Mechanisms of fracture healing in aged mice, which is dependent on COX-2 derived PGE_2

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Abstract : COX-2-induced PGE2, which can be provided by mechanical stimulation, crucially affects endochondral remodeling phase in fracture repair of aged mice. It not only orchestrates downstream molecules such as VEGFa and matrix metalloproteinases, but also controls FGF-2. Introduction : Fracture healing slows with age. In order to characterize the role of COX-2 in the delayed repair process in aged COX-2 knockout mice, we applied low-intensity pulsed ultrasound (LIPUS), which, we previously reported, induces COX-2 and is clinically used to accelerate repair processes. Methods : In one-yr-old COX-2 KO mice and their wild type littermates, micro focused X-ray computed tomography, (immuno) histochemical and mRNA analyses were conducted to characterize delay in healing of closed stabilized femur fracture. By administering combined EP2 and EP4 agonists from day 4 post fracture, rescue from the defect of both control and the LIPUS treated callus was confirmed to the level of wild type counterparts. Results : Cartilage formed relatively normally up to day 10. Thereafter, the repair process slowed down and was not accelerated by LIPUS. The treatment, however, effectively increased the rate of endochondral remodeling in the wild type littermates, a process prolonged in senescence. In the knockout callus, transcripts of such critical components as VEGFa and MMP-9 were entirely missing at day 7, regardless of exposure to LIPUS. In addition, the basal FGF-2 level was significantly elevated in the knockouts without further elevation by LIPUS. Conclusion : COX-2 is indispensable for fracture healing in aged mice ; if absent, endochondral remodeling is halted and the fracture gap filled with mesenchymal tissue persists. In addition to the loss of downstream VEGFa and matrix metalloproteinases, increased FGF-2 is likely to further delay the remodeling process.