Occupancy Analysis of Water Molecules inside Channels within 25 Å Radius of the Oxygen-Evolving Center of Photosystem II in Molecular Dynamics Simulations.

At room temperature and neutral pH, the oxygen-evolving center (OEC) of photosystem II (PSII) catalyzes water oxidation. During this process, oxygen is released from the OEC, while substrate waters are delivered to the OEC and protons are passed from the OEC to the lumen through water channels known as the narrow or the O4 channel, broad or the Cl1 channel, and large or the O1 channel. Protein residues lining the surfaces of these channels play a critical role in stabilizing the hydrogen-bonding networks that assist in the process. We carried out an occupancy analysis to better understand the structural and possible substrate water dynamics in full PSII monomer molecular dynamics (MD) trajectories in both the S1 and S2 states. We find that the equilibrated positions of water molecules derived from MD-derived electron density maps largely match the experimentally observed positions in crystallography. Furthermore, the occupancy reduction in MD simulations of some water molecules inside the single-filed narrow channel also correlates well with the crystallographic data during a structural transition when the S1 state of the OEC advances to the S2 state. The overall reduced occupancies of water molecules are the source of their "vacancy-hopping" dynamic nature inside these channels, unlike water molecules inside an ice lattice where all water molecules have a fixed unit occupancy. We propose on the basis of findings in our structural and molecular dynamics analysis that the water molecule occupying a pocket formed by D1-D61, D1-S169, and O4 of the OEC could be the last steppingstone to enter into the OEC and that the broad channel may be favored for proton transfer.

Lewy body radius growth: The hypothesis of the cube root of time dependency.

This paper presents a model for the growth of Lewy bodies (LBs), which are pathological hallmarks of Parkinson's disease (PD). The model simulates the growth of classical LBs, consisting of a core and a halo. The core is assumed to comprise lipid membrane fragments and damaged organelles, while the halo consists of radiating alpha-synuclein (α-syn) fibrils. The Finke-Watzky model is employed to simulate the aggregation of lipid fragments and α-syn monomers. Analytical and numerical exploration of the governing equations yielded approximate solutions applicable for larger times. The application of these approximate solutions to simulate LB radius growth led to the discovery of the cube root hypothesis, which posits that the LB radius is proportional to the cube root of its growth time. Sensitivity analysis revealed that the LB radius is unaffected by the kinetic rates of nucleation and autocatalytic growth, with growth primarily regulated by the production rates of lipid membrane fragments and α-syn monomers. The model indicates that the formation of large LBs associated with PD is dependent on the malfunction of the machinery responsible for the degradation of lipid membrane fragments, α-syn monomers, and their aggregates.

Homozygous SMAD6 variants in two unrelated patients with craniosynostosis and radioulnar synostosis.

BACKGROUND: SMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, rare heterozygous loss-of-function variants in SMAD6 were demonstrated to increase the risk of disparate clinical disorders including cardiovascular disease, craniosynostosis and radioulnar synostosis. Only two unrelated patients harbouring biallelic SMAD6 variants presenting a complex cardiovascular phenotype and facial dysmorphism have been described. CASES: Here, we present the first two patients with craniosynostosis harbouring homozygous SMAD6 variants. The male probands, both born to healthy consanguineous parents, were diagnosed with metopic synostosis and bilateral or unilateral radioulnar synostosis. Additionally, one proband had global developmental delay. Echocardiographic evaluation did not reveal cardiac or outflow tract abnormalities. MOLECULAR ANALYSES: The novel missense (c.[584T>G];[584T>G], p.[(Val195Gly)];[(Val195Gly)]) and missense/splice-site variant (c.[817G>A];[817G>A], r.[(817g>a,817delins[a;817+2_817+228])];[(817g>a,817delins[a;817+2_817+228])], p.[(Glu273Lys,Glu273Serfs*72)];[(Glu273Lys,Glu273Serfs*72)]) both locate in the functional MH1 domain of the protein and have not been reported in gnomAD database. Functional analyses of the variants showed reduced inhibition of BMP signalling or abnormal splicing, respectively, consistent with a hypomorphic mechanism of action. CONCLUSION: Our data expand the spectrum of variants and phenotypic spectrum associated with homozygous variants of SMAD6 to include craniosynostosis.

Diversity of hydrodynamic radii of intrinsically disordered proteins.

Intrinsically disordered proteins (IDPs) form an important class of biomolecules regulating biological processes in higher organisms. The lack of a fixed spatial structure facilitates them to perform their regulatory functions and allows the efficiency of biochemical reactions to be controlled by temperature and the cellular environment. From the biophysical point of view, IDPs are biopolymers with a broad configuration state space and their actual conformation depends on non-covalent interactions of its amino acid side chain groups at given temperature and chemical conditions. Thus, the hydrodynamic radius (Rh) of an IDP of a given polymer length (N) is a sequence- and environment-dependent variable. We have reviewed the literature values of hydrodynamic radii of IDPs determined experimentally by SEC, AUC, PFG NMR, DLS, and FCS, and complement them with our FCS results obtained for a series of protein fragments involved in the regulation of human gene expression. The data collected herein show that the values of hydrodynamic radii of IDPs can span the full space between the folded globular and denatured proteins in the Rh(N) diagram.

Assessment of models for calculating the hydrodynamic radius of intrinsically disordered proteins.

Diffusion measurements by pulsed-field gradient NMR and fluorescence correlation spectroscopy can be used to probe the hydrodynamic radius of proteins, which contains information about the overall dimension of a protein in solution. The comparison of this value with structural models of intrinsically disordered proteins is nonetheless impaired by the uncertainty of the accuracy of the methods for computing the hydrodynamic radius from atomic coordinates. To tackle this issue, we here build conformational ensembles of 11 intrinsically disordered proteins that we ensure are in agreement with measurements of compaction by small-angle x-ray scattering. We then use these ensembles to identify the forward model that more closely fits the radii derived from pulsed-field gradient NMR diffusion experiments. Of the models we examined, we find that the Kirkwood-Riseman equation provides the best description of the hydrodynamic radius probed by pulsed-field gradient NMR experiments. While some minor discrepancies remain, our results enable better use of measurements of the hydrodynamic radius in integrative modeling and for force field benchmarking and parameterization.

A prospective case-control pilot study to evaluate bone microarchitecture in children and teenagers on long-term parenteral nutrition using HR-pQCT.

Long-term parenteral nutrition (PN) may induce bone complications. Tridimensional bone imaging techniques such as high-resolution peripheral quantitative computed tomography (HR-pQCT) allow the assessment of both compartmental volumetric densities and microarchitecture. Our aim was to evaluate these parameters in children and teenagers receiving long-term PN. This cross-sectional, case-control study included children older than 9 years undergoing PN for at least 2 years. They were age-, gender- and puberty-matched with healthy controls (1:2). Evaluation included biological assessment of bone metabolism (serum calcium, phosphate, and albumin; urinary calcium and creatinine; 25-OH vitamin D, osteocalcin and PTH), dual X-ray absorptiometry (DXA) and HR-pQCT at the ultradistal tibia and radius. Results are presented as median [range]. Eleven patients (3 girls) with a median age of 16 [9-19] years were included. Bone parameters assessed by HR-pQCT at the ultradistal radius and tibia were similar in patients and controls. Parathyroid hormone (PTH) levels were higher (14 [7-115] vs 16 [12-27]) and osteocalcin levels were lower (44 [15-65] vs 65 [38-142]) in patients than in controls, although within the normal range. Conclusions: there were no differences for compartmental bone densities and microarchitecture in patients undergoing chronic PN. Further longitudinal studies are required to confirm these quite reassuring preliminary results.

Effectiveness of a biodegradable 3D polylactic acid/poly(ɛ-caprolactone)/hydroxyapatite scaffold loaded by differentiated osteogenic cells in a critical-sized radius bone defect in rat.

The effects of a scaffold made of polylactic acid, poly (ɛ-caprolactone) and hydroxyapatite by indirect 3D printing method with and without differentiated bone cells was tested on the regeneration of a critical radial bone defect in rat. The scaffold characterization and mechanical performance were determined by the rheology, scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, and Fourier transform infrared spectrometry. The defects were created in forty Wistar rats which were randomly divided into the untreated, autograft, scaffold cell-free, and differentiated bone cell-seeded scaffold groups (n = 10 in each group). The expression level of angiogenic and osteogenic markers, analyzed by quantitative real time-polymerase chain reaction (in vitro), significantly improved (p < 0.05) in the scaffold group compared to the untreated one. Radiology and computed tomography scan demonstrated a significant improvement in the cell-seeded scaffold group compared to the untreated one (p < 0.001). Biomechanical, histopathological, histomorphometric, and immunohistochemical investigations showed significantly better regeneration scores in the cell-seeded scaffold and autograft groups compared to the untreated group (p < 0.05). The cell-seeded scaffold and autograft groups did show comparable results on the 80th day post-treatment (p > 0.05), however, most results in the scaffold group were significantly higher than the untreated group (p < 0.05). Differentiated bone cells can enhance bone regeneration potential of the scaffold.

Association between forearm cortical bone properties and handgrip strength in women with distal radius fractures: A cross-sectional study.

OBJECTIVES: Mechanical and biochemical bone properties are influenced by muscles. However, the muscle-bone interaction has not been fully elucidated regarding the upper extremities. The objective of the present study was to evaluate the mechanical muscle-bone interaction at the forearm by evaluating the relationship between the properties of three-dimensional (3D) forearm cortical bone models derived from conventional computed tomography (CT) images and handgrip strength (HGS). METHODS: A total of 108 women (mean age, 75.2 ± 9.4 years; range, 62-101 years) with a distal radius fracture who took conventional CT scans for the assessment of the fracture were included in this study. Distal radius 3D models were reconstructed and the average cortical bone density (Cd) and thickness (Ct) of the region of interest (ROI), which might be affected by the forearm flexor muscles, were calculated using a 3D modeling software. Clinical parameters including HGS, lumbar and hip bone mineral densities (BMDs), and other demographic factors were also obtained. A multivariate linear regression analysis was performed to identify relevant factors associated with HGS. RESULTS: HGS was found to be independently associated with height and Cd, but no significant difference was found between HGS and Ct, age, weight, as well as lumber and hip BMDs. CONCLUSIONS: Cortical bone density might be associated with HGS, which is generated by the forearm flexor muscles. Hence, the mechanical muscle-bone interaction in the upper extremities could be supported by the present study.

Effectiveness of mesenchymal stem cell-seeded onto the 3D polylactic acid/polycaprolactone/hydroxyapatite scaffold on the radius bone defect in rat.

PURPOSE: The importance of regeneration in large bone defects forces the orthopedic surgeons to search for a proper methodology. The present experiment evaluated the capability of polylactic acid/polycaprolactone/hydroxyapatite (PLA/PCL/HA) scaffold loaded with and without mesenchymal stem cells (MSCs) on bone regeneration. METHODS: Fourier transform infrared spectrometry, X-ray diffraction, scanning electron microscopy, and rheology methodologies were used to characterize the scaffold. Forty Wistar rats were randomly divided into the four groups including the untreated defects as the control group and three other groups in which the bone defects were treated with autologous bones (autograft group), the PLA/PCL/HA scaffolds (PLA/PCL/HA group), and the MSCs-seeded scaffolds (MSCs-seeded PLA/PCL/HA group). RESULTS: Based on the qRT-PCR results, significantly higher expression levels of osteocalcin, osteopontin, and CD31 were seen in the cell-seeded scaffold group compared to the control group (P < 0.05). The CT scanning and radiographic images depicted significantly more newly formed bonny tissue in the MSCs-loaded scaffold and autograft groups than the untreated group (P < 0.001). The immunohistochemistry, biomechanical, histopathologic, and histomorphometric evaluations demonstrated significantly improved regeneration in the autograft and MSCs-loaded scaffold groups compared to the non-treated group (P < 0.05). There were significant differences between the scaffold and untreated groups in all in vivo evaluations (P < 0.05). CONCLUSION: The MSCs enhanced bone healing potential of the PLA/PCL/HA scaffold and the MSCs-seeded scaffold was comparable to the autograft as the golden treatment regimen (P > 0.05).

Nanoscale perfluorocarbon expediates bone fracture healing through selectively activating osteoblastic differentiation and functions.

BACKGROUND AND RATIONALE: Fracture incidence increases with ageing and other contingencies. However, the strategy of accelerating fracture repair in clinical therapeutics remain a huge challenge due to its complexity and a long-lasting period. The emergence of nano-based drug delivery systems provides a highly efficient, targeted and controllable drug release at the diseased site. Thus far, fairly limited studies have been carried out using nanomedicines for the bone repair applications. Perfluorocarbon (PFC), FDA-approved clinical drug, is received increasing attention in nanomedicine due to its favorable chemical and biologic inertness, great biocompatibility, high oxygen affinity and serum-resistant capability. In the premise, the purpose of the current study is to prepare nano-sized PFC materials and to evaluate their advisable effects on promoting bone fracture repair. RESULTS: Our data unveiled that nano-PFC significantly enhanced the fracture repair in the rabbit model with radial fractures, as evidenced by increased soft callus formation, collagen synthesis and accumulation of beneficial cytokines (e.g., vascular endothelial growth factor (VEGF), matrix metalloprotein 9 (MMP-9) and osteocalcin). Mechanistic studies unraveled that nano-PFC functioned to target osteoblasts by stimulating their differentiation and activities in bone formation, leading to accelerated bone remodeling in the fractured zones. Otherwise, osteoclasts were not affected upon nano-PFC treatment, ruling out the potential target of nano-PFC on osteoclasts and their progenitors. CONCLUSIONS: These results suggest that nano-PFC provides a potential perspective for selectively targeting osteoblast cell and facilitating callus generation. This study opens up a new avenue for nano-PFC as a promising agent in therapeutics to shorten healing time in treating bone fracture.

Inverse association of plasma leptin with cortical thickness at distal radius determined with a quantitative ultrasound device in patients with type 2 diabetes mellitus.

AIMS/INTRODUCTION: Osteoporosis is known to be intimately related to sympathetic nerve activity. We examined the relationship of plasma leptin with cortical and trabecular bone components in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: The present cross-sectional study included 182 type 2 diabetes mellitus patients (93 men, 89 women). Cortical thickness (CoTh) and trabecular bone mineral density (BMD) were determined at the 5.5% distal radius using an LD-100 ultrasonic bone densitometry device. Plasma leptin along with physical and laboratory measurements was simultaneously determined. RESULTS: Plasma leptin, but not body mass index (BMI), was inversely correlated with CoTh (ρ = -0.487, P < 0.001), while BMI, but not plasma leptin, was positively correlated with trabecular BMD (ρ = 0.369, P < 0.001). In multivariable regression analysis, after adjustments for age, sex, duration of diabetes, glycated hemoglobin A1c, albumin, estimated glomerular filtration rate, parathyroid hormone and handgrip strength, plasma leptin was inversely associated with CoTh (ß = -0.258, P < 0.001), but not trabecular BMD. Furthermore, plasma leptin level retained a significant association with CoTh after further adjustment for BMI (ß = -0.237, P < 0.001) and BMI plus waist-to-hip ratio (ß = -0.243, P < 0.001). In contrast, the "sex × leptin" interaction was not significant (P = 0.596). CONCLUSIONS: Leptin level in plasma, independent of BMI and BMI plus waist-to-hip ratio, was shown to be inversely associated with CoTh, but not trabecular BMD, suggesting that hyperleptinemia resulting from obesity might contribute to cortical porosis in patients with type 2 diabetes mellitus.

Orthogonal test design for the optimization of superparamagnetic chitosan plasmid gelatin microspheres that promote vascularization of artificial bone.

The optimal conditions for the preparation of superparamagnetic chitosan plasmid (pReceiver-M29-VEGF165/DH5a) gelatin microspheres (SPCPGMs) were determined. Then, the performance of the SPCPGMs during neovascularization was evaluated in vivo. The SPCPGMs were prepared through a cross-linking curing method and then filled into the hollow scaffold of an artificial bone. Neovascularization at the bone defect position was histologically examined in samples collected 2, 4, 6, and 8 weeks after the operation. The cellular magnetofection rate of superparamagnetic chitosan nanoparticles/plasmid (pReceiver-M29-VEGF165/DH5a) complexes reached 1-3% under static magnetic field (SMF). Meanwhile, the optimal conditions for SPCPGM fabrication were 20% Fe3 O4 (w/v), 4 mg of plasmid, 5.3 mg of glutaraldehyde, and 500 rpm of emulsification rotate speed. Under oscillating magnetic fields (OMFs), 4-6 µg of plasmids was released daily for 21 days. Under the combined application of SMF and OMF, evident neovascularization occurred at the bone defect position 6 weeks after the operation. This result is expected to provide a new type of angiogenesis strategy for the research of bone tissue engineering.

Distinct biomarkers for different bones in osteoporosis with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is known to cause secondary osteoporosis and fragility fractures. This study aimed to identify biomarkers predictive of bone mineral density (BMD) change at three anatomical sites in patients with RA. METHODS: We conducted a prospective longitudinal study in patients with RA. In 2012, we recruited 379 patients from an RA cohort, 329 of whom underwent evaluation of blood and urine biomarkers together with measurement of BMD in the lumbar spine, proximal femur, and distal forearm. The BMD in these three regions was reassessed in 2014. We performed multivariate linear regression analysis to identify those factors associated with BMD change. RESULTS: The averages of age, body mass index, and disease activity score in 28 joints (DAS28) at baseline were 63.2 (minimum to maximum, 32-85), 21.3 (12.3-30.0), and 3.2 (0.1-5.9), respectively. Univariate analysis showed that the annual BMD change was significantly associated with the use of steroid, bisphosphonate (BP) or vitamin D (VitD), and serum homocysteine in the lumber spine; DAS28, the use of BP or VitD, CRP, and anti-cyclic citrullinated peptide antibody (ACPA) in the proximal femur; and the dosage of MTX, the use of BP or VitD, and serum tartrate-resistant acid phosphatase 5b (TRACP-5b) in the distal forearm, respectively. CONCLUSIONS: Predictive biomarkers for BMD change in RA patients differ at each anatomical site. Practitioners should treat each anatomical site with different markers and prescribe osteoporosis drugs to prevent fractures for RA patients.

Pentosidine Is Associated With Cortical Bone Geometry and Insulin Resistance in Otherwise Healthy Children.

Pentosidine is an advanced glycation end product (AGE) associated with fracture in adults with diabetes. AGE accumulation in bone collagen contributes to bone fragility but might also adversely influence bone turnover and, consequently, bone geometry. The relationships between AGEs and bone health have yet to be studied in children. Thus, the objective of this study was to assess relationships between pentosidine and cortical bone volumetric density, geometry, and estimated strength in children. Participants were otherwise healthy black and white boys and girls, ages 9 to 13 years, who were at sexual maturation stage 2 or 3 (N = 160). Tibia and radius cortical bone and muscle area (66% site) were assessed via pQCT. In fasting sera, insulin, glucose, and pentosidine were measured. The Quantitative Insulin Sensitivity Check Index (QUICKI), a measure of insulin sensitivity, was calculated. While controlling for race, sex, maturation, and height, pentosidine negatively correlated with QUICKI (P < 0.05). In unadjusted analyses, pentosidine was associated with lower radius and tibia cortical volumetric bone mineral density, bone mineral content (Ct.BMC), area (Ct.Ar), and thickness (Ct.Th); a larger radius endosteal circumference (Endo.Circ); and lower tibia polar strength strain index (all P < 0.05). While controlling for race, sex, maturation, height, and muscle area, pentosidine was negatively associated with tibia Ct.BMC, Ct.Ar, and Ct.Th but positively associated with Endo.Circ (all P < 0.05). Linear regression revealed a significant interaction between pentosidine and QUICKI in relation to tibia Ct.Th (pinteraction = 0.049), indicating that the negative relationship between pentosidine and Ct.Th was stronger in those with lower QUICKI (ie, greater insulin resistance). This is the first study to report evidence of a potentially adverse influence of AGEs on bone strength in otherwise healthy children. This relationship was strongest in children with the greatest insulin resistance, supporting further work in youth with chronic metabolic health conditions. © 2019 American Society for Bone and Mineral Research.

Langerhans cell histiocytosis and multiple reticulohistiocytomas in a patient with TAR syndrome: An association not previously described.

We describe a patient with thrombocytopenia-absent radius (TAR) syndrome, multisystemic Langerhans cell histiocytosis and multiple reticulohistiocytomas. A mutational study by massive sequencing identified the Val600Glu (V600E) BRAF mutation in the Langerhans cell histiocytosis lesions, but no molecular alterations were found in the reticulohistiocytoma lesions. The concomitant presence in the same patient of more than one type of histiocytosis from two different groups recognized in the most recent Histiocyte Society classification is an extremely rare event. Our case is the first reported case of multisystemic Langerhans cell histiocytosis and multiple reticulohistiocytomas in a patient with TAR syndrome.

The stability of Magoh and Y14 depends on their heterodimer formation and nuclear localization.

Reduced expression of the Y14 gene is a cause of Thrombocytopenia-absent radius (TAR) syndrome. This gene contains a conserved RNA recognition motif (RRM) in the central region and nuclear localization/export sequences (NLS/NES) in the N-terminal. Y14 and Magoh proteins form tight heterodimers and are the core of exon junction complexes (EJCs), which mediate various processes of mRNA metabolism after transcription. In this report, we found that protein expression levels of exogenously expressed Magoh L136R and Y14 L118R (leucine-to-arginine substitution at amino acid residue 136 and 118 respectively, that results in the formation of the complex being lost) are lower than their wild-types. This reduction is likely caused by protein levels, as no difference in mRNA levels was detected. Meanwhile, a cycloheximide chase assay determined that the degradation rates of Magoh L136R and Y14 L118R were faster than their wild-types. Both Y14 L118R and Magoh L136R lost the ability to form heterodimers with corresponding wild-type proteins. However, Y14 L118R is able to still localize in the nucleus which causes the stability of Y14 L118R to be higher than Magoh L136R. These results reveal that the stability of Magoh and Y14 is not only dependent on the heterodimer structure, but also dependent on nuclear localization.

Skeletal responses to an all-female unassisted Antarctic traverse.

PURPOSE: To investigate the skeletal effects of the first all-female trans-Antarctic traverse. METHODS: Six women (mean ±â€¯SD, age 32 ±â€¯3 years, height 1.72 ±â€¯0.07 m, body mass 72.8 ±â€¯4.0 kg) hauled 80 kg sledges over 1700 km in 61 days from coast-to-coast across the Antarctic. Whole-body areal bone mineral density (aBMD) (dual-energy X-ray absorptiometry) and tibial volumetric BMD (vBMD), geometry, microarchitecture and estimated mechanical properties (high-resolution peripheral quantitative computed tomography) were assessed 39 days before (pre-expedition) and 15 days after the expedition (post-expedition). Serum and plasma markers of bone turnover were assessed pre-expedition, and 4 and 15 days after the expedition. RESULTS: There were reductions in trunk (-2.6%), ribs (-5.0%) and spine (-3.4%) aBMD from pre- to post-expedition (all P ≤ 0.046); arms, legs, pelvis and total body aBMD were not different (all P ≥ 0.075). Tibial vBMD, geometry, microarchitecture and estimated mechanical properties at the metaphysis (4% site) and diaphysis (30% site) were not different between pre- and post-expedition (all P ≥ 0.082). Bone-specific alkaline phosphatase was higher 15 days post- than 4 days post-expedition (1.7 µg∙l-1, P = 0.028). Total 25(OH)D decreased from pre- to 4 days post-expedition (-36 nmol∙l-1, P = 0.008). Sclerostin, procollagen 1 N-terminal propeptide, C-telopeptide cross-links of type 1 collagen and adjusted calcium were unchanged (all P ≥ 0.154). CONCLUSION: A decline in aBMD of the axial skeleton may be due to indirect and direct effects of prolonged energy deficit. We propose that weight-bearing exercise was protective against the effects of energy deficit on tibial vBMD, geometry, microarchitecture and strength.

External Bone Size Is a Key Determinant of Strength-Decline Trajectories of Aging Male Radii.

Given prior work showing associations between remodeling and external bone size, we tested the hypothesis that wide bones would show a greater negative correlation between whole-bone strength and age compared with narrow bones. Cadaveric male radii (n = 37 pairs, 18 to 89 years old) were evaluated biomechanically, and samples were sorted into narrow and wide subgroups using height-adjusted robustness (total area/bone length). Strength was 54% greater (p < 0.0001) in wide compared with narrow radii for young adults (<40 years old). However, the greater strength of young-adult wide radii was not observed for older wide radii, as the wide (R2 = 0.565, p = 0.001), but not narrow (R2 = 0.0004, p = 0.944) subgroup showed a significant negative correlation between strength and age. Significant positive correlations between age and robustness (R2 = 0.269, p = 0.048), cortical area (Ct.Ar; R2 = 0.356, p = 0.019), and the mineral/matrix ratio (MMR; R2 = 0.293, p = 0.037) were observed for narrow, but not wide radii (robustness: R2 = 0.015, p = 0.217; Ct.Ar: R2 = 0.095, p = 0.245; MMR: R2 = 0.086, p = 0.271). Porosity increased with age for the narrow (R2 = 0.556, p = 0.001) and wide (R2 = 0.321, p = 0.022) subgroups. The wide subgroup (p < 0.0001) showed a significantly greater elevation of a new measure called the Cortical Pore Score, which quantifies the cumulative effect of pore size and location, indicating that porosity had a more deleterious effect on strength for wide compared with narrow radii. Thus, the divergent strength-age regressions implied that narrow radii maintained a low strength with aging by increasing external size and mineral content to mechanically offset increases in porosity. In contrast, the significant negative strength-age correlation for wide radii implied that the deleterious effect of greater porosity further from the centroid was not offset by changes in outer bone size or mineral content. Thus, the low strength of elderly male radii arose through different biomechanical mechanisms. Consideration of different strength-age regressions (trajectories) may inform clinical decisions on how best to treat individuals to reduce fracture risk. © 2019 American Society for Bone and Mineral Research.

Glucocorticoids and Body Fat Inversely Associate With Bone Marrow Density of the Distal Radius in Healthy Youths.

CONTEXT: Elevated bone marrow adipose tissue (BMAT) is associated with lower bone quality, higher fracture rates, and an unfavorable overall metabolic profile. Apart from age, particularly glucocorticoids (GC), body fat, and diet are discussed to influence BMAT. We hypothesized that already in healthy youths, higher fat intake, higher fat mass index (FMI), and higher GC secretion, still within the normal range, may associate with increased BMAT. DESIGN: In a subsample of healthy 6- to 18-year-old participants of the Dortmund Nutritional and Anthropometric Longitudinally Designed Study, peripheral quantitative CT of the nondominant proximal forearm was used to determine bone marrow density of the distal radius as an inverse surrogate parameter for BMAT. In those participants (n = 172) who had collected two, 24-hour urines within around one year before bone measurement, major urinary GC metabolites were measured by gas chromatography-mass spectrometry and summed up to assess daily adrenal GC secretion (ΣC21). Dietary intake was assessed by 3-day weighed dietary records. FMI was anthropometrically calculated. Separate multiple linear regression models were used to analyze the relationships of ΣC21, FMI, and fat intake with BMAT. RESULTS: After controlling for confounders, such as age, energy intake, and forearm muscle area, ΣC21 (ß = -0.042) and FMI (ß = -0.002) showed inverse relationships with bone marrow density (P < 0.05), whereas fat intake did not associate significantly. CONCLUSION: Our results indicate that already a moderately elevated GC secretion and higher body fatness during adolescence may adversely impact BMAT, an indicator for long-term bone health.

Synergistic effect of strontium, bioactive glass and nano-hydroxyapatite promotes bone regeneration of critical-sized radial bone defects.

Critical-sized bone defects constitute a major health issue in orthopedics and usually cause mal-unions due to an inadequate number of migrated progenitor cells into the defect site or their incomplete differentiation into osteogenic precursor cells. The current study aimed to develop an optimized osteoinductive and angiogenic scaffold by incorporation of strontium (Sr) and bioglass (BG) into gelatin/nano-hydroxyapatite (G/nHAp) seeded with bone marrow mesenchymal stem cells to enhance bone regeneration. The scaffolds were fabricated by a freeze-drying technique and characterized in terms of morphology, structure, porosity and degradation rate. The effect of fabricated scaffolds on cell viability, attachment and differentiation into osteoblastic lineages was evaluated under in vitro condition. Micro computed tomography scan, histological and histomorphometric analysis were performed after implantation of scaffolds into the radial bone defects in rat. RT-PCR analysis showed that G/nHAp/BG/Sr scaffold significantly increased the expression level of osteogenic and angiogenic markers in comparison to other groups (P < 0.05). Moreover, the defects treated with the BMSCs-seeded scaffolds showed superior bone formation and mechanical properties compared to the cell-free scaffolds 4 and 12 weeks post-implantation. Finally, the BMSCs-seeded G/nHAp/BG/Sr scaffold showed the greatest bone regenerative capacity which was more similar to autograft. It is concluded that combination of Sr, BG, and nHAp can synergistically enhance the bone regeneration process. In addition, our results demonstrated that the BMSCs have the potential to considerably increase the bone regeneration ability of osteoinductive scaffolds. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 50-64, 2019.