Philip M Roper

Loyola University Medical Center, Maywood, Illinois, United States

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Publications (4)5.2 Total impact

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    ABSTRACT: BACKGROUND: Alcohol abuse is a risk factor for bone damage and fracture-related complications. Through precise β-catenin signaling, canonical Wnt signaling plays a key role in fracture repair by promoting the differentiation of new bone and cartilage cells. In this study, we examined the effects of alcohol on the Wnt pathway in injured bone using a murine model of alcohol-induced impaired fracture healing. METHODS: Male C57Bl/6 or T cell factor (TCF)-transgenic mice were administered 3 daily intraperitoneal doses of alcohol or saline. One hour following the final injection, mice were subjected to a stabilized, mid-shaft tibial fracture. Injured and contralateral tibias were harvested at 6, 9, or 14 days post-fracture for the analysis of biomechanical strength, callus tissue composition, and Wnt/β-catenin signaling. RESULTS: Acute alcohol treatment was associated with a significant decrease in fracture callus volume, diameter, and biomechanical strength at day 14 post-fracture. Histology revealed an alcohol-related reduction in cartilage and bone formation at the fracture site, and that alcohol inhibited normal cartilage maturation. Acute alcohol exposure caused a significant 2.3-fold increase in total β-catenin protein at day 6 and a significant decrease of 53 and 56% at days 9 and 14, respectively. lacZ staining in β-galactosidase-expressing TCF-transgenic mice revealed spatial and quantitative differences in Wnt-specific transcriptional activation at day 6 in the alcohol group. Days 9 and 14 post-fracture showed that acute alcohol exposure decreased Wnt transcriptional activation, which correlates with the modulation of total β-catenin protein levels observed at these time points. CONCLUSIONS: Acute alcohol exposure resulted in significant impairment of fracture callus tissue formation, perturbation of the key Wnt pathway protein β-catenin, and disruption of normal Wnt-mediated transcription. These data suggest that the canonical Wnt pathway is a target for alcohol in bone and may partially explain why impaired fracture healing is observed in alcohol-abusing individuals.
    Alcoholism Clinical and Experimental Research 06/2012; · 3.42 Impact Factor
  • Alcohol. 03/2012; 46(2):177.
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    ABSTRACT: Background: Alcohol abuse is a risk factor for bone damage and fracture-related complications. Through precise b-catenin signaling, canonical Wnt signaling plays a key role in fracture repair by pro-moting the differentiation of new bone and cartilage cells. In this study, we examined the effects of alco-hol on the Wnt pathway in injured bone using a murine model of alcohol-induced impaired fracture healing. Methods: Male C57Bl/6 or T cell factor (TCF)-transgenic mice were administered 3 daily intraperi-toneal doses of alcohol or saline. One hour following the final injection, mice were subjected to a stabilized, mid-shaft tibial fracture. Injured and contralateral tibias were harvested at 6, 9, or 14 days post-fracture for the analysis of biomechanical strength, callus tissue composition, and Wnt/b-catenin signaling. Results: Acute alcohol treatment was associated with a significant decrease in fracture callus vol-ume, diameter, and biomechanical strength at day 14 post-fracture. Histology revealed an alcohol-related reduction in cartilage and bone formation at the fracture site, and that alcohol inhibited normal cartilage maturation. Acute alcohol exposure caused a significant 2.3-fold increase in total b-catenin protein at day 6 and a significant decrease of 53 and 56% at days 9 and 14, respectively. lacZ staining in b-galactosidase-expressing TCF-transgenic mice revealed spatial and quantitative differences in Wnt-specific transcriptional activation at day 6 in the alcohol group. Days 9 and 14 post-fracture showed that acute alcohol exposure decreased Wnt transcriptional activation, which correlates with the modu-lation of total b-catenin protein levels observed at these time points. Conclusions: Acute alcohol exposure resulted in significant impairment of fracture callus tissue formation, perturbation of the key Wnt pathway protein b-catenin, and disruption of normal Wnt-mediated transcription. These data suggest that the canonical Wnt pathway is a target for alcohol in bone and may partially explain why impaired fracture healing is observed in alcohol-abusing individuals. F RACTURE NONUNION, OR cessation of bone heal-ing without bridging, occurs in 5 to 10% of the esti-mated 13 million fractures that are treated annually in the United States (American Academy of Orthopaedic Sur-geons, 2008; Einhorn, 1995; Marsh, 1998). The rate of frac-ture among alcoholics is up to 4 times higher than in nonabusers (Kristensson et al., 1980), and alcoholics fre-quently present with osteopenia or osteoporosis (Bikle et al., 1985; Spencer et al., 1986). Additionally, acute alcohol intox-ication is demonstrated in 25 to 40% of patients presenting with orthopedic trauma, highlighting the prevalence of this type of alcohol consumption and incidence of fracture injury (Blake et al., 1997; Levy et al., 1996). Numerous clinical studies have associated alcohol abuse with a significantly increased risk of developing nonunion and delayed union (Duckworth et al., 2011; Foulk and Szabo, 1995; Mathog et al., 2000; Perlman and Thordarson, 1999; Williams et al., 2008), and several animal studies using models of alcohol exposure and bone injury report similar observations (Chak-kalakal et al., 2005; Jaicke-Lorenz and Lorenz, 1984; Trevi-siol et al., 2007). Fracture repair requires the mobilization and differentia-tion of mesenchymal stem cells and osteoblast precursors from local and distant niches to the site of injury (Devine et al., 2002; Kumagai et al., 2008; Shen et al., 2002; Taguchi et al., 2005). The initiation of repair requires differentiation of mesenchymal stem cells into bone-and cartilage-forming cells, a process that is tightly controlled by canonical Wnt/ b-catenin signaling (Baksh et al., 2007; Day et al., 2005; Hill et al., 2005). Canonical Wnt signaling has emerged as a com-plex pathway that is tightly regulated during bone repair and appears to control the fracture repair process (Chen et al., 2007; Huang et al., 2011; Komatsu et al., 2010). In the absence of pathway stimulation, stabilized b-catenin levels in
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    ABSTRACT: Alcohol consumption is a known risk factor for traumatic injuries of all types and has been shown to produce detrimental effects on bone metabolism. Although the mechanisms responsible for these detrimental effects are not well characterized, oxidative stress from alcohol exposure appears to play a central role. This study was designed to examine the effect of a short-term binge alcohol consumption pattern on fracture repair and the effect of an antioxidant, N-acetylcysteine, on fracture healing after binge alcohol consumption. One hundred forty-four adult male Sprague-Dawley rats underwent unilateral closed femur fracture after injection of either saline or alcohol to simulate a binge alcohol cycle. Animals in the antioxidant treatment group received daily N-acetylcysteine after fracture. Femurs were harvested at 1, 2, 4, and 6 weeks after injury and underwent biomechanical testing and histologic analysis. Binge alcohol administration was associated with significant decreases in biomechanical strength at 1- and 2-week time points with a trend toward decreased strength at 4- and 6-week time points as well. Alcohol-treated animals had less cartilage component within the fracture callus and healed primarily by intramembranous ossification. Administration of N-acetylcysteine in alcohol-treated animals improved biomechanical strength to levels comparable to the control animals and was associated with increased endochondral ossification. Our results indicate that binge alcohol alters the quality of fracture healing after a traumatic injury and that concurrent administration of an antioxidant is able to reverse these effects.
    Journal of orthopaedic trauma 08/2011; 25(8):516-21. · 1.78 Impact Factor