Burgers, T. A., Vivanco, J. F., Zahatnansky, J., Moren, A. J. V., Mason, J. J., & Williams, B. O. (2016). Mice with a heterozygous Lrp6 deletion have impaired fracture healing. Bone Res., 4, 9 pp.
Abstract: Bone fracture non-unions, the failure of a fracture to heal, occur in 10%-20% of fractures and are a costly and debilitating clinical problem. The Wnt/beta-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 (LRP6), a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 (Lrp6(+/-)) and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6(+/-) mice and wild-type controls (Lrp6(+/+)). Fractures were analyzed using micro-computed tomography (mu CT) scans, biomechanical testing, and histological analysis. Lrp6(+/-) mice had significantly decreased stiffness and strength at 28 days post fracture (PF) and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing.
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Collins, C. J., Vivanco, J. F., Sokn, S. A., Williams, B. O., Burgers, T. A., & Ploeg, H. L. (2015). Fracture healing in mice lacking Pten in osteoblasts: a micro-computed tomography image-based analysis of the mechanical properties of the femur. J. Biomech., 48(2), 310–317.
Abstract: In the United States, approximately eight million osseous fractures are reported annually, of which 5-10% fail to create a bony union. Osteoblast-specific deletion of the gene Pten in mice has been found to stimulate bone growth and accelerate fracture healing. Healing rates at four weeks increased in femurs from Pten osteoblast conditional knock-out mice (Pten-CKO) compared to wild-type mice (WT) of the same genetic strain as measured by an increase in mechanical stiffness and failure load in four-point bending tests. Preceding mechanical testing, each femur was imaged using a Skyscan 1172 micro-computed tomography (mu CT) scanner (Skyscan, Kontich, Belgium). The present study used μCT image-based analysis to test the hypothesis that the increased femoral fracture force and stiffness in Pten-CKO were due to greater section properties with the same effective material properties as that of the WT. The second moment of area and section modulus were computed in ImageJ 1.46 (National Institutes of Health) and used to predict the effective flexural modulus and the stress at failure for fourteen pairs of intact and callus WT and twelve pairs of intact and callus Pten-CKO femurs. For callus and intact femurs, the failure stress and tissue mineral density of the Pten-CKO and WT were not different; however, the section properties of the Pten-CKO were more than twice as large 28 days post-fracture. It was therefore concluded, when the gene Pten was conditionally knocked-out in osteoblasts, the resulting increased bending stiffness and force to fracture were due to increased section properties. (C) 2014 Elsevier Ltd. All rights reserved.
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Vivanco, J. F., Burgers, T. A., Garcia-Rodriguez, S., Crookshank, M., Kunz, M., MacIntyre, N. J., et al. (2014). Estimating the density of femoral head trabecular bone from hip fracture patients using computed tomography scan data. Proc. Inst. Mech. Eng. Part H-J. Eng. Med., 228(6), 616–626.
Abstract: The purpose of this study was to compare computed tomography density (rho(CT)) obtained using typical clinical computed tomography scan parameters to ash density (rho(ash)), for the prediction of densities of femoral head trabecular bone from hip fracture patients. An experimental study was conducted to investigate the relationships between rho(ash) and rho(CT) and between each of these densities and rho(bulk) and rho(dry). Seven human femoral heads from hip fracture patients were computed tomography-scanned ex vivo, and 76 cylindrical trabecular bone specimens were collected. Computed tomography density was computed from computed tomography images by using a calibration Hounsfield units-based equation, whereas rho(bulk), rho(dry) and rho(ash) were determined experimentally. A large variation was found in the mean Hounsfield units of the bone cores (HUcore) with a constant bias from rho(CT) to rho(ash) of 42.5 mg/cm(3). Computed tomography and ash densities were linearly correlated (R-2 = 0.55, p < 0.001). It was demonstrated that rho(ash) provided a good estimate of rho(bulk) (R-2 = 0.78, p < 0.001) and is a strong predictor of rho(dry) (R-2 = 0.99, p < 0.001). In addition, the rho(CT) was linearly related to rho(bulk) (R-2 = 0.43, p < 0.001) and rho(dry) (R-2 = 0.56, p < 0.001). In conclusion, mineral density was an appropriate predictor of rho(bulk) and rho(dry), and rho(CT) was not a surrogate for rho(ash). There were linear relationships between rho(CT) and physical densities; however, following the experimental protocols of this study to determine rho(CT), considerable scatter was present in the rho(CT) relationships.
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