Prolonged Endochondral Bone Healing in Senescence is Shortened by Low-Intensity Pulsed Ultrasound in a Manner Dependent on COX-2

To test whether mechanical loading produces faster healing in aged mice, fractured femurs of aged 1-year-old mice were subjected to low-intensity pulsed ultrasound (LIPUS), a treatment that is routinely used to help heal fractures in humans. Cyclooxygenase-2 knockout mice (COX-2−/−), which lack an immediate early mediator of mechanical stimulation, were also studied by histochemistry, microcomputed tomography and quantitative polymerase chain reaction to determine the role of COX-2. The healing in the aged COX-2−/− mice is slow during the endochondral bone remodeling (>30 d), a period generally prolonged in senescence. For aged wild-type mice, LIPUS halved the endochondral phase to about 10 d, whereas that was not the case for aged COX-2−/− mice, which showed no apparent shortening of the prolonged endochondral-phase healing time. Injecting prostaglandin E2 receptor agonists, however, rescued the COX-2−/− callus from insensitivity to LIPUS. In conclusion, COX-2 is a limiting factor in the delayed endochondral bone healing and is induced by LIPUS, which normalizes healing rate to the wild-type level. (E-mail: yukomtak@kdcnet.ac.jp)