutic target for promoting osteoporotic fracture repair, highly selective ERbeta antagonist should be investigated as an osteoporotic fracture repair drug.