Oxidative metabolism is impaired by phosphate deficiency during fracture healing and is mechanistically related to BMP induced chondrocyte differentiation.

Prior studies of acute phosphate restriction during the endochondral phase of fracture healing showed delayed chondrocyte differentiation was mechanistically linked to decreased bone morphogenetic protein signaling. In the present study, transcriptomic analysis of fracture callus gene expression in three strains of mice was used to identify differentially expressed (FDR = q ≤ 0.05) genes in response to phosphate (Pi) restriction.

Dosimetry of [Pb]VMT01, a MC1R-Targeted Alpha Therapeutic Compound, and Effect of Free Tl on Tissue Absorbed Doses.

[Pb]VMT01 is a melanocortin 1 receptor (MC1R) targeted theranostic ligand in clinical development for alpha particle therapy for melanoma. Pb has an elementally matched gamma-emitting isotope Pb; thus, [Pb]VMT01 can be used as an imaging surrogate for [Pb]VMT01. [Pb]VMT01 human serum stability studies have demonstrated retention of the Bi daughter within the chelator following beta emission of parent Pb.

Temporal and Quantitative Transcriptomic Differences Define Sexual Dimorphism in Murine Postnatal Bone Aging.

Time is a central element of the sexual dimorphic patterns of development, pathology, and aging of the skeleton. Because the transcriptome is a representation of the phenome, we hypothesized that both sex and sex-specific temporal, transcriptomic differences in bone tissues over an 18-month period would be informative to the underlying molecular processes that lead to postnatal sexual dimorphism. Regardless of age, sex-associated changes of the whole bone transcriptomes were primarily associated not only with bone but also vascular and connective tissue ontologies.

Tributyltin protects against ovariectomy-induced trabecular bone loss in C57BL/6J mice with an attenuated effect in high fat fed mice.

Risk factors for poor bone quality include estrogen loss at menopause, a high fat diet and exposures to drugs/chemicals that activate peroxisome proliferator activated receptor gamma (PPARγ). We previously reported that the PPARγ and retinoid X receptor dual ligand, tributyltin (TBT), repressed periosteal bone formation but enhanced trabecular bone formation in vivo. Here, we examined the interaction of diet, ovariectomy (OVX) and TBT exposure on bone structure.

Bayesian modeling of factorial time-course data with applications to a bone aging gene expression study.

Many scientific studies, especially in the biomedical sciences, generate data measured simultaneously over a multitude of units, over a period of time, and under different conditions or combinations of factors. Often, an important question of interest asked relates to which units behave similarly under different conditions, but measuring the variation over time complicates the analysis significantly. In this article we address such a problem arising from a gene expression study relating to bone aging, and develop a Bayesian statistical method that can simultaneously detect and uncover signals on three levels within such data: factorial, longitudinal, and transcriptional.

Are Narrative Letters of Recommendation for Medical Students Interpreted as Intended by Orthopaedic Surgery Residency Programs?

Background: Narrative letters of recommendation are an important component of the residency application process. However, because narrative letters of recommendation are almost always positive, it is unclear whether those reviewing the letters understand the writer's intended strength of support for a given applicant.

Questions/purposes: (1) Is the perception of letter readers for narrative letters of recommendation consistent with the intention of the letter's author? (2) Is there inter-reviewer consistency in selection committee members' perceptions of the narrative letters of recommendation?

Methods: Letter writers who wrote two or more narrative letters of recommendation for applicants to one university-based orthopaedic residency program for the 2014 to 2015 application cycle were sent a survey linked to a specific letter of recommendation they authored to assess the intended meaning regarding the strength of an applicant.

Association of vertebral endplate microstructure with bone strength in men and women.

Epidemiological and biomechanical evidence indicates that the risk of vertebral fracture differs between men and women, and that vertebral fracture frequently involves failure of the endplate region. The goal of this study was to compare the bone microstructure of the endplate region-defined as the (bony) vertebral endplate and underlying subchondral trabecular bone-between sexes and to determine whether any such sex differences are associated with vertebral strength. The bone density (volume fraction, apparent density and tissue mineral density) of the superior-most 2 mm of the vertebra, and the bone density and trabecular architecture of the next 5 mm were quantified using micro-computed tomography in human T8 (12 female, 16 male) and L1 (13 female, 12 male) vertebrae.

Hypophosphatemia Regulates Molecular Mechanisms of Circadian Rhythm.

Transcriptomic analysis showed that the central circadian pathway genes had significantly altered expression in fracture calluses from mice fed a low phosphate diet. This led us to hypothesize that phosphate deficiency altered the circadian cycle in peripheral tissues. Analysis of the expression of the central clock genes over a 24-36 hour period in multiple peripheral tissues including fracture callus, proximal tibia growth plate and cardiac tissues after 12 days on a low phosphate diet showed higher levels of gene expression in the hypophosphatemia groups (p < 0.

Bone Mechanical Properties in Healthy and Diseased States.

The mechanical properties of bone are fundamental to the ability of our skeletons to support movement and to provide protection to our vital organs. As such, deterioration in mechanical behavior with aging and/or diseases such as osteoporosis and diabetes can have profound consequences for individuals' quality of life. This article reviews current knowledge of the basic mechanical behavior of bone at length scales ranging from hundreds of nanometers to tens of centimeters.

Differences in Trabecular Microarchitecture and Simplified Boundary Conditions Limit the Accuracy of Quantitative Computed Tomography-Based Finite Element Models of Vertebral Failure.

Vertebral fractures are common in the elderly, but efforts to reduce their incidence have been hampered by incomplete understanding of the failure processes that are involved. This study's goal was to elucidate failure processes in the lumbar vertebra and to assess the accuracy of quantitative computed tomography (QCT)-based finite element (FE) simulations of these processes. Following QCT scanning, spine segments (n = 27) consisting of L1 with adjacent intervertebral disks and neighboring endplates of T12 and L2 were compressed axially in a stepwise manner.

Serum proteomic assessment of the progression of fracture healing.

A targeted proteomic analysis of murine serum over a 35-day course of fracture healing was carried out to determine if serum proteomic changes could be used to monitor the biological progression of fracture healing. Transverse, closed femoral fractures where generated and stabilized with intramedullary fixation. A single stranded DNA aptamer-based multiplexed proteomic approach was used to assay 1,310 proteins.

Carbonic anhydrase III protects osteocytes from oxidative stress.

Osteocytes are master orchestrators of bone remodeling; they control osteoblast and osteoclast activities both directly cell-to-cell communication and indirectly secreted factors, and they are the main postnatal source of sclerostin and RANKL (receptor activator of NF-kB ligand), two regulators of osteoblast and osteoclast function. Despite progress in understanding osteocyte biology and function, much remains to be elucidated. Recently developed osteocytic cell lines-together with new genome editing tools-has allowed a closer look at the biology and molecular makeup of these cells.

Correlation between RUST assessments of fracture healing to structural and biomechanical properties.

Radiographic Union Score for Tibia (RUST) and modified RUST (mRUST) are radiographic tools for quantitatively evaluating fracture healing using a cortical scoring system. This tool has high intra-class correlation coefficients (ICCs); however, little evidence has evaluated the scores against the physical properties of bone healing. Closed, stabilized fractures were made in the femora of C3H/HeJ male mice (8-12 week-old) of two dietary groups: A control and a phosphate restricted diet group.

Acute Phosphate Restriction Impairs Bone Formation and Increases Marrow Adipose Tissue in Growing Mice.

Phosphate plays a critical role in chondrocyte maturation and skeletal mineralization. Studies examining the consequences of dietary phosphate restriction in growing mice demonstrated not only the development of rickets, but also a dramatic decrease in bone accompanied by increased marrow adipose tissue (MAT). Thus studies were undertaken to determine the effects of dietary phosphate restriction on bone formation and bone marrow stromal cell (BMSC) differentiation.

Quantitative, 3D Visualization of the Initiation and Progression of Vertebral Fractures Under Compression and Anterior Flexion.

The biomechanical mechanisms leading to vertebral fractures are not well understood. Clinical and laboratory evidence suggests that the vertebral endplate plays a key role in failure of the vertebra as a whole, but how this role differs for different types of vertebral loading is not known. Mechanical testing of human thoracic spine segments, in conjunction with time-lapsed micro-computed tomography, enabled quantitative assessment of deformations occurring throughout the entire vertebral body under axial compression combined with anterior flexion ("combined loading") and under axial compression only ("compression loading").

Elastic Anisotropy of Trabecular Bone in the Elderly Human Vertebra.

Knowledge of the nature of the elastic symmetry of trabecular bone is fundamental to the study of bone adaptation and failure. Previous studies have classified human vertebral trabecular bone as orthotropic or transversely isotropic but have typically obtained samples from only selected regions of the centrum. In this study, the elastic symmetry of human vertebral trabecular bone was characterized using microfinite element (μFE) analyses performed on 1019 cubic regions of side length equal to 5 mm, obtained via thorough sampling of the centrums of 18 human L1 vertebrae (age = 81.

Endplate deflection is a defining feature of vertebral fracture and is associated with properties of the underlying trabecular bone.

Endplate deflection frequently occurs with vertebral failure, but the relationship between the two remains poorly defined. This study examined associations between endplate deflection under compressive loading and characteristics of the neighboring subchondral bone and intervertebral disc (IVD). Ten L1 vertebrae with adjacent IVDs were dissected, compressed axially in a stepwise manner to failure, and imaged with micro-computed tomography before each loading step.

Effect of specimen-specific anisotropic material properties in quantitative computed tomography-based finite element analysis of the vertebra.

Intra- and inter-specimen variations in trabecular anisotropy are often ignored in quantitative computed tomography (QCT)-based finite element (FE) models of the vertebra. The material properties are typically estimated solely from local variations in bone mineral density (BMD), and a fixed representation of elastic anisotropy ("generic anisotropy") is assumed. This study evaluated the effect of incorporating specimen-specific, trabecular anisotropy on QCT-based FE predictions of vertebral stiffness and deformation patterns.

Presence of intervertebral discs alters observed stiffness and failure mechanisms in the vertebra.

Ex vivo mechanical testing is an essential tool for study of vertebral mechanics. However, the common method of testing vertebral bodies in the absence of adjacent intervertebral discs (IVDs) may limit the physiological relevance of the results. The goal of this study was to determine the influence of IVDs on vertebral mechanical properties and failure mechanisms.

Digital Volume Correlation for Study of the Mechanics of Whole Bones.

Full-field measurement of deformation in biological structures such as bones is a promising experimental approach for study of the spatial heterogeneity in mechanical behavior. With the advent of high-resolution, 3-D imaging, digital volume correlation (DVC) allows for the measurement of spatially heterogeneous, 3-D deformation fields throughout entire volumes. For bones such as the vertebra, use of DVC to detect the onset and progression of failure is of direct relevance to the study of osteoporotic fractures.

Vascular development during distraction osteogenesis proceeds by sequential intramuscular arteriogenesis followed by intraosteal angiogenesis.

Vascular formation is intimately associated with bone formation during distraction osteogenesis (DO). While prior studies on this association have focused on vascular formation locally within the regenerate, we hypothesized that this vascular formation, as well as the resulting osteogenesis, relies heavily on the response of the vascular network in surrounding muscular compartments. To test this hypothesis, the spatiotemporal sequence of vascular formation was assessed in both muscular and osseous compartments in a murine model of DO and was compared to the progression of osteogenesis.