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Anita Ignatius - One of the best experts on this subject based on the ideXlab platform.
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Simulating Metaphyseal Fracture Healing in the Distal Radius
Biomechanics, 2021Co-Authors: Lucas Engelhardt, Anita Ignatius, Frank Niemeyer, Patrik Christen, Ralph Müller, Kerstin Stock, Michael Blauth, Karsten Urban, Ulrich SimonAbstract:Simulating diaphyseal Fracture Healing via numerical models has been investigated for a long time. It is apparent from in vivo studies that metaphyseal Fracture Healing should follow similar biomechanical rules although the speed and Healing pattern might differ. To investigate this hypothesis, a pre-existing, well-established diaphyseal Fracture Healing model was extended to study metaphyseal bone Healing. Clinical data of distal radius Fractures were compared to corresponding geometrically patient-specific Fracture Healing simulations. The numerical model, was able to predict a realistic Fracture Healing process in a wide variety of radius geometries. Endochondral and mainly intramembranous ossification was predicted in the Fractured area without callus formation. The model, therefore, appears appropriate to study metaphyseal bone Healing under differing mechanical conditions and metaphyseal Fractures in different bones and Fracture types. Nevertheless, the outlined model was conducted in a simplified rotational symmetric case. Further studies may extend the model to a three-dimensional representation to investigate complex Fracture shapes. This will help to optimize clinical treatments of radial Fractures, medical implant design and foster biomechanical research in metaphyseal Fracture Healing.
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Mouse Models in Bone Fracture Healing Research
Current Molecular Biology Reports, 2016Co-Authors: Melanie Haffner-luntzer, Anna Kovtun, Anna E. Rapp, Anita IgnatiusAbstract:Bone Fracture Healing is a tightly regulated process involving many cell types, mediators, and signaling pathways and is still not well understood. During decades, bone Healing was mainly studied in large animals, including dogs, rabbits, or sheep. In recent years, mice have become increasingly popular as a model organism for Fracture Healing research. The benefits of mice are the possibility of genetic modification, the availability of clinically relevant disease models, low costs, easy handling, short breeding cycles and fast regeneration. Furthermore, various Fracture Healing models have been developed, which are adapted to the small skeleton and allow standardized investigations. However, attention has to be paid to species differences between mice and humans and the influence of the background strain, age and gender of the mice. This review focuses on the main advantages and disadvantaged of mice as a model organism for bone Fracture Healing research and critically discusses the translational aspect.
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Mouse Models in Bone Fracture Healing Research
Current Molecular Biology Reports, 2016Co-Authors: Melanie Haffner-luntzer, Anna Kovtun, Anna E. Rapp, Anita IgnatiusAbstract:Bone Fracture Healing is a tightly regulated process involving many cell types, mediators, and signaling pathways and is still not well understood. During decades, bone Healing was mainly studied in large animals, including dogs, rabbits, or sheep. In recent years, mice have become increasingly popular as a model organism for Fracture Healing research. The benefits of mice are the possibility of genetic modification, the availability of clinically relevant disease models, low costs, easy handling, short breeding cycles and fast regeneration. Furthermore, various Fracture Healing models have been developed, which are adapted to the small skeleton and allow standardized investigations. However, attention has to be paid to species differences between mice and humans and the influence of the background strain, age and gender of the mice. This review focuses on the main advantages and disadvantaged of mice as a model organism for bone Fracture Healing research and critically discusses the translational aspect.
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The SERM raloxifene improves diaphyseal Fracture Healing in mice
Journal of Bone and Mineral Metabolism, 2013Co-Authors: Alexander S Spiro, Shahram Khadem, Robert Percy Marshall, Pia Pogoda, Anke Jeschke, Anita Ignatius, Michael Amling, Frank Timo BeilAbstract:Although several studies reported that raloxifene treatment improves postmenopausal osteoporotic bone structure and reduces Fracture risk, only a few animal and no human studies have examined its effects on the Fracture Healing process. Thus the aim of the present study was to determine, whether systemic application of the selective estrogen receptor modulator raloxifene promotes Fracture Healing compared to untreated control-, estrogen-deficient-, as well as estrogen-treated mice using a standardized femoral osteotomy model ( n = 60 mice). Ten days after surgery, contact radiography and undecalcified histomorphometric analysis revealed that raloxifene administration significantly improved the early stage of Fracture Healing compared to all other groups. At day 20, raloxifene and estrogen treatment led to a significant increase in callus mineralization and trabecular thickness compared to control mice. μCT analyses revealed no evidence of complete bony bridging of the Fracture site in any control-, nor estrogen-deficient mouse after 20 days, while all femoral Fractures in the raloxifene and estrogen group already healed adequately at this time. These data indicate that raloxifene treatment significantly improves all phases of Fracture Healing at least in mice. Therefore, raloxifene could be a possible pharmaceutical to enhance Fracture Healing in women, without the known side effects of estrogen.
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Fracture Healing under healthy and inflammatory conditions
Nature Reviews Rheumatology, 2012Co-Authors: Lutz Claes, Stefan Recknagel, Anita IgnatiusAbstract:The interplay between the cells that regulate bone architecture and the immune system is increasingly recognized. In this Review, as well as providing an overview of Fracture treatment and Healing, the authors discuss our current knowledge of the part played by inflammation in the Fracture repair process. The influence of biomechanical and biological factors on bone Healing is also considered, focusing on the effects of excessive local and systemic inflammation, as occurs in autoimmune diseases such as rheumatoid arthritis. Fracture Healing is a complex, highly regulated process with consecutive and closely linked phases of inflammation, repair and remodeling Optimal Fracture Healing requires suitable biological as well as biomechanical conditions The mechanical environment considerably influences tissue differentiation during bone Healing: stable Fracture fixation induces direct bone formation, moderate stability provokes endochondral ossification, whereas unstable fixation inhibits bone Healing The immune system is intimately involved in the Fracture Healing process, especially during the early inflammatory Healing phase Disorders associated with systemic inflammation, such as diabetes mellitus, trauma, sepsis and rheumatoid arthritis, can prolong or disturb Fracture Healing and increase the risk of non-unions by incompletely understood mechanisms Optimal Fracture treatment requires knowledge of the complex physiological process of bone Healing. The course of bone Healing is mainly influenced by Fracture fixation stability (biomechanics) and the blood supply to the Healing site (revascularization after trauma). The repair process proceeds via a characteristic sequence of events, described as the inflammatory, repair and remodeling phases. An inflammatory reaction involving immune cells and molecular factors is activated immediately in response to tissue damage and is thought to initiate the repair cascade. Immune cells also have a major role in the repair phase, exhibiting important crosstalk with bone cells. After bony bridging of the fragments, a slow remodeling process eventually leads to the reconstitution of the original bone structure. Systemic inflammation, as observed in patients with rheumatoid arthritis, diabetes mellitus, multiple trauma or sepsis, can increase Fracture Healing time and the rate of complications, including non-unions. In addition, evidence suggests that insufficient biomechanical conditions within the Fracture zone can influence early local inflammation and impair bone Healing. In this Review, we discuss the main factors that influence Fracture Healing, with particular emphasis on the role of inflammation.
Kurt D Hankenson - One of the best experts on this subject based on the ideXlab platform.
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Biological perspectives of delayed Fracture Healing.
Injury, 2014Co-Authors: Kurt D Hankenson, G. Zimmerman, Ralph S MarcucioAbstract:Fracture Healing is a complex biological process that requires interaction among a series of different cell types. Maintaining the appropriate temporal progression and spatial pattern is essential to achieve robust Healing. We can temporally assess the biological phases via gene expression, protein analysis, histologically, or non-invasively using biomarkers as well as imaging techniques. However, determining what leads to normal versus abnormal Healing is more challenging. Since the ultimate outcome of Fracture Healing is to restore the original functions of bone, assessment of Fracture Healing should include not only monitoring the restoration of structure and mechanical function, but also an evaluation of the restoration of normal bone biology. Currently few non-invasive measures of biological factors of Healing exist; however, recent studies that have correlated non-invasive measures with Fracture Healing outcome in humans have shown that serum TGFbeta1 levels appear to be an indicator of Healing versus non-Healing. In the future, developing additional measures to assess biological Healing will improve the reliability and permit us to assess stages of Fracture Healing. Additionally, new functional imaging technologies could prove useful for better understanding both normal Fracture Healing and predicting dysfunctional Healing in human patients.
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disruption of thrombospondin 2 accelerates ischemic Fracture Healing
Journal of Orthopaedic Research, 2013Co-Authors: Emily L Miedel, Ralph S Marcucio, Michael I Dishowitz, Marc H Myers, Derek Dopkin, Yan Yiu Yu, Ted Miclau, Kurt D HankensonAbstract:Thrombospondin-2 (TSP2) is a matricellular protein that is highly up-regulated during Fracture Healing. TSP2 negatively regulates vascularity, vascular reperfusion following ischemia, and cutaneous wound Healing. As well, TSP2-null mice show increased endocortical bone formation due to an enhanced number of mesenchymal progenitor cells and show increased cortical thickness. Mice deficient in TSP2 (TSP2-null) show an alteration in Fracture Healing, that is unrelated to their cortical bone phenotype, which is characterized by enhanced vascularization with a shift towards an intramembranous Healing phenotype; thus, we hypothesized that there would be enhanced ischemic Fracture Healing in the absence of TSP2. We investigated whether an absence of TSP2 would enhance ischemic Fracture Healing utilizing Laser doppler, µCT and histological analysis. Ischemic tibial Fractures were created in wildtype (WT) and TSP2-null mice and harvested 10, 20, or 40 days post-Fracture. TSP2-null mice show enhanced vascular perfusion following ischemic Fracture. At day 10 post-Fracture, TSP2-null mice have 115% greater bone volume than WT mice. This is associated with a 122% increase in vessel density, 20% increase in cell proliferation, and 15% decrease in apoptosis compared to WT. At day 20, TSP2-null mice have 34% more bone volume, 51% greater bone volume fraction, and 37% more bone tissue mineral density than WT. By 40 days after Fracture the TSP2-null mice have a 24% increase in bone volume fraction, but other parameters show no significant differences. These findings indicate TSP2 is a negative regulator of ischemic Fracture Healing and that in the absence of TSP2 bone regeneration is enhanced. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 935–943, 2013
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Disruption of thrombospondin‐2 accelerates ischemic Fracture Healing
Journal of Orthopaedic Research, 2012Co-Authors: Emily L Miedel, Ralph S Marcucio, Michael I Dishowitz, Marc H Myers, Derek Dopkin, Yan Yiu Yu, Ted Miclau, Kurt D HankensonAbstract:Thrombospondin-2 (TSP2) is a matricellular protein that is highly up-regulated during Fracture Healing. TSP2 negatively regulates vascularity, vascular reperfusion following ischemia, and cutaneous wound Healing. As well, TSP2-null mice show increased endocortical bone formation due to an enhanced number of mesenchymal progenitor cells and show increased cortical thickness. Mice deficient in TSP2 (TSP2-null) show an alteration in Fracture Healing, that is unrelated to their cortical bone phenotype, which is characterized by enhanced vascularization with a shift towards an intramembranous Healing phenotype; thus, we hypothesized that there would be enhanced ischemic Fracture Healing in the absence of TSP2. We investigated whether an absence of TSP2 would enhance ischemic Fracture Healing utilizing Laser doppler, µCT and histological analysis. Ischemic tibial Fractures were created in wildtype (WT) and TSP2-null mice and harvested 10, 20, or 40 days post-Fracture. TSP2-null mice show enhanced vascular perfusion following ischemic Fracture. At day 10 post-Fracture, TSP2-null mice have 115% greater bone volume than WT mice. This is associated with a 122% increase in vessel density, 20% increase in cell proliferation, and 15% decrease in apoptosis compared to WT. At day 20, TSP2-null mice have 34% more bone volume, 51% greater bone volume fraction, and 37% more bone tissue mineral density than WT. By 40 days after Fracture the TSP2-null mice have a 24% increase in bone volume fraction, but other parameters show no significant differences. These findings indicate TSP2 is a negative regulator of ischemic Fracture Healing and that in the absence of TSP2 bone regeneration is enhanced. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 935–943, 2013
Ralph S Marcucio - One of the best experts on this subject based on the ideXlab platform.
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AGE-RELATED CHANGES TO MACROPHAGES AFFECT Fracture Healing.
Innovation in Aging, 2019Co-Authors: Daniel Clark, Theodore Miclau, Mary C. Nakamura, Ralph S MarcucioAbstract:Abstract Fracture Healing follows a strict temporal sequence characterized by an initial inflammatory phase. Perturbation of the inflammatory phase may be responsible for the poorer Fracture Healing outcomes in older adults. Herein, we examine age-related changes to the macrophage during Fracture Healing. Macrophages regulate inflammation through pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Anti-inflammatory activity is promoted via activation of triggering receptor expressed on myeloid cells 2 (TREM2). Tibia Fractures were made in old (24 months) and young (3 months) mice. Immune cells from the Fracture callus were analyzed via RNAseq and FACS, and Fracture Healing was evaluated histologically. Old mice demonstrated significantly delayed Fracture Healing compared to young (p<0.05). The quantity of infiltrating macrophages into the Fracture callus was similar in young and old mice. However, 1222 genes were significantly differentially regulated (FDR<0.1) in callus macrophages from old mice compared to young, and old macrophages demonstrated a more pro-inflammatory phenotype. TREM2 expression was increased in macrophages after Fracture in both groups but was significantly less in old mice compared to young via RNAseq and FACS (FDR<0.1, p<0.05). TREM2-/- mice demonstrated increased pro-inflammatory cytokine expression within the callus with resulting significant delays in Fracture Healing compared to age-matched controls (p<0.05). Inhibition of macrophage infiltration into the Fracture callus significantly improved Fracture Healing in old mice compared to age-matched controls. Age-related changes to macrophages, including increased pro-inflammatory cytokine expression and dysregulated TREM2 expression, may explain Fracture Healing deficits observed in older adults. Therapeutically targeting macrophages may improve management of Fractures in older adults.
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Effects of Aging on Fracture Healing.
Current osteoporosis reports, 2017Co-Authors: Daniel Clark, Mary C. Nakamura, T. Miclau, Ralph S MarcucioAbstract:Purpose of Review This review summarizes research on the physiological changes that occur with aging and the resulting effects on Fracture Healing.
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Biological perspectives of delayed Fracture Healing.
Injury, 2014Co-Authors: Kurt D Hankenson, G. Zimmerman, Ralph S MarcucioAbstract:Fracture Healing is a complex biological process that requires interaction among a series of different cell types. Maintaining the appropriate temporal progression and spatial pattern is essential to achieve robust Healing. We can temporally assess the biological phases via gene expression, protein analysis, histologically, or non-invasively using biomarkers as well as imaging techniques. However, determining what leads to normal versus abnormal Healing is more challenging. Since the ultimate outcome of Fracture Healing is to restore the original functions of bone, assessment of Fracture Healing should include not only monitoring the restoration of structure and mechanical function, but also an evaluation of the restoration of normal bone biology. Currently few non-invasive measures of biological factors of Healing exist; however, recent studies that have correlated non-invasive measures with Fracture Healing outcome in humans have shown that serum TGFbeta1 levels appear to be an indicator of Healing versus non-Healing. In the future, developing additional measures to assess biological Healing will improve the reliability and permit us to assess stages of Fracture Healing. Additionally, new functional imaging technologies could prove useful for better understanding both normal Fracture Healing and predicting dysfunctional Healing in human patients.
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disruption of thrombospondin 2 accelerates ischemic Fracture Healing
Journal of Orthopaedic Research, 2013Co-Authors: Emily L Miedel, Ralph S Marcucio, Michael I Dishowitz, Marc H Myers, Derek Dopkin, Yan Yiu Yu, Ted Miclau, Kurt D HankensonAbstract:Thrombospondin-2 (TSP2) is a matricellular protein that is highly up-regulated during Fracture Healing. TSP2 negatively regulates vascularity, vascular reperfusion following ischemia, and cutaneous wound Healing. As well, TSP2-null mice show increased endocortical bone formation due to an enhanced number of mesenchymal progenitor cells and show increased cortical thickness. Mice deficient in TSP2 (TSP2-null) show an alteration in Fracture Healing, that is unrelated to their cortical bone phenotype, which is characterized by enhanced vascularization with a shift towards an intramembranous Healing phenotype; thus, we hypothesized that there would be enhanced ischemic Fracture Healing in the absence of TSP2. We investigated whether an absence of TSP2 would enhance ischemic Fracture Healing utilizing Laser doppler, µCT and histological analysis. Ischemic tibial Fractures were created in wildtype (WT) and TSP2-null mice and harvested 10, 20, or 40 days post-Fracture. TSP2-null mice show enhanced vascular perfusion following ischemic Fracture. At day 10 post-Fracture, TSP2-null mice have 115% greater bone volume than WT mice. This is associated with a 122% increase in vessel density, 20% increase in cell proliferation, and 15% decrease in apoptosis compared to WT. At day 20, TSP2-null mice have 34% more bone volume, 51% greater bone volume fraction, and 37% more bone tissue mineral density than WT. By 40 days after Fracture the TSP2-null mice have a 24% increase in bone volume fraction, but other parameters show no significant differences. These findings indicate TSP2 is a negative regulator of ischemic Fracture Healing and that in the absence of TSP2 bone regeneration is enhanced. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 935–943, 2013
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Disruption of thrombospondin‐2 accelerates ischemic Fracture Healing
Journal of Orthopaedic Research, 2012Co-Authors: Emily L Miedel, Ralph S Marcucio, Michael I Dishowitz, Marc H Myers, Derek Dopkin, Yan Yiu Yu, Ted Miclau, Kurt D HankensonAbstract:Thrombospondin-2 (TSP2) is a matricellular protein that is highly up-regulated during Fracture Healing. TSP2 negatively regulates vascularity, vascular reperfusion following ischemia, and cutaneous wound Healing. As well, TSP2-null mice show increased endocortical bone formation due to an enhanced number of mesenchymal progenitor cells and show increased cortical thickness. Mice deficient in TSP2 (TSP2-null) show an alteration in Fracture Healing, that is unrelated to their cortical bone phenotype, which is characterized by enhanced vascularization with a shift towards an intramembranous Healing phenotype; thus, we hypothesized that there would be enhanced ischemic Fracture Healing in the absence of TSP2. We investigated whether an absence of TSP2 would enhance ischemic Fracture Healing utilizing Laser doppler, µCT and histological analysis. Ischemic tibial Fractures were created in wildtype (WT) and TSP2-null mice and harvested 10, 20, or 40 days post-Fracture. TSP2-null mice show enhanced vascular perfusion following ischemic Fracture. At day 10 post-Fracture, TSP2-null mice have 115% greater bone volume than WT mice. This is associated with a 122% increase in vessel density, 20% increase in cell proliferation, and 15% decrease in apoptosis compared to WT. At day 20, TSP2-null mice have 34% more bone volume, 51% greater bone volume fraction, and 37% more bone tissue mineral density than WT. By 40 days after Fracture the TSP2-null mice have a 24% increase in bone volume fraction, but other parameters show no significant differences. These findings indicate TSP2 is a negative regulator of ischemic Fracture Healing and that in the absence of TSP2 bone regeneration is enhanced. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 935–943, 2013
Mersedeh Tohidnezhad - One of the best experts on this subject based on the ideXlab platform.
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Role of Nrf2 in Fracture Healing: Clinical Aspects of Oxidative Stress
Calcified Tissue International, 2019Co-Authors: Yusuke Kubo, Athanassios Fragoulis, Christoph Jan Wruck, Wolf Drescher, Philipp Lichte, Mersedeh Tohidnezhad, Frank Hildebrand, Hans-christoph Pape, Horst Fischer, Thomas PufeAbstract:Fracture Healing is a natural process that recapitulates embryonic skeletal development. In the early phase after Fracture, reactive oxygen species (ROS) are produced under inflammatory and ischemic conditions due to vessel injury and soft tissue damage, leading to cell death. Usually, such damage during the course of Fracture Healing can be largely prevented by protective mechanisms and functions of antioxidant enzymes. However, intrinsic oxidative stress can cause excessive toxic radicals, resulting in irreversible damage to cells associated with bone repair during the Fracture Healing process. Clinically, patients with type-2 diabetes mellitus, osteoporosis, habitual drinkers, or heavy smokers are at risk of impaired Fracture Healing due to elevated oxidative stress. Although increased levels of oxidative stress markers upon Fracture and effects of antioxidants on Fracture Healing have been reported, a detailed understanding of what causes impaired Fracture Healing under intrinsic conditions of oxidative stress is lacking. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been identified as a key transcriptional regulator of the expression of antioxidants and detoxifying enzymes. It further not only plays a crucial role in preventing degenerative diseases in multiple organs, but also during Fracture Healing. This narrative review evaluates the influence of intrinsic oxidative stress on Fracture Healing and sheds new light on the intriguing role of Nrf2 during bone regeneration in pathological Fractures.
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Impaired Fracture Healing after Hemorrhagic Shock
Mediators of inflammation, 2015Co-Authors: Philipp Lichte, Mersedeh Tohidnezhad, Horst Fischer, Philipp Kobbe, Roman Pfeifer, Graeme C. Campbell, Rainer Beckmann, Christian Bergmann, Mamed Kadyrov, Christian C. GlüerAbstract:Impaired Fracture Healing can occur in severely injured patients with hemorrhagic shock due to decreased soft tissue perfusion after trauma. We investigated the effects of Fracture Healing in a standardized pressure controlled hemorrhagic shock model in mice, to test the hypothesis that bleeding is relevant in the bone Healing response. Male C57/BL6 mice were subjected to a closed femoral shaft Fracture stabilized by intramedullary nailing. One group was additionally subjected to pressure controlled hemorrhagic shock (HS, mean arterial pressure (MAP) of 35 mmHg for 90 minutes). Serum cytokines (IL-6, KC, MCP-1, and TNF-) were analyzed 6 hours after shock. Fracture Healing was assessed 21 days after Fracture. Hemorrhagic shock is associated with a significant increase in serum inflammatory cytokines in the early phase. Histologic analysis demonstrated a significantly decreased number of osteoclasts, a decrease in bone quality, and more cartilage islands after hemorrhagic shock. μCT analysis showed a trend towards decreased bone tissue mineral density in the HS group. Mechanical testing revealed no difference in tensile failure. Our results suggest a delay in Fracture Healing after hemorrhagic shock. This may be due to significantly diminished osteoclast recruitment. The exact mechanisms should be studied further, particularly during earlier stages of Fracture Healing.
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Nrf2 Deficiency Impairs Fracture Healing in Mice
Calcified Tissue International, 2014Co-Authors: Sebastian Lippross, Mersedeh Tohidnezhad, Rainer Beckmann, Nadine Streubesand, Ferda Ayub, Graeme Campbell, Yuet Wai Kan, Fischer Horst, Tolga Taha Sönmez, Deike VarogaAbstract:Oxidative stress plays an important role in wound Healing but data relating oxidative stress to Fracture Healing are scarce. Nuclear factor erythroid 2-related factor 2 (Nrf2) is the major transcription factor that controls the cellular defence essential to combat oxidative stress by regulating the expression of antioxidative enzymes. This study examined the impact of Nrf2 on Fracture Healing using a standard closed femoral shaft Fracture model in wild-type (WT) and Nrf2-knockout (Nrf2-KO)-mice. Healing was evaluated by histology, real-time RT-PCR, µCT and biomechanical measurements. We showed that Nrf2 expression is activated during Fracture Healing. Bone Healing and remodelling were retarded in the Nrf2-KO compared to the WT-mice. Nrf2-KO-mice developed significantly less callus tissue compared to WT-mice. In addition, biomechanical testing demonstrated lower strength against shear stress in the Nrf2-KO-group compared to WT. The expression of vascular endothelial growth factor (VEGF) and osteocalcin is reduced during Fracture Healing in Nrf2-KO-mice. Taken together, our results demonstrate that Nrf2 deficiency in mice results in impaired Fracture Healing suggesting that Nrf2 plays an essential role in bone regeneration. Pharmacological activation of Nrf2 may have therapeutic potential for the enhancement of Fracture Healing.
Emily L Miedel - One of the best experts on this subject based on the ideXlab platform.
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disruption of thrombospondin 2 accelerates ischemic Fracture Healing
Journal of Orthopaedic Research, 2013Co-Authors: Emily L Miedel, Ralph S Marcucio, Michael I Dishowitz, Marc H Myers, Derek Dopkin, Yan Yiu Yu, Ted Miclau, Kurt D HankensonAbstract:Thrombospondin-2 (TSP2) is a matricellular protein that is highly up-regulated during Fracture Healing. TSP2 negatively regulates vascularity, vascular reperfusion following ischemia, and cutaneous wound Healing. As well, TSP2-null mice show increased endocortical bone formation due to an enhanced number of mesenchymal progenitor cells and show increased cortical thickness. Mice deficient in TSP2 (TSP2-null) show an alteration in Fracture Healing, that is unrelated to their cortical bone phenotype, which is characterized by enhanced vascularization with a shift towards an intramembranous Healing phenotype; thus, we hypothesized that there would be enhanced ischemic Fracture Healing in the absence of TSP2. We investigated whether an absence of TSP2 would enhance ischemic Fracture Healing utilizing Laser doppler, µCT and histological analysis. Ischemic tibial Fractures were created in wildtype (WT) and TSP2-null mice and harvested 10, 20, or 40 days post-Fracture. TSP2-null mice show enhanced vascular perfusion following ischemic Fracture. At day 10 post-Fracture, TSP2-null mice have 115% greater bone volume than WT mice. This is associated with a 122% increase in vessel density, 20% increase in cell proliferation, and 15% decrease in apoptosis compared to WT. At day 20, TSP2-null mice have 34% more bone volume, 51% greater bone volume fraction, and 37% more bone tissue mineral density than WT. By 40 days after Fracture the TSP2-null mice have a 24% increase in bone volume fraction, but other parameters show no significant differences. These findings indicate TSP2 is a negative regulator of ischemic Fracture Healing and that in the absence of TSP2 bone regeneration is enhanced. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 935–943, 2013
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Disruption of thrombospondin‐2 accelerates ischemic Fracture Healing
Journal of Orthopaedic Research, 2012Co-Authors: Emily L Miedel, Ralph S Marcucio, Michael I Dishowitz, Marc H Myers, Derek Dopkin, Yan Yiu Yu, Ted Miclau, Kurt D HankensonAbstract:Thrombospondin-2 (TSP2) is a matricellular protein that is highly up-regulated during Fracture Healing. TSP2 negatively regulates vascularity, vascular reperfusion following ischemia, and cutaneous wound Healing. As well, TSP2-null mice show increased endocortical bone formation due to an enhanced number of mesenchymal progenitor cells and show increased cortical thickness. Mice deficient in TSP2 (TSP2-null) show an alteration in Fracture Healing, that is unrelated to their cortical bone phenotype, which is characterized by enhanced vascularization with a shift towards an intramembranous Healing phenotype; thus, we hypothesized that there would be enhanced ischemic Fracture Healing in the absence of TSP2. We investigated whether an absence of TSP2 would enhance ischemic Fracture Healing utilizing Laser doppler, µCT and histological analysis. Ischemic tibial Fractures were created in wildtype (WT) and TSP2-null mice and harvested 10, 20, or 40 days post-Fracture. TSP2-null mice show enhanced vascular perfusion following ischemic Fracture. At day 10 post-Fracture, TSP2-null mice have 115% greater bone volume than WT mice. This is associated with a 122% increase in vessel density, 20% increase in cell proliferation, and 15% decrease in apoptosis compared to WT. At day 20, TSP2-null mice have 34% more bone volume, 51% greater bone volume fraction, and 37% more bone tissue mineral density than WT. By 40 days after Fracture the TSP2-null mice have a 24% increase in bone volume fraction, but other parameters show no significant differences. These findings indicate TSP2 is a negative regulator of ischemic Fracture Healing and that in the absence of TSP2 bone regeneration is enhanced. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 935–943, 2013
