Genetic variation in the LDL receptor-related protein 5 (LRP5) gene : Association with bone health and metabolic parameters

Bone mass accrual and maintenance are regulated by a complex interplay between genetic and environmental factors. Recent studies have revealed an important role for the low-density lipoprotein receptor-related protein 5 (LRP5) in this process. The aim of this thesis study was to identify novel variants in the LRP5 gene and to further elucidate the association of LRP5 and its variants with various bone health related clinical characteristics. The results of our studies show that loss-of-function mutations in LRP5 cause severe osteoporosis not only in homozygous subjects but also in the carriers of these mutations, who have significantly reduced bone mineral density (BMD) and increased susceptibility to fractures. In addition, we demonstrated for the first time that a common polymorphic LRP5 variant (p.A1330V) was associated with reduced peak bone mass, an important determinant of BMD and osteoporosis in later life. The results from these two studies are concordant with results seen in other studies on LRP5 mutations and in association studies linking genetic variation in LRP5 with BMD and osteoporosis. Several rare LRP5 variants were identified in children with recurrent fractures. Sequencing and multiplex ligation-dependent probe amplification (MLPA) analyses revealed no disease-causing mutations or whole-exon deletions. Our findings from clinical assessments and family-based genotype-phenotype studies suggested that the rare LRP5 variants identified are not the definite cause of fractures in these children. Clinical assessments of our study subjects with LPR5 mutations revealed an unexpectedly high prevalence of impaired glucose tolerance and dyslipidaemia. Moreover, in subsequent studies we discovered that common polymorphic LRP5 variants are associated with unfavorable metabolic characteristics. Changes in lipid profile were already apparent in pre-pubertal children. These results, together with the findings from other studies, suggest an important role for LRP5 also in glucose and lipid metabolism. Our results underscore the important role of LRP5 not only in bone mass accrual and maintenance of skeletal health but also in glucose and lipid metabolism. The role of LRP5 in bone metabolism has long been studied, but further studies with larger study cohorts are still needed to evaluate the specific role of LRP5 variants as metabolic risk factors.

Vascular calcification and mineral bone disorder in chronic kidney disease

Chronic Kidney Disease (CKD), osteoporosis and mild hyponatremia are all prevalent chronic conditions that may coexist and are often under-recognized. Mineral-Bone Disorder begins early in the natural history of CKD and results in complex abnormalities of bone which ultimately confers a well-established increased risk of fragility fractures in End Stage Kidney Disease. Hyponatremia is a novel, usually renal mediated metabolic perturbation, that most commonly occurs independently of the stage of renal dysfunction but which may also predispose to increased fracture risk. The extent -if any- to which either early stages of renal dysfunction or the presence of hyponatremia contribute to fracture occurrence in the general population, independently of osteoporosis, is unclear. Renal transplantation is the treatment of choice for ESKD and although it restores endogenous renal function it typically fails to normalize either the long term cardiovascular or fracture risk. One potential mechanism contributing to these elevated long-term risks and to diminished Health Related Quality of Life is persistent, post-transplant hyperparathyroidism. In this study we retrospectively examine the association of renal function and serum sodium with Bone Mineral Density and fracture occurrence in a retrospective cohort of 1930 female members of the general population who underwent routine DXA scan. We then prospectively recruited a cohort of 90 renal transplant recipients in order to examine the association of post transplant parathyroid hormone (PTH) level with measures of CKD Mineral Bone Disorder, including, DXA Bone Mineral Density, Vascular Calcification (assessed using both abdominal radiography and CT techniques, as well as indirectly by carotid-femoral Pulse Wave Velocity) and Quality of Life (using the Short Form-12 and a PTH specific symptom score). In the retrospective DXA cohort, moderate CKD (eGFR 30-59ml/min/1.73m2) and hyponatremia (<135mmol/L) were associated with fracture occurrence, independently of BMD, with an adjusted Odds Ratio (95% Confidence Interval), of 1.37 (1.0, 1.89) and 2.25 (1.24, 4.09) respectively. In the renal transplant study, PTH was independently associated with the presence of osteoporosis, adjusted Odds Ratio (95% Confidence Interval), 1.15 (per 10ng/ml increment), (1.04, 1.26). The presence of osteoporosis but not PTH was independently associated with measures of vascular calcification, adjusted ß (95% Confidence Interval), 12.45, (1.16, 23.75). Of the eight quality-of-life domains examined, post-transplant PTH (per 10ng/ml increment), was only significantly and independently associated with reduced Physical Functioning, (95% Confidence Interval), 1.12 (1.01, 1.23). CKD and hyponatremia are both common health problems that may contribute to fracture occurrence in the general population, a major on-going public health concern. PTH and decreased Bone Mineral Density may signal sub-optimal long-term outcomes post renal transplantation, influencing bone and vascular health and to a limited extent long term Health Related Quality of Life

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.

Natural products as alternative treatments for metabolic bone disorders and for maintenance of bone health

Bone metabolism involves a complex balance between the deposition of matrix and mineralization and resorption. There is now good evidence that dietary components and herbal products can influence these processes, particularly by inhibiting bone resorption, thus having beneficial effects on the skeleton. For example, it has been reported that a number of common vegetables, including onion, garlic and parsley, can inhibit bone resorption in ovariectomized rats. Essential oils derived from sage, rosemary, thyme and other herbs inhibit osteoclast activity in vitro and in vitro and leading to an increase in bone mineral density. Soya, a rich source of isoflavones, has shown promising results and epidemiological evidence to support a use in maintaining bone health, and various traditional herbal formulae in Chinese and Ayurvedic medicine also have demonstrable effects in pharmacological models of osteoporosis. Recently, cannabinoids have been described as having positive effects on osteoblast differentiation, and the presence of cannabinoid receptors in bone tissue indicates a more complex role in bone metabolism than previously thought. The first part of this review briefly discusses normal bone metabolism and disorders caused by its disruption, with particular reference to osteoporosis and current pharmacological treatments. The effects of natural products on bone and connective tissue are then discussed, to include items of diet, herbal extracts and food supplements, with evidence for their efficacy outlined. Copyright (c) 2006 John Wiley & Sons, Ltd.

Mitochondrial ion transport pathways: Role in metabolic diseases

Mitochondria are the central coordinators of energy metabolism and alterations in their function and number have long been associated with metabolic disorders such as obesity, diabetes and hyperlipidemias. Since oxidative phosphorylation requires an electrochemical gradient across the inner mitochondrial membrane, ion channels in this membrane certainly must play an important role in the regulation of energy metabolism. However, in many experimental settings, the relationship between the activity of mitochondrial ion transport and metabolic disorders is still poorly understood. This review briefly summarizes some aspects of mitochondrial H(+) transport (promoted by uncoupling proteins, UCPs). Ca(2+) and K(+) uniporters which may be determinant in metabolic disorders. (C) 2009 Elsevier B.V. All rights reserved.

HDAC inhibition as a therapeutic potential to treat metabolic diseases

Type 2 diabetes is one of the leading threats to human health. The research focused to identify new drugs that could partly mimic the positive effects of exercise and to test whether these drugs could have the potential to treat metabolic diseases such as obesity and type 2 diabetes

Interleukin-10 inhibits bone resorption: a potential therapeutic strategy in periodontitis and other bone loss diseases

Periodontitis and other bone loss diseases, decreasing bone volume and strength, have a significant impact on millions of people with the risk of tooth loss and bone fracture. The integrity and strength of bone are maintained through the balance between bone resorption and bone formation by osteoclasts and osteoblasts, respectively, so the loss of bone results from the disruption of such balance due to increased resorption or/and decreased formation of bone. The goal of therapies for diseases of bone loss is to reduce bone loss, improve bone formation, and then keep healthy bone density. Current therapies have mostly relied on long-term medication, exercise, anti-inflammatory therapies, and changing of the life style. However there are some limitations for some patients in the effective treatments for bone loss diseases because of the complexity of bone loss. Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine, and recent studies have indicated that IL-10 can contribute to the maintenance of bone mass through inhibition of osteoclastic bone resorption and regulation of osteoblastic bone formation. This paper will provide a brief overview of the role of IL-10 in bone loss diseases and discuss the possibility of IL-10 adoption in therapy of bone loss diseases therapy.

What doesn’t kill you makes you fitter: A systematic review of high-intensity interval exercise for patients with cardiovascular and metabolic diseases

High-intensity interval exercise (HIIE) has gained popularity in recent years for patients with cardiovascular and metabolic diseases. Despite potential benefits, concerns remain about the safety of the acute response (during and/or within 24 hours postexercise) to a single session of HIIE for these cohorts. Therefore, the aim of this study was to perform a systematic review to evaluate the safety of acute HIIE for people with cardiometabolic diseases. Electronic databases were searched for studies published prior to January 2015, which reported the acute responses of patients with cardiometabolic diseases to HIIE (≥80% peak power output or ≥85% peak aerobic power, VO2peak). Eleven studies met the inclusion criteria (n = 156; clinically stable, aged 27-66 years), with 13 adverse responses reported (∼8% of individuals). The rate of adverse responses is somewhat higher compared to the previously reported risk during moderate-intensity exercise. Caution must be taken when prescribing HIIE to patients with cardiometabolic disease. Patients who wish to perform HIIE should be clinically stable, have had recent exposure to at least regular moderate-intensity exercise, and have appropriate supervision and monitoring during and after the exercise session.

Dietary whey protein lessens several risk factors for metabolic diseases: a review

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Impact of diabetes mellitus and metabolic control on bone healing around osseointegrated implants: Removal torque and histomorphometric analysis in rats

Objectives: To evaluate bone healing around dental implants with established osseointegration in experimental diabetes mellitus (DM) and insulin therapy by histomorphometric and removal torque analysis in a rat model. Materials and methods: A total of 80 male Wistar rats received a titanium implant in the tibiae proximal methaphysis. After a healing period of 60 days, the rats were divided into four groups of 20 animals each: a 2-month control group, sacrificed at time (group A), a diabetic group (group D), an insulin group (group I), and a 4-month control group (group C), subdivided half for removal torque and half for histomorphometric analysis. In the D and I groups the DM was induced by a single injection of 40 mg/kg body weight streptozotocin (STZ). Two days after DM induction, group I received subcutaneous doses of insulin twice a day, during 2 months. Groups C and D received only saline. Two months after induction of DM, the animals of groups D, C and I were sacrificed. The plasmatic levels of glucose (GPL) were monitored throughout the experiment. Evaluation of the percentages of bone-to-implant contact and bone area within the limits of the implant threads was done by histomorphometric and mechanical torque analysis. Data were analyzed by anova at significant level of 5%. Results: The GPL were within normal range for groups A, C and I and higher for group D. The means and standard deviations (SD) for histomorphometric bone area showed significant difference between group D (69.34 ± 5.00%) and groups C (78.20 ± 4.88%) and I (79.63 ± 4.97%). Related to bone-to-implant contact there were no significant difference between the groups D (60.81 + 6.83%), C (63.37 + 5.88%) and I (66.97 + 4.13%). The means and SD for removal torque showed that group D (12.91 ± 2.51 Ncm) was statistically lower than group I (17.10 ± 3.06 Ncm) and C (16.95 ± 5.39 Ncm). Conclusions: Diabetes mellitus impaired the bone healing around dental implants with established osseointegration because the results presented a lower percentage of bone area in group D in relation to groups C and I resulting in a lowest torque values for implant removal. Moreover, insulin therapy prevents the occurrence of bone abnormalities found in diabetic animals and osseointegration was not compromised. © 2012 John Wiley & Sons A/S.

Effect of physical training on metabolic and bone profile in weaning rats

Introduction: The practice of moderate-intensity exercise can reduce the risk of infections and improve metabolic aspects of the person. Objective: To investigate the effects of aerobic physical training on endocrine and metabolic aspects, bone and immune systems. Methods: Twenty Wistar rats were divided in two groups: sedentary (SG) and trained group (TG). Training program consisted in swimming, 6 weeks, supporting a workload corresponding to 5% of body weight. At the end of the experiment, were performed counting total and differential leukocyte count and hematocrit. After training period, were analyzed glucose, total protein, triglycerides, cholesterol, liver and muscle samples for the determination of the levels of glycogen, and determination of the tibia length and bone area. All dependent variables were analyzed by one-way analysis of variance (ANOVA) and a significance level of P < 0.05 was used for all comparisons. Results: Hematocrit (%) analyzed showed a significant difference, with higher values ffor TG (54.63 ± 1.41) than for the SG (49.5 ± 1.65). The total leukocyte count was not significantly different, as there was no difference in the differential count. Total cholesterol showed significant decrease in TG (TG = 68.27 ± 13.71 mg/dL; SG = 94.44 ± 28.09), the total protein levels also showed significant reduction (TG = 7.3 ± 0.40 g/dL; SG = 7.74 ± 0.36 g/dL) glucose levels and triglyceride showed no significant differences. The bone length showed significant difference (TG = 40±0.14 mm; SG = 42.10 ± 0.12mm). Tibial area showed a lower value for TG (1.53 ± 0.12cm2) than for SG (1.67 ± 0.18cm2); however, the difference was not statistically significant. Conclusion: It can be concluded that aerobic exercise training is able to produce some unique physiological changes in young rats. There is also the need to prescribe exercises that meet the particular maturational stage of development.

Congenital bone malformation in a rainbow boa Epicrates cenchria crassus - case report

Bone malformation in snakes stems from inbreeding or temperature variations during gestation or incubation. Differential diagnosis are osteoarthropathy due to nutritional, metabolic and infectious diseases. For an accurate diagnosis of these changes, a radiographic exam is essential because it provides a general view of the skeleton and detects morphological abnormalities. This study aimed to report the clinical care of a rainbow boa (Epicrates cenchria crassus) with congenital kyphosis and changes in scales, from a snake pit with controlled temperature and humidity since its gestation. Multiple dorsal deviations of the column without the presence of osteoarthrosis were seen upon radiographic examination. Studies aiming to understand the cases of congenital malformation in snakes should be performed to prevent the birth of animals with this type of change.

Advanced QSAR Studies on PPAR delta Ligands Related to Metabolic Diseases

PPAR delta is a nuclear receptor that, when activated, regulates the metabolism of carbohydrates and lipids and is related to metabolic syndrome and type 2 diabetes. To understand the main interactions between ligands and PPAR delta, we have constructed 2D and 3D QSAR models and compared them with HOMO, LUMO and electrostatic potential maps of the compounds studied, as well as docking results. All QSAR models showed good statistical parameters and prediction outcomes. The QSAR models were used to predict the biological activity of an external test set, and the predicted values are in good agreement with the experimental results. Furthermore, we employed all maps to evaluate the possible interactions between the ligands and PPAR delta. These predictive QSAR models, along with the HOMO, LUMO and MEP maps, can provide insights into the structural and chemical properties that are needed in the design of new PPAR delta ligands that have improved biological activity and can be employed to treat metabolic diseases.