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For all that it reports a success, the open access paper here is an excellent example of the prevalent, inferior approach to the development of therapies for age-related conditions. Instead of looking for causes of the problem in question, the slow and dysfunction regeneration of bone fractures in older individuals, the scientists find a way to tinker with the dysfunctional state of aged metabolism, overriding one of the detrimental regulatory changes to some degree. As a strategy this will always be far less effective than tackling the underlying root causes of age-related dysfunction: trying to tinker a damaged engine into continued operation without fixing the damage is always going to be a challenging task. Nonetheless, this strategy remains much more popular in the research community, more is the pity.
Almost a third of humans will fracture a bone, and most often these injuries go on to successfully heal. However, various environmental and biological factors can hinder this regenerative process. With age, the pace of fracture repair slows, and the risk of non-union increases. This slower pace of repair in older individuals is responsible for increased morbidity and even mortality.
While there are many factors that could impair fracture healing with aging, the pace of fracture repair can be rejuvenated by circulating factors present in young animals. Recent data suggests that factors produced by young macrophage cells pay a critical role in the rejuvenation process. While these factors regulate the pace of repair, their effects on mesenchymal cells differentiating to osteoblasts are mediated by signaling pathways such as β-catenin.
β-catenin signaling plays different roles in mesenchymal differentiation at different repair stages. In the initial phase of repair, the level of β-catenin needs to be precisely regulated as levels that are too high or too low will prevent undifferentiated mesenchymal cells from becoming osteochondral progenitors and will inhibit fracture healing. Once the cells differentiate to osteochondral progenitors, higher levels of β-catenin stimulate osteogenesis and enhance fracture repair.
Here we examined the ability of pharmacologic agents that target β-catenin to improve the quality of fracture repair in old mice. 20 month old mice were treated with Nefopam or the tankyrase inhibitor XAV939 after a tibia fracture. Fractures were examined 21 days later by micro-CT and histology, and 28 days later using mechanical testing. Daily treatment with Nefopam for three or seven days but not ten days improved the amount of bone present at the fracture site, inhibited β-catenin protein level, and increased colony forming units osteoblastic from bone marrow cells. This data supports the notion that high levels of β-catenin in the early phase of fracture healing in old animals slows osteogenesis, and suggests a pharmacologic approach that targets β-catenin to improve fracture repair in the elderly.