Alcohol‐related deficient fracture healing is associated with activation of FoxO transcription factors in mice

Abstract

The process of fracture healing is complex, and poor or incomplete healing remains a significant health problem. Proper fracture healing relies upon resident mesenchymal stem cell (MSC) differentiation into chondrocytes and osteoblasts, which are necessary for callus formation and ossification. Alcohol abuse is a leading contributor to poor fracture healing. Although the mechanism behind this action is unknown, excessive alcohol consumption is known to promote systemic oxidative stress. The family of FoxO transcription factors is activated by oxidative stress, and FoxO activation antagonizes Wnt signaling, which regulates mesenchymal stem cell differentiation. We hypothesize that alcohol exposure increases oxidative stress leading to deficient fracture repair by activating FoxO transcription factors within the fracture callus which disrupts chondrogenesis of mesenchymal stem cells. Our laboratory has developed an experimental model of delayed fracture union in mice using ethanol administration. We have found that ethanol administration significantly decreases external, cartilaginous callus formation, and hallmarks of endochondral ossification, and these changes are concomitant with increases in FoxO expression and markers of activation in fracture callus tissue of these mice. We were able to prevent these alcohol-induced effects with the administration of the antioxidant n-acetyl cysteine (NAC), suggesting that alcohol-induced oxidative stress produces the perturbed endochondral ossification and FoxO expression.

Partial Protection by Dietary Antioxidants Against Ethanol‐Induced Osteopenia and Changes in Bone Morphology in Female Mice

“…The NAC supplemented sponge supported bone healing significantly better than the sponge alone (Yamada et al, 2013). In addition, NAC has previously been shown to block osteopenia in rats fed EtOH intragastrically via total enteral nutrition and to prevent alcohol-related deficient fracture healing in mice (Chen et al 2012; Roper et al 2016). …”

N‐Acetyl Cysteine Treatment Restores Early Phase Fracture Healing in Ethanol‐Fed Rats

“…Previous work carried out by Ronis and colleagues has shown that EtOH increases the RANKL/RANK signaling between osteoblasts and osteoclasts, thereby increasing bone resorption, making bone fracture healing difficult (Alund et al., ; Mercer et al., ). Treatment with the antioxidant NAC has been shown by a number of groups to diminish the effects of EtOH and oxidative stress on fracture healing (Alund et al., ; Chen et al., ; Roper et al., ; Volkmer et al., ). To determine the efficacy of using NAC in treatment for fractures in the veteran population, we developed a rat model that mimics the age and chronicity of EtOH abused seen in these individuals.…”

“…In fact, forkhead box O, a transcription factor that regulates Wnt signaling, is partially responsible for oxidative stress resistance and cell cycle inhibition. These molecules have been shown to be increased in a mouse alcohol fracture model, which could be augmented with the addition of the antioxidant N‐acetyl cysteine (NAC) (Roper et al., ). To counteract the effects of oxidative stress following ethanol (EtOH) administration, antioxidants have been demonstrated to play a key role in suppression of the ROS system.…”

“…To counteract the effects of oxidative stress following ethanol (EtOH) administration, antioxidants have been demonstrated to play a key role in suppression of the ROS system. Studies have shown that the antioxidant NAC can reduce bone loss by decreasing the number of osteoclast and increasing osteoblastic activity (Chen et al., , ), thereby reducing the effects of EtOH on fracture healing (Roper et al., ). NAC has been shown to reduce oxidative stress following alcohol and fracture in a rat model of binge exposure (Volkmer et al., ).…”

Biologische Einflussfaktoren auf die Knochenbruchheilung

“…Dies hat eine hohe klinische Relevanz, da gerade bei jungen Patienten bis zu 40 % einen erhöhten Blutalkoholspiegel zum Zeitpunkt einer Fraktur aufweisen. Im Tiermodell konnte gezeigt werden, dass Alkoholadministration zu erhöhten Konzentrationen an ROS, inflammatorischen Zytokinen und einer verringerten Expression von osteoanabolen Wachstumsfaktoren führt und dadurch die Knochenheilung stört [39]. Besonders der osteoanabole Wnt-Signalweg scheint durch Alkoholabusus beeinträchtigt zu werden.…”