Advances in bone imaging techniques have provided tools for analyzing bone structure at the macro-, micro- and nano-level. Quantitative assessment of macrostructure can be achieved using dual X-ray ...absorptiometry (DXA) and quantitative computed tomography (QCT), particularly volumetric quantitative CT (vQCT). In vivo quantitative techniques for assessing the microstructure of trabecular bone non-invasively and non-destructively include high-resolution CT (HR-CT) and high-resolution magnetic resonance (HR-MR). Compared with MR imaging, CT-based techniques have the advantage of directly visualizing the bone in the axial skeleton, with high spatial resolution, but the disadvantage of delivering a considerable radiation dose. Micro-CT (μCT), which provides a higher resolution of the microstructure and is principally applicable in vitro, has undergone technological advances such that it is now able to elucidate the physiological skeletal change mechanisms associated with aging and determine the effects of therapeutic intervention on the bone microstructure. In particular, synchrotron μCT (SR-CT) provides a more detailed view of trabecular structure at the nano-level. For the assessment of hip geometry, DXA-based hip structure analysis (HSA) and CT-based HSA have been developed. DXA-based HSA is a convenient tool for analyzing biomechanical properties and for assuming cross-sectional hip geometry based on two-dimensional (2D) data, whereas CT-based HSA provides these parameters three-dimensionally in robust relationship with biomechanical properties, at the cost of greater radiation exposure and the lengthy time required for the analytical procedure. Further progress in bone imaging technology is promising to bring new aspects of bone structure in relation to bone strength to light, and to establish a means for analyzing bone structural properties in the everyday clinical setting.
We have investigated the potential of bile acid (BA)-binding short-chain peptides for suppressing cholesterol absorption in the intestine. In our previous report, we have revealed the physicochemical ...characteristics of high binding peptides using principal component analysis. In this study, we investigated the characteristics of amino acid residues of BA-binding short-chain peptides. We found that short-chain peptides containing lysine (K) and arginine (R) had a higher BA-binding ability than peptides containing other amino acids. Since short-chain tryptic peptides contain K or R residues, we focused on 4-mer, 5-mer, and 6-mer peptides, which were expectedly released from the edible proteins by trypsin. Forty-four short-chain peptides from lactoproteins (Bos taurus) and glutelin (Oryza sativa subsp. Japonica) were synthesized, and their BA micelle disruption activity was evaluated. We could observe such activities in nearly all tested peptides. We found that CEVFR, NGLK, and NSVFR had particularly high disruption activities. We determined that the 50% cholesterol concentration decrease value (DC50) of the micellar solution upon peptide addition was almost the same in case of the aforementioned peptides as that of the VAWWMY as a positive control. In addition, 4-mer and 5-mer peptides had higher BA micelle disruption activity than 6-mer peptides. Our results confirmed that the BA binding and micelle disruption activities were significantly higher if the short-chain peptides contained K and R residues.
Bone remodeling is characterized by the sequential, local tethering of osteoclasts and osteoblasts and is key to the maintenance of bone integrity. While bone matrix-mobilized growth factors, such as ...TGF-β, are proposed to regulate remodeling, no in vivo evidence exists that an osteoclast-produced molecule serves as a coupling factor for bone resorption to formation. We found that CTHRC1, a protein secreted by mature bone-resorbing osteoclasts, targets stromal cells to stimulate osteogenesis. Cthrc1 expression was robustly induced when mature osteoclasts were placed on dentin or hydroxyapatite, and also by increasing extracellular calcium. Cthrc1 expression in bone increased in a high-turnover state (such as that induced by RANKL injections in vivo), but decreased in conditions associated with suppressed bone turnover (such as with aging and after alendronate treatment). Targeted deletion of Cthrc1 in mice eliminated Cthrc1 expression in bone, whereas its deficiency in osteoblasts did not exert any significant effect. Osteoclast-specific deletion of Cthrc1 resulted in osteopenia due to reduced bone formation and impaired the coupling process after resorption induced by RANKL injections, impairing bone mass recovery. These data demonstrate that CTHRC1 is an osteoclast-secreted coupling factor that regulates bone remodeling.
We previously proposed a new method for exploring functional peptides using both spot-synthesis peptide libraries and principal component analysis (PCA). Here, we applied these methods to determine ...if high-binding 6-mer peptides can be used on bile acid for the inhibition of intestinal cholesterol absorption. We used a binding assay of 512 basal 4-mer peptides to bile acid, and from these selected high-binding and low-binding peptides. PCA was performed on data from both these binding groups and many physicochemical variables of the 512 peptides tested, and then through this, the variables were reduced to two principal components (PCs). The peptides were plotted on the PCA chart, and we identified distinct clusters of high- and low-binding regions. These PCA regions were applied to 6-mer random peptides, and we identified 6-mer peptides with high and low binding capacity to bile acid. We confirmed that the average fluorescence intensity of high-binding peptides was 3.0-fold higher than that of low-binding peptides. We succeeded in identifying 6-mer peptides with high and low-binding affinity based on the PCA analysis of 4-mer peptides. These results were compared and discussed with regard to those acquired by our previous computational analysis based on neural networks.
The plexiform lesion is the hallmark of severe pulmonary arterial hypertension. However, its genesis and hemodynamic effects are largely unknown because of the limited availability of lung tissue ...samples from patients with pulmonary arterial hypertension and the lack of appropriate animal models. This study investigated whether rats with severe progressive pulmonary hypertension developed plexiform lesions.
After a single subcutaneous injection of the vascular endothelial growth factor receptor blocker Sugen 5416, rats were exposed to hypoxia for 3 weeks. They were then returned to normoxia for an additional 10 to 11 weeks. Hemodynamic and histological examinations were performed at 13 to 14 weeks after the Sugen 5416 injection. All rats developed pulmonary hypertension (right ventricular systolic pressure approximately 100 mm Hg) and severe pulmonary arteriopathy, including concentric neointimal and complex plexiform-like lesions. There were 2 patterns of complex lesion formation: a lesion forming within the vessel lumen (stalk-like) and another that projected outside the vessel (aneurysm-like). Immunohistochemical analyses showed that these structures had cellular and molecular features closely resembling human plexiform lesions.
Severe, sustained pulmonary hypertension in a very late stage of the Sugen 5416/hypoxia/normoxia-exposed rat is accompanied by the formation of lesions that are indistinguishable from the pulmonary arteriopathy of human pulmonary arterial hypertension. This unique model provides a new and rigorous approach for investigating the genesis, hemodynamic effects, and reversibility of plexiform and other occlusive lesions in pulmonary arterial hypertension.
Introduction
Eldecalcitol increases bone mineral density (BMD) and reduces vertebral fracture in patients with primary osteoporosis. However, the effect of eldecalcitol on BMD and fracture in ...glucocorticoid-induced osteoporosis (GIO) patients is unknown. This study was undertaken to compare the effect of eldecalcitol on BMD and fracture with that of alfacalcidol in GIO patients.
Materials and methods
A randomized, open-label, parallel group study was conducted to identify the effectiveness and safety of monotherapy with 0.75 μg eldecalcitol compared with 1.0 μg alfacalcidol in GIO patients.
Results
Lumbar spine BMD increased with eldecalcitol, but decreased with alfacalcidol at 12 and 24 months (between group difference 1.29%,
p <
0.01, and 1.10%,
p <
0.05, respectively). Total hip and femoral neck BMD were maintained until 24 months by eldecalcitol, but decreased by alfacalcidol (between group difference 0.97%,
p <
0.05 and 1.22%,
p <
0.05, respectively). Both bone formation and resorption markers were more strongly suppressed by eldecalcitol than by alfacalcidol. Eldecalcitol showed better effect on BMD than alfacalcidol in patients with no prevalent fracture and BMD > 70% of the young adult mean, and with ≤ 3 months of previous glucocorticoid treatment. No significant difference in the incidence of vertebral fracture was found, and the incidence of adverse events was similar between the two groups.
Conclusions
Eldecalcitol was more effective than alfacalcidol in maintaining BMD in GIO patients. Because eldecalcitol was effective in patients with no or short-term previous glucocorticoid treatment, as well as those without prevalent fracture or low BMD, eldecalcitol can be a good candidate for primary prevention of GIO.
Clinical trial registration number
UMIN000011700.
Abstract Background Eldecalcitol is an analog of 1,25-dihydroxyvitamin D3 that improves bone mineral density; however, the effect of eldecalcitol on the risk of fractures is unclear. The objective of ...this study is to examine whether eldecalcitol is superior to alfacalcidol in preventing osteoporotic fractures. This trial is registered with ClinicalTrials.gov, number NCT00144456. Methods and results This 3 year randomized, double-blind, active comparator, superiority trial tested the efficacy of daily oral 0.75 μg eldecalcitol versus 1.0 μg alfacalcidol for prevention of osteoporotic fractures. 1054 osteoporotic patients 46 to 92 years old were randomly assigned 1:1 to receive eldecalcitol (n = 528) or alfacalcidol (n = 526). Patients were stratified by study site and serum 25-hydroxyvitamin D level. Patients with low serum 25-hydroxyvitamin D levels (< 50 nmol/L) were supplemented with 400 IU/day vitamin D3 . Primary end point was incident vertebral fractures. Secondary end points included any non-vertebral fractures and change in bone mineral density and bone turnover markers. Compared with the alfacalcidol group, the incidence of vertebral fractures was lower in eldecalcitol group after 36 months of treatment (13.4 vs. 17.5%; hazard ratio, 0.74; predefined 90% confidence interval CI, 0.56–0.97). Eldecalcitol reduced turnover markers and increased bone mineral density more strongly than alfacalcidol. Eldecalcitol reduced the incidence of three major non-vertebral fractures, which was due to a marked reduction in wrist fractures by a post-hoc analysis (1.1 vs. 3.6%; hazard ratio, 0.29; 95% CI, 0.11–0.77). Among the adverse events, the incidence of increase in serum and urinary calcium was higher in the eldecalcitol group, without any difference in glomerular filtration rate between the two groups. Conclusions Eldecalcitol is more efficacious than alfacalcidol in preventing vertebral and wrist fractures in osteoporotic patients with vitamin D sufficiency, with a safety profile similar to alfacalcidol.
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