Does cancellous screw insertion torque depend on bone mineral density and/or microarchitecture?

During insertion of a cancellous bone screw, the torque level reaches a plateau, at the engagement of all the screw threads prior to the screw head contact. This plateau torque (T_Plateau) was found to be a good predictor of the insertion failure torque (stripping) and also exhibited strong positive correlations with areal bone mineral density (aBMD) in ovine bone. However, correlations between T_Plateau and aBMD, as well as correlations between T_Plateau and bone microarchitecture, have never been explored in human bone.     

Ibandronate increases cortical bone density in patients with systemic lupus erythematosus on long-term glucocorticoid

Introduction

The purpose of this research is to assess the effects of oral ibandronate on bone microarchitecture by using high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with systemic lupus erythematosus (SLE) taking a long-term glucocorticoid.

Methods

In this double-blind placebo-controlled study, 40 Chinese female SLE patients taking prednisolone were randomly assigned to receive either monthly oral ibandronate (150 mg) or placebo with daily 1-hydroxycholecalciferol (Alfacalcidol; 1 μg) and calcium supplement for 12 months. Assessments of bone microarchitecture by using HR-pQCT and area bone mineral density (aBMD) of the lumbar spine and hip with dual-energy x-ray absorptiometry (DXA) were performed at baseline and 12 months.

Results

No differences in baseline characteristics were found between the two groups. After 12 months, no statistical differences were noted in any of the bone densities, microarchitectural parameters, or percentage changes of these parameters, as measured with HR-pQCT or DXA between the two groups. However, within the active group, the percentage improvement was significant in cortical bone density (P = 0.023) which was absent in the placebo group. Improvement was also seen in the aBMD of both the lumbar spine (P < 0.0001) and the hip (P < 0.005). In the placebo group, the percentage increase in trabecular separation was significant (P = 0.04), and the percentage improvement in aBMD in the spine also was significant (P = 0.049).

Conclusions

Oral ibandronate treatment improves microarchitecture in SLE patients taking long-term glucocorticoid assessed with HR-pQCT, and this new technology may have a role in assessing bony changes in future longitudinal studies in SLE patients.

Trial registration

ClinicalTrials.gov identifier: NCT00668330.     

Genome-wide association meta-analysis of cortical bone mineral density unravels allelic heterogeneity at the RANKL locus and potential pleiotropic effects on bone

Previous genome-wide association (GWA) studies have identified SNPs associated with areal bone mineral density (aBMD). However, this measure is influenced by several different skeletal parameters, such as periosteal expansion, cortical bone mineral density (BMD_C) cortical thickness, trabecular number, and trabecular thickness, which may be under distinct biological and genetic control. We have carried out a GWA and replication study of BMD_C, as measured by peripheral quantitative computed tomography (pQCT), a more homogenous and valid measure of actual volumetric bone density. After initial GWA meta-analysis of two cohorts (ALSPAC n = 999, aged ∼15 years and GOOD n = 935, aged ∼19 years), we attempted to replicate the BMD_C associations that had p<1×10⁻⁵ in an independent sample of ALSPAC children (n = 2803) and in a cohort of elderly men (MrOS Sweden, n = 1052). The rs1021188 SNP (near RANKL) was associated with BMD_C in all cohorts (overall p = 2×10⁻¹⁴, n = 5739). Each minor allele was associated with a decrease in BMD_C of ∼0.14SD. There was also evidence for an interaction between this variant and sex (p = 0.01), with a stronger effect in males than females (at age 15, males −6.77mg/cm³ per C allele, p = 2×10⁻⁶; females −2.79 mg/cm³ per C allele, p = 0.004). Furthermore, in a preliminary analysis, the rs1021188 minor C allele was associated with higher circulating levels of sRANKL (p<0.005). We show this variant to be independent from the previously aBMD associated SNP (rs9594738) and possibly from a third variant in the same RANKL region, which demonstrates important allelic heterogeneity at this locus. Associations with skeletal parameters reflecting bone dimensions were either not found or were much less pronounced. This finding implicates RANKL as a locus containing variation associated with volumetric bone density and provides further insight into the mechanism by which the RANK/RANKL/OPG pathway may be involved in skeletal development.     

The relation between membrane ionic current and ATP synthesis in chromatophores from Rhodopseudomonas capsulata

(1) Under conditions in which membrane potential (Δψ) was the sole contributor to the proton-motive force, the steady-state rate of ATP synthesis in chromatophores increased disproportionately when Δψ was increased: the rate had an approximately sixth-power dependence on Δψ. (2) Simultaneous measurements showed that the dissipative ionic current (J_DIS) across the chromatophore membrane had a related dependence on Δψ, i.e., the membrane conductance increased markedly as Δψ increased. (3) For comparable Δψ values, J_DIS was greater in phosphorylating than in non-phosphorylating chromatophores. For comparable actinic light intensities, Δψ was smaller in phosphorylating than in non-phosphorylating chromatophores. (4) At either low pH or in the presence of venturicidin, oligomycin or dicyclohexylcarbodiimide to inhibit ATP synthesis, J_DIS was substantially depressed, particularly at high Δψ. Even under these conditions the membrane conductance was dependent on Δψ. (5) Also in intact cells, J_DIS was depressed in the presence of venturicidin. Points 1–5 are interpreted in terms of a Δψ -driven H⁺ flux through the F₀ channel of the ATPase synthase. The high-power dependence of the F₀ conductance on Δψ determines the dependence of the rate of ATP synthesis on Δψ. The Δψ -dependent conductance of F₀ dominates the electrical properties of the membrane. In chromatophores the ionic current accompanying ATP synthesis was more than 50% of the total membrane ionic current at maximal Δψ. (6) The rate of cyclic electron transport was calculated from J_DIS. This led to an estimate of 0.77 ± 0.22 for the $\text{ATP}\text{2}\text{e}{}^{\mathrm{?}}$ ratio and of 3.5 ± 1.3 for the $\text{H}{}^{\mathrm{+}}\text{ATP}$ ratio. (7) Severe inhibition of the electron-transport rate by decreasing the light intensity led to an almost proportionate decrease in the rate of ATP synthesis. The chromatophores were able to maintain proportionality by confining electron-transport phosphorylation to a narrow range of Δψ. This is a consequence of the remarkable conductance properties of the membrane.     

Increased exercise after stable closed fracture fixation does not affect fracture healing in mice

PurposeThe aim of the present study was to evaluate the systemic biological effect of increased exercise on bone repair after stable fracture fixation.MethodsTwo groups of SKH-1 h mice were studied. Animals of the first group (n=36) were housed in cages supplied with a running wheel, while mice of the second group (n=37) were housed in standard cages for control. Using a closed femur fracture model, bone repair was analysed by histomorphometry and biomechanical testing at 2 and 5 weeks. At 2 weeks, we additionally evaluated the expression of the proliferation marker PCNA (proliferating cell nuclear antigen) and the angiogenic and osteogenic growth factor VEGF (vascular endothelial growth factor). To standardise the mechanical conditions in the fracture gap, we used an intramedullary compression screw for stable fracture fixation.ResultsEach mouse of the exercise group run a mean total distance of 23.5 km after 2 weeks and 104.3 km after 5 weeks. Histomorphometric analysis of the size and tissue composition of the callus could not reveal significant differences between mice undergoing exercise and controls. Accordingly, biomechanical testing showed a comparable torsional stiffness, peak rotation angle, and load at failure of the healing bones in the two groups. The expression of PCNA and VEGF did also not differ between mice of the exercise group and controls.ConclusionWe conclude that increased exercise does not affect bone repair after stable fracture fixation.     

Distal skeletal tibia assessed by HR-pQCT is highly correlated with femoral and lumbar vertebra failure loads

Dual energy X-ray absorptiometry (DXA) is the standard for assessing fragility fracture risk using areal bone mineral density (aBMD), but only explains 60–70% of the variation in bone strength. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides 3D-measures of bone microarchitecture and volumetric bone mineral density (vBMD), but only at the wrist and ankle. Finite element (FE) models can estimate bone strength with 86–95% precision. The purpose of this study is to determine how well vBMD and FE bone strength at the wrist and ankle relate to fracture strength at the hip and spine, and to compare these relationships with DXA measured directly at those axial sites. Cadaveric samples (radius, tibia, femur and L4 vertebra) were compared within the same body. The radius and tibia specimens were assessed using HR-pQCT to determine vBMD and FE failure load. aBMD from DXA was measured at the femur and L4 vertebra. The femur and L4 vertebra specimens were biomechanically tested to determine failure load. aBMD measures of the axial skeletal sites strongly correlated with the biomechanical strength for the L4 vertebra (r = 0.77) and proximal femur (r = 0.89). The radius correlated significantly with biomechanical strength of the L4 vertebra for vBMD (r = 0.85) and FE-derived strength (r = 0.72), but not with femur strength. vBMD at the tibia correlated significantly with femoral biomechanical strength (r = 0.74) and FE-estimated strength (r = 0.83), and vertebral biomechanical strength for vBMD (r = 0.97) and FE-estimated strength (r = 0.91). The higher correlations at the tibia compared to radius are likely due to the tibia’s weight-bearing function.     

Exercise training in childhood-onset systemic lupus erythematosus: a controlled randomized trial

Introduction

Exercise training has emerged as a promising therapeutic strategy to counteract physical dysfunction in adult systemic lupus erythematosus. However, no longitudinal studies have evaluated the effects of an exercise training program in childhood-onset systemic lupus erythematosus (C-SLE) patients. The objective was to evaluate the safety and the efficacy of a supervised aerobic training program in improving the cardiorespiratory capacity in C-SLE patients.

Methods

Nineteen physically inactive C-SLE patients were randomly assigned into two groups: trained (TR, n = 10, supervised moderate-intensity aerobic exercise program) and non-trained (NT, n = 9). Gender-, body mass index (BMI)- and age-matched healthy children were recruited as controls (C, n = 10) for baseline (PRE) measurements only. C-SLE patients were assessed at PRE and after 12 weeks of training (POST). Main measurements included exercise tolerance and cardiorespiratory measurements in response to a maximal exercise (that is, peak VO₂, chronotropic reserve (CR), and the heart rate recovery (ΔHRR) (that is, the difference between HR at peak exercise and at both the first (ΔHRR1) and second (ΔHRR2) minutes of recovery after exercise).

Results

The C-SLE NT patients did not present changes in any of the cardiorespiratory parameters at POST (P > 0.05). In contrast, the exercise training program was effective in promoting significant increases in time-to-exhaustion (P = 0.01; ES = 1.07), peak speed (P = 0.01; ES = 1.08), peak VO₂ (P = 0.04; ES = 0.86), CR (P = 0.06; ES = 0.83), and in ΔHRR1 and ΔHRR2 (P = 0.003; ES = 1.29 and P = 0.0008; ES = 1.36, respectively) in the C-SLE TR when compared with the NT group. Moreover, cardiorespiratory parameters were comparable between C-SLE TR patients and C subjects after the exercise training intervention, as evidenced by the ANOVA analysis (P > 0.05, TR vs. C). SLEDAI-2K scores remained stable throughout the study.

Conclusion

A 3-month aerobic exercise training was safe and capable of ameliorating the cardiorespiratory capacity and the autonomic function in C-SLE patients.

Trial registration

NCT01515163.     

Effects of combined exercise on cardiovascular risk factors and serum BDNF level in mid-aged women

[Purpose]

The purposes of this study is first to examine a positive effect of long term combined exercise including aerobic and resistance exercise on increasing level of serum BDNF, and investigate how aerobic exercise is related to improving BDNF circulation and resistance exercise improves fat oxidation in mid-aged women.

[Methods]

Initially, 30 mid-aged women, according to their exercise preference, was randomly assigned as a non-exercise group (n=7, control group; CG) and exercise group (n=23). Then, 23 exercise participants were divided by aerobic exercise group (n=15, AEG) and combination of aerobic and resistance exercise group (n=8, CEG). Prior to the experiment, all participants’maximal oxygen uptake (VO₂max), body composition, and blood factors were measured. Changes (Δ delta value) in body composition, fitness level, and serum BDNF level of the different groups were tested through one way ANOVA.

[Results]

For AEG and CG after 24 weeks, VO₂max and high-density lipoprotein cholesterol (HDL-C) were significantly increased. During this period, CEG had significant increase in muscular strength and decrease in triglyceride (TG) total cholesterol (TC)/HDL-C (p=0.013). Continuously, serum BDNF concentration of both AEG and CEG was significantly increased (F=6.328, p=0.001) compared to CG. There, however, was no significant between-group difference.

[Conclusion]

Although there was no difference in serum BDNF level between AEG and CEG, we confirmed that CEG may have a possibility of positive changes in increase of serum BDNF level in mid-aged women.     

A school-curriculum-based exercise intervention program for two years in pre-pubertal girls does not influence hip structure

Background

It is known that physical activity during growth has a positive influence on bone mineral accrual, and is thus possibly one strategy to prevent osteoporosis. However, as bone geometry, independent of areal bone mineral density (aBMD), influences fracture risk, this study aimed to evaluate whether hip structure in pre-pubertal girls is also affected by a two-year exercise intervention program.

Methods

Forty-two girls aged 7–9 years in a school-curriculum-based exercise intervention program comprising 40 minutes of general physical activity per school day (200 minutes per week) were compared with 43 age-matched girls who participated in the general Swedish physical education curriculum comprising a mean of 60 minutes per week. The hip was scanned by dual energy X-ray absorptiometry (DXA) and the hip structural analysis (HSA) software was applied to evaluate bone mineral content (BMC, g), areal bone mineral density (aBMD, g/cm²), periosteal diameter, cross-sectional area (CSA, cm²), section modulus (Z, cm³) and cross-sectional moment of inertia (CSMI, cm⁴) of the femoral neck (FN). Annual changes were compared. Subjective duration of physical activity was estimated by questionnaire and objective level of everyday physical activity at follow-up by means of accelerometers worn for four consecutive days. All children remained at Tanner stage 1 throughout the study. Group comparisons were made by independent student's t-test between means and analyses of covariance (ANCOVA).

Results

At baseline, the two groups did not differ with regard to age, anthropometrics or bone parameters. No between-group differences were observed for annual changes in the FN variables measured.

Conclusion

A two-year school-based moderately intense general exercise program for 7–9-year-old pre-pubertal girls does not influence structural changes in the FN.

     

Adipose-derived stem cells alleviate osteoporosis by enchancing osteogenesis and inhibiting adipogenesis in a rabbit model

Background aimsOsteoporosis (OP) is characterized by a reduction in bone quality, which is associated with inadequacies in bone marrow mesenchymal stromal cells (BMSCs). As an alternative cell source to BMSCs, adipose-derived stem cells (ASCs) have been investigated for bone repair because of their osteogenic potential and self-renewal capability. Nevertheless, whether autologous ASCs can be used to promote bone regeneration under osteoporotic conditions has not been elucidated.MethodsThe OP rabbit model was established by means of bilateral ovariectomy (OVX). Both BMSCs and ASCs were harvested from OVX rabbits and expanded in vitro. The effects of osteogenic-induced ASCs on the in vitro adipogenic and osteogenic capabilities of BMSCs were evaluated. Autologous ASCs were then encapsulated by calcium alginate gel and transplanted into the distal femurs of OVX rabbits (n = 12). Hydrogel without loading cells was injected into the contralateral femurs as a control. Animals were killed for investigation at 12 weeks after transplantation.ResultsOsteogenic-induced ASCs were able to promote osteogenesis and inhibit adipogenesis of osteoporotic BMSCs through activation of the bone morphogenetic protein 2/bone morphogenetic protein receptor type IB signal pathway. Local bone mineral density began to increase at 8 weeks after ASC transplantation (P < 0.05). At 12 weeks, micro–computed tomography and histological evaluation revealed more new bone formation in the cell-treated femurs than in the control group (P < 0.05).ConclusionsThis study demonstrated that ASCs could stimulate proliferation and osteogenic differentiation of BMSCs in vitro and enhance bone regeneration in vivo, which suggests that autologous osteogenic-induced ASCs might be useful to alleviate OP temporally.     

Simple evaluation method for osteoinductive capacity of cells or scaffolds using ceramic cubes

Mesenchymal stem cells are good candidates for the clinical application of bone repair because of their osteogenic differentiation potential, but in vivo osteoinduction potential should be verified for culture expanded cells before clinical application. This study analyzed in vivo bone formation by MSCs quantitatively after implantation of MSCs planted porous biphasic ceramic cubes into athymic mice. MSCs were divided into osteogenic differentiation-induced and normal groups and also tested in vitro to evaluate the degree of differentiation into osteoblasts. The osteogenic induced group showed higher alkaline phosphatase and calcium level in vitro and corresponding higher level of bone formation in vivo compared to control group. Whereas there was no bone formation observed in fibroblast-implanted negative control group. In critical sized bone defect models, commonly used for evaluation of bone regeneration ability, it is difficult to distinguish between osteoinduction and osteoconduction, and quantitative analysis is not simple. However, this method for evaluating osteoinduction is both accurate and simple. In conclusion, the analysis of in vivo bone formation using porous ceramic cubes is a powerful and simple method for evaluating the osteoinduction ability of target cells and, furthermore, can be applied for evaluation of scaffolds for their osteoinductive properties.     

The effect of temperature on the respiration rate of meiofauna

Summary The effect of temperature on respiration rate has been established, using Cartesian divers, for the meiofaunal sabellid polychaeteManayunkia aestuarina, the free-living nematodeSphaerolaimus hirsutus and the harpacticoid copepodTachidius discipes from a mudflat in the Lynher estuary, Cornwall, U.K. Over the temperature range normally experienced in the field, i.e. 5–20° C the size-compensated respiration rate (R _c) was related to the temperature (T) in °C by the equation Log₁₀ R _c=-0.635+0.0339T forManayunkia, Log₁₀ R _c=0.180+0.0069T forSphaerolaimus and Log₁₀ R _c=-0.428+0.0337T forTachidius, being equivalent toQ ₁₀ values of 2.19, 1.17 and 2.17 respectively. In order to derive the temperature response forManayunkia a relationship was first established between respiration rate and body size: Log₁₀ R=0.05+0.75 Log₁₀ V whereR=respiration in nl·O₂·ind^-1·h^-1 andV=body volume in nl.TheQ ₁₀ values are compared with values for other species derived from the literature. From these limited data a dichotomy emerges: species with aQ ₁₀2 which apparently feed on diatoms and bacteria, the abundance of which are subject to large short term variability, and species withQ ₁₀1 apparently dependent on more stable food sources.     

Moderate-Intensity Rotating Magnetic Fields Do Not Affect Bone Quality and Bone Remodeling in Hindlimb Suspended Rats

Abundant evidence has substantiated the positive effects of pulsed electromagnetic fields (PEMF) and static magnetic fields (SMF) on inhibiting osteopenia and promoting fracture healing. However, the osteogenic potential of rotating magnetic fields (RMF), another common electromagnetic application modality, remains poorly characterized thus far, although numerous commercial RMF treatment devices have been available on the market. Herein the impacts of RMF on osteoporotic bone microarchitecture, bone strength and bone metabolism were systematically investigated in hindlimb-unloaded (HU) rats. Thirty two 3-month-old male Sprague-Dawley rats were randomly assigned to the Control (n = 10), HU (n = 10) and HU with RMF exposure (HU+RMF, n = 12) groups. Rats in the HU+RMF group were subjected to daily 2-hour exposure to moderate-intensity RMF (ranging from 0.60 T to 0.38 T) at 7 Hz for 4 weeks. HU caused significant decreases in body mass and soleus muscle mass of rats, which were not obviously altered by RMF. Three-point bending test showed that the mechanical properties of femurs in HU rats, including maximum load, stiffness, energy absorption and elastic modulus were not markedly affected by RMF. µCT analysis demonstrated that 4-week RMF did not significantly prevent HU-induced deterioration of femoral trabecular and cortical bone microarchitecture. Serum biochemical analysis showed that RMF did not significantly change HU-induced decrease in serum bone formation markers and increase in bone resorption markers. Bone histomorphometric analysis further confirmed that RMF showed no impacts on bone remodeling in HU rats, as evidenced by unchanged mineral apposition rate, bone formation rate, osteoblast numbers and osteoclast numbers in cancellous bone. Together, our findings reveal that RMF do not significantly affect bone microstructure, bone mechanical strength and bone remodeling in HU-induced disuse osteoporotic rats. Our study indicates potentially obvious waveform-dependent effects of electromagnetic fields-stimulated osteogenesis, suggesting that RMF, at least in the present form, might not be an optimal modality for inhibiting disuse osteopenia/osteoporosis.     

Development of a surrogate model based on patient weight,bone mass and geometry to predict femoral neck strains and fracture loads

Osteoporosis and related bone fractures are an increasing global burden in our ageing society. Areal bone mineral density assessed through dual energy X-ray absorptiometry (DEXA), the clinically accepted and most used method, is not sufficient to assess fracture risk individually. Finite element (FE) modelling has shown improvements in prediction of fracture risk, better than aBMD from DEXA, but is not practical for widespread clinical use. The aim of this study was to develop an adaptive neural network (ANN)-based surrogate model to predict femoral neck strains and fracture loads obtained from a previously developed population-based FE model. The surrogate model performance was assessed in simulating two loading conditions: the stance phase of gait and a fall.The surrogate model successfully predicted strains estimated by FE (r² = 0.90–0.98 for level gait load case, r² = 0.92–0.96 for the fall load case). Moreover, an ANN model based on three measurements obtainable in clinics (femoral neck length (level gait) or maximum femoral neck diameter (fall), femoral neck bone mass, body weight) was able to give reasonable predictions (r² = 0.84–0.94) for all of the strain metrics and the estimated femoral neck fracture load. Overall, the surrogate model has potential for clinical applications as they are based on simple measures of geometry and bone mass which can be derived from DEXA images, accurately predicting FE model outcomes, with advantages over FE models as they are quicker and easier to perform.     

Effects of Home-Based Interval Walking Training on Thigh Muscle Strength and Aerobic Capacity in Female Total Hip Arthroplasty Patients: A Randomized,Controlled Pilot Study

Due to the reduced physical activity of patients who have undergone total hip arthroplasty (THA), there are no home-based exercise training regimens for preventing muscle atrophy and aerobic capacity impairment in these patients. We examined whether interval walking training (IWT) could prevented these issues. Twenty-eight female patients (∼60 years of age) who had undergone THA more than 2 months prior were randomly divided into IWT (n = 14) and control (CNT, n = 14) groups. The IWT subjects trained at a target of 60 min of fast walking at >70% peak aerobic capacity for walking (O_2peak) per wk for 12 wk, while those in the CNT maintained their previous sedentary life during the same period. We measured the energy expenditure of the daily physical activity, except during sleeping and bathing, every minute and every day during the intervention. We also measured the isometric knee extension (F_EXT) and flexion (F_FLX) forces, O_2peak, and anaerobic threshold during the graded cycling exercise (O_2AT) before and after the intervention. All subjects, except for one in IWT, completed the protocol. F_FLX increased by 23% on the operated side (P = 0.003) and 14% on the non-operated side of IWT (P = 0.006), while it only increased on the operated side of CNT (P = 0.03). The O_2peak and O_2AT in IWT increased by 8% (P = 0.08) and 13% (P = 0.002), respectively, and these changes were significantly higher in the IWT than in CNT group (both, P<0.05). In conclusion, IWT might be an effective home-based training regimen for preventing the muscle atrophy from reduced daily physical activity in THA patients.

Trial Registration

UMIN-CTR UMIN000013172     

A Trisubstituted Benzimidazole Cell Division Inhibitor with Efficacy against Mycobacterium tuberculosis

Trisubstituted benzimidazoles have demonstrated potency against Gram-positive and Gram-negative bacterial pathogens. Previously, a library of novel trisubstituted benzimidazoles was constructed for high throughput screening, and compounds were identified that exhibited potency against M. tuberculosis H37Rv and clinical isolates, and were not toxic to Vero cells. A new series of 2-cyclohexyl-5-acylamino-6-N, N-dimethylaminobenzimidazoles derivatives has been developed based on SAR studies. Screening identified compounds with potency against M. tuberculosis. A lead compound from this series, SB-P17G-A20, was discovered to have an MIC of 0.16 µg/mL and demonstrated efficacy in the TB murine acute model of infection based on the reduction of bacterial load in the lungs and spleen by 1.73±0.24 Log₁₀ CFU and 2.68±Log₁₀ CFU, respectively, when delivered at 50 mg/kg by intraperitoneal injection (IP) twice daily (bid). The activity of SB-P17G-A20 was determined to be concentration dependent and to have excellent stability in mouse and human plasma, and liver microsomes. Together, these studies demonstrate that SB-P17G-A20 has potency against M. tuberculosis clinical strains with varying susceptibility and efficacy in animal models of infection, and that trisubstituted benzimidazoles continue to be a platform for the development of novel inhibitors with efficacy.     

Human Amnion-Derived Mesenchymal Stem Cells Protect Human Bone Marrow Mesenchymal Stem Cells against Oxidative Stress-Mediated Dysfunction via ERK1/2 MAPK Signaling

Epidemiological evidence suggests that bone is especially sensitive to oxidative stress, causing bone loss in the elderly. Previous studies indicated that human amnion-derived mesenchymal stem cells (HAMSCs), obtained from human amniotic membranes, exerted osteoprotective effects in vivo. However, the potential of HAMSCs as seed cells against oxidative stress-mediated dysfunction is unknown. In this study, we systemically investigated their antioxidative and osteogenic effects in vitro. Here, we demonstrated that HAMSCs signi cantly promoted the proliferation and osteoblastic differentiation of H₂O₂-induced human bone marrow mesenchymal stem cells (HBMSCs), and down-regulated the reactive oxygen species (ROS) level. Further, our results suggest that activation of the ERK1/2 MAPK signal transduction pathway is essential for both HAMSCs-mediated osteogenic and protective effects against oxidative stress-induced dysfunction in HBMSCs. U0126, a highly selective inhibitor of extracellular ERK1/2 MAPK signaling, significantly suppressed the antioxidative and osteogenic effects in HAMSCs. In conclusion, by modulating HBMSCs, HAMSCs show a strong potential in treating oxidative stress- mediated bone deficiency.     

The Associations of Serum Serotonin with Bone Traits Are Age- and Gender-Specific

Context

Serotonin plays a potential role in bone metabolism, but the nature and extent of this relationship is unclear and human studies directly addressing the skeletal effect of circulating serotonin are rare.

Objective

The study aimed to investigate the associations between serum serotonin and bone traits at multiple skeletal sites in women and men.

Subjects and Methods

Subjects were part of the CALEX-family study and comprised 235 young women, 121 premenopausal women, 124 postmenopausal women, and 168 men. Body composition was assessed using DXA, as was areal bone mineral density (aBMD) of spine, femur and whole body. In addition, pQCT was used to determine bone properties at tibial midshaft and distal radius. Fasting serum serotonin concentration was assessed using a competitive enzyme-linked immunosorbent assay.

Results

Serum serotonin declined with advancing age both in females and males (all p<0.01). Serotonin was negatively correlated with weight, BMI, lean and fat mass in women (r = −0.22 to −0.39, all p<0.001), but positively with height and lean mass in men (all p<0.01). In the premenopausal women, serotonin was negatively correlated with lumbar spine aBMD (r = −0.23, p<0.05) but the statistical significance disappeared after adjustment for weight. Conversely, in postmenopausal women, serotonin was positively correlated with whole body and femur aBMD, as well as with distal radius bone mineral content and volumetric BMD (r = 0.20 to 0.30, all p<0.05), and these associations remained significant after adjustment for weight. In men, no significant associations were found between serotonin and bone traits.

Conclusion

Serum serotonin is positively associated with bone traits in postmenopausal women, but not in premenopausal women or men. This partially supports the idea of circulating serotonin playing a role in the regulation of bone metabolism, but also indicates the importance of gender and age specific factors.     

Adenoviral Mediated Expression of BMP2 by Bone Marrow Stromal Cells Cultured in 3D Copolymer Scaffolds Enhances Bone Formation

Selection of appropriate osteoinductive growth factors, suitable delivery method and proper supportive scaffold are critical for a successful outcome in bone tissue engineering using bone marrow stromal cells (BMSC). This study examined the molecular and functional effect of a combination of adenoviral mediated expression of bone morphogenetic protein-2 (BMP2) in BMSC and recently developed and characterized, biodegradable Poly(L-lactide-co-є-caprolactone){poly(LLA-co-CL)}scaffolds in osteogenic molecular changes and ectopic bone formation by using in vitro and in vivo approaches. Pathway-focused custom PCR array, validation using TaqMan based quantitative RT-PCR (qRT-PCR) and ALP staining showed significant up-regulation of several osteogenic and angiogenic molecules, including ALPL and RUNX2 in ad-BMP2 BMSC group grown in poly(LLA-co-CL) scaffolds both at 3 and 14 days. Micro CT and histological analyses of the subcutaneously implanted scaffolds in NOD/SCID mice revealed significantly increased radiopaque areas, percentage bone volume and formation of vital bone in ad-BMP2 scaffolds as compared to the control groups both at 2 and 8 weeks. The increased bone formation in the ad-BMP2 group in vivo was paralleled at the molecular level with concomitant over-expression of a number of osteogenic and angiogenic genes including ALPL, RUNX2, SPP1, ANGPT1. The increased bone formation in ad-BMP2 explants was not found to be associated with enhanced endochondral activity as evidenced by qRT-PCR (SOX9 and FGF2) and Safranin O staining. Taken together, combination of adenoviral mediated BMP-2 expression in BMSC grown in the newly developed poly(LLA-co-CL) scaffolds induced expression of osteogenic markers and enhanced bone formation in vivo.     

Azabenzthiazole inhibitors of leukotriene A4 hydrolase

Previously, benzthiazole containing LTA₄H inhibitors were discovered that were potent (1–3), but were associated with the potential for a hERG liability. Utilizing medicinal chemistry first principles (e.g., introducing rigidity, lowering c Log D) a new benzthiazole series was designed, congeners of 1–3, which led to compounds 7a, 7c, 12a–d which exhibited LTA₄H IC₅₀ = 3–6 nM and hERG Dofetilide Binding IC₅₀ = 8.9–> >10 μM.