IntroductionTransforming growth factor-beta 1(TGF-β1) is a regulatory protein, involved in bone fracture healing. Circulating TGF-β1 levels have been reported to be a predictor of delayed bone healing and non-union, suggesting active relationship between tissue and circulating TGF-β1 in fracture healing. The purpose of this study was to analyse TGF-β1 local and serum concentrations in fracture healing to further contribute to the understanding of molecular regulation of fracture healing.Patients and methodsSerum samples of 113 patients with long bone fractures were collected over a period of 6 months following a standardised time schedule. TGF-β1 serum concentrations were measured using ELISA. Patients were assigned to 2 groups: Group 1 contained 103 patients with physiological healing. Group 2 contained 10 patients with impaired healing. Patients in both groups were matched. One patient of the group 2 had to be excluded because of missing match partner. In addition, fracture haematoma from 11 patients of group 1 was obtained to analyse local TGF-β1 concentrations. 33 volunteers donated serum which served as control.ResultsTGF-β1 serum concentrations increased during the early healing period and were significantly higher in patients with physiological healing compared to controls (P = 0.04). Thereafter, it decreased continuously between weeks 2 and 8 and fell again after week 8. TGF-β1 serum concentrations in patients with physiological healing were significantly higher at week 24 compared to controls (P = 0.05). In non-unions, serum concentrations differed significantly from those of controls at week 6 (P = 0.01). No significant difference in between patients with physiological and impaired fracture healing was observed. Fracture haematoma contained significantly higher TGF-β1 concentrations than peripheral serum of the patients (P = 0.017).ConclusionElevated levels of TGF-β1 in haematoma and in serum after bone fracture especially during the entire healing process indicate its importance for fracture healing.
Vascular endothelial growth factor (VEGF) plays an important role in the bone repair process as a potent mediator of angiogenesis and it influences directly osteoblast differentiation. Inhibiting VEGF suppresses angiogenesis and callus mineralization in animals. However, no data exist so far on systemic expression of VEGF with regard to delayed or failed fracture healing in humans. One hundred fourteen patients with long bone fractures were included in the study. Serum samples were collected over a period of 6 months following a standardized time schedule. VEGF serum concentrations were measured. Patients were assigned to one of two groups according to their course of fracture healing. The first group contained 103 patients with physiological fracture healing. Eleven patients with delayed or nonunions formed the second group of the study. In addition, 33 healthy volunteers served as controls. An increase of VEGF serum concentration within the first 2 weeks after fracture in both groups with a following decrease within 6 months after trauma was observed. Serum VEGF concentrations in patients with impaired fracture healing were higher compared to the patients with physiological healing during the entire observation period. However, statistically significant differences were not observed at any time point between both groups. VEGF concentrations in both groups were significantly higher than those in controls. The present results show significantly elevated serum concentrations of VEGF in patients after fracture of long bones especially at the initial healing phase, indicating the importance of VEGF in the process of fracture healing in humans. ß
Direct epicardial low-energy shock wave therapy induces angiogenesis and improves ventricular function in a rodent model of ischemic heart failure.
Aims/hypothesisBetatrophin has recently been introduced as a novel hormone and promotor of beta cell proliferation and improved glucose tolerance in mouse models of insulin resistance. In obese and diabetic humans altered levels were reported and a role in pathophysiology of metabolic diseases was therefore hypothesized. However its release and regulation in women with gestational diabetes mellitus (GDM), as well as its associations with markers of obesity, glucose and lipid metabolism during pregnancy still remain unclear.MethodsCirculating betatrophin was quantified in 21 women with GDM and 19 pregnant body mass index-matched women with normal glucose tolerance (NGT) as well as 10 healthy age-matched non-pregnant women by enzyme-linked immunosorbent assay. Additionally we performed radioimmunassay (RIA) to confirm the results.ResultsBetatrophin concentrations measured by ELISA were significantly higher in GDM than in NGT (29.3±4.4 ng/ml vs. 18.1±8.7 ng/ml, p<0.001) which was confirmed by RIA. Betatrophin did not correlate with BMI or insulin resistance but showed a weak association with leptin levels in pregnancy and negative relationship with fasting C-peptide levels in all women. Moreover it correlated significantly with lipid parameters including triglycerides and total cholesterol in pregnancy, as well as estrogen, progesteron and birth weight.Conclusions/interpretationCirculating betatrophin concentrations are dramatically increased in pregnancy and are significantly higher in GDM versus pregnant NGT. In the light of the previously reported role in lipid metabolism, betatrophin may represent a novel endocrine regulator of lipid alterations in pregnancy. However additional studies are needed to elucidate whether hormonal factors, such as estrogen, control the production of betatrophin and if targeting betatrophin could hold promise in the fight against metabolic disease.
Pollen elimination provides an effective containment method to reduce direct gene flow from transgenic trees to their wild relatives. Until now, only limited success has been achieved in controlling pollen production in trees. A pine (Pinus radiata) male cone-specific promoter, PrMC2, was used to drive modified barnase coding sequences (barnaseH102E, barnaseK27A, and barnaseE73G) in order to determine their effectiveness in pollen ablation. The expression cassette PrMC2-barnaseH102E was found to efficiently ablate pollen in tobacco (Nicotiana tabacum), pine, and Eucalyptus (spp.). Large-scale and multiple-year field tests demonstrated that complete prevention of pollen production was achieved in greater than 95% of independently transformed lines of pine and Eucalyptus (spp.) that contained the PrMC2-barnaseH102E expression cassette. A complete pollen control phenotype was achieved in transgenic lines and expressed stably over multiple years, multiple test locations, and when the PrMC2-barnaseH102E cassette was flanked by different genes. The PrMC2-barnaseH102E transgenic pine and Eucalyptus (spp.) trees grew similarly to control trees in all observed attributes except the pollenless phenotype. The ability to achieve the complete control of pollen production in field-grown trees is likely the result of a unique combination of three factors: the male cone/anther specificity of the PrMC2 promoter, the reduced RNase activity of barnaseH102E, and unique features associated with a polyploid tapetum. The field performance of the PrMC2-barnaseH102E in representative angiosperm and gymnosperm trees indicates that this gene can be used to mitigate pollen-mediated gene flow associated with large-scale deployment of transgenic trees.
Sclerostin (SOST), an antagonist of Wnt signaling, is an important negative regulator of bone formation. However, no data on the role of SOST in the human fracture healing have been published so far. This study addressed this issue. Seventy-five patients with long bone fractures were included into the study and divided in two groups. The first group contained 69 patients with normal fracture healing. Six patients with impaired fracture healing formed the second group. Thirty-four volunteers donated blood samples as control. Serum samples were collected over a period of 1 year following a standardized time schedule. In addition, SOST levels were measured in fracture hematoma and serum of 16 patients with bone fractures. Fracture hematoma contained significantly higher SOST concentrations compared to patient's serum. SOST levels in fracture hematoma and in patient's serum were both significantly higher than in the serum of controls. Highly elevated SOST serum concentrations were found in patients with physiological fracture healing. SOST levels were decreased in patients with impaired fracture healing. However, this difference was not statistically significant. This is the first study to provide evidence of strongly enhanced SOST levels in patients with bone fracture. Keywords: sclerostin; fracture healing; non-union; serum; human Fracture healing is a complex physiological process, which involves many different tissue and cell types. During this process callus is formed. Fracture callus contains a mixture of bone-and cartilage cells as well as connective tissue. Callus formation and maturation is regulated by complex interactions of hormones, cytokines, extracellular matrix proteins, and growth factors.1 Within the last 10 years the bone remodeling process has been intensively investigated. Numerous cytokines, angiogenic factors, proteases, and morphogens with significant roles in fracture healing were described. [2][3][4] Recently, the expression of various Wnts has been reported to be up regulated during fracture repair, and increased b-catenin signaling by lithium administration has been shown to improve fracture healing.5 Conversely, inhibition of the Wnt/b-catenin pathway through Dickkopf 1 over-expression have shown to inhibit the fracture healing process.5-7 These results suggest that agents that activate the Wnt/bcatenin pathway may have the potential to improve fracture healing. The activation of the Wnt signaling pathway leads to an increased proliferation and differentiation of osteoblastic precursor cells which favor the deposition of new bone and an increase of bone density. Wnt signaling is triggered when the appropriate Wnt peptide binds to a coreceptor complex at the osteoclast cell membrane involving low density lipoprotein receptor-related protein (LRP) 5 or LRP 6 and the frizzled (Fz) receptor.8 Sclerostin (SOST) is an antagonist of Wnt signaling, therefore an important negative regulator of bone formation. Studies in animals as well as in humans have shown that inhibition of the oste...
Previously we have shown that epicardial shock-wave therapy improves left ventricular ejection fraction (LVEF) in a rat model of myocardial infarction. In the present experiments we aimed to address the safety and efficacy of epicardial shock-wave therapy in a preclinical large animal model and to further evaluate mechanisms of action of this novel therapy. Four weeks after left anterior descending (LAD) artery ligation in pigs, the animals underwent re-thoracotomy with (shock-wave group, n = 6) or without (control group, n = 5) epicardial shock waves (300 impulses at 0.38 mJ/mm ) applied to the infarcted anterior wall. Efficacy endpoints were improvement of LVEF and induction of angiogenesis 6 weeks after shock-wave therapy. Safety endpoints were haemodynamic stability during treatment and myocardial damage. Four weeks after LAD ligation, LVEF decreased in both the shock-wave (43 ± 3%, p < 0.001) and control (41 ± 4%, p = 0.012) groups. LVEF markedly improved in shock-wave animals 6 weeks after treatment (62 ± 9%, p = 0.006); no improvement was observed in controls (41 ± 4%, p = 0.36), yielding a significant difference. Quantitative histology revealed significant angiogenesis 6 weeks after treatment (controls 2 ± 0.4 arterioles/high-power field vs treatment group 9 ± 3; p = 0.004). No acute or chronic adverse effects were observed. As a potential mechanism of action in vitro experiments showed stimulation of VEGF receptors after shock-wave treatment in human coronary artery endothelial cells. Epicardial shock-wave treatment in a large animal model of ischaemic heart failure exerted a positive effect on LVEF improvement and did not show any adverse effects. Angiogenesis was induced by stimulation of VEGF receptors. Copyright © 2014 John Wiley & Sons, Ltd.
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