Abstract
β-catenin protein needs to be precisely regulated for effective fracture repair. The pace of fracture healing slows with age, associated with a transient increase in β-catenin during the initial phase of the repair process. 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. At 28 days, treatment increased the work to fracture of the injured tibia. XAV939 had a more modest effect on β-catenin protein, colony forming units osteoblastic, and the amount of bone at the fracture site. 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.
Highlights
Yoon Hae Kwak 1,2, Tomasa Barrientos[1], Bridgette Furman 1, Hazel Zhang[1], Vijitha Puviindran[1], Hattie Cutcliffe[1], Jonas Herfarth[1], Eugene Nwankwo 1 & Benjamin A
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
To determine if pharmacologic modulation of β-catenin might improve fracture repair in older animals, twentymonth-old male mice were treated with nefopam after generating a tibia fracture
Summary
Yoon Hae Kwak 1,2, Tomasa Barrientos[1], Bridgette Furman 1, Hazel Zhang[1], Vijitha Puviindran[1], Hattie Cutcliffe[1], Jonas Herfarth[1], Eugene Nwankwo 1 & Benjamin A. XAV939 had a more modest effect on β-catenin protein, colony forming units osteoblastic, and the amount of bone at the fracture site 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. Recent data suggests that factors produced by young macrophage cells pay a critical role in the rejuvenation process[7] 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. Since β-catenin protein level regulates the capacity of undifferentiated mesenchymal cells to become osteochondral progenitors, an elevated protein level in older animals will prevent this differentiation and instead cells will maintain a fibroblastic like phenotype Such a cell type will not contribute to normal fracture repair. Correspondence and requests for materials should be addressed to B.A.A
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