LAUSR

Previously published experimental studies have shown contradictory results regarding hemorrhagic shock and its impact on fracture healing. Some suggest that trauma hemorrhage leads to increased osteocyte necrosis and delayed fracture healing [10, 12], whereas others identified a positive effect of traumarelated hemorrhage on fracture healing [2, 11]. In the present study, Bundkirchen and colleagues have added another piece of the fracture healing puzzle by using a rodent model to induce a sustained degree and duration of hemorrhage. We know that mouse bone regeneration lasts around 30 days [4]—a hematoma is formed by Day 5 followed by the formation of a soft callus consisting of unmineralized cartilage, a period during which angiogenesis also occurs by Day 10. The current study, and the previously obtained data by Lichte and colleagues [10], suggest an effect of hemorrhagic shock on the formation of the callus and in neovascularization. During the first 2 weeks, many of the proinflammatory cytokines (IL-1b, IL-6, TNFa) induce osteoclastogenesis through stimulation of osteoblasts or activated T cells to release RANKL, which interacts with a receptor activator of nuclear factor kB (RANK) on the osteoclast surface leading to osteoclast activation [3, 6]. Hypoxia, induced by hemorrhagic shock, further activates NFkB, which in turn, increases the activation of the inflammatory system and the secretion of IL-1b, IL-6, TNFa. Similarly, hypoxia induces expression of HIF1a, which plays an important role in promoting angiogenesis through VEGF. It appears that hemorrhagic shock dysregulates the ongoing bone healing processes and delays callus formation and neovascularization. Although the current study found no difference in osseous healing after 2 weeks, this result is far from unprecedented. Similar effects, related to large vessels, can be seen in revascularization following venous thrombosis. Additionally, months after a deep vein thrombosis, revascularization or collateral circulation can be found. I suspect that ischemia-induced coagulopathy may influence local perfusion, which resolves just as revascularization occurs at amicrovascular level. In fact, in a large-animal model, our group found a close relationship between these factors and systemic effects [7, 8]. Thisfinding is important, as it underlines the relevance of translational research for bone healing and associated effects.