Thyroid diseases and bone health.

Thyroid hormones are essential for skeletal development and are important regulators of bone maintenance in adults. Childhood hypothyroidism causes delayed skeletal development, retarded linear growth and impaired bone mineral accrual. Epiphyseal dysgenesis is evidenced by classic features of stippled epiphyses on X-ray. In severe cases, post-natal growth arrest results in a complex skeletal dysplasia. Thyroid hormone replacement stimulates catch-up growth and bone maturation, but recovery may be incomplete dependent on the duration and severity of hypothyroidism prior to treatment. A severe phenotype characteristic of hypothyroidism occurs in children with resistance to thyroid hormone due to mutations affecting THRA encoding thyroid hormone receptor α (TRα). Discovery of this rare condition recapitulated animal studies demonstrating that TRα mediates thyroid hormone action in the skeleton. In adults, thyrotoxicosis is well known to cause severe osteoporosis and fracture, but cases are rare because of prompt diagnosis and treatment. Recent data, however, indicate that subclinical hyperthyroidism is associated with low bone mineral density (BMD) and an increased risk of fracture. Population studies have also shown that variation in thyroid status within the reference range in post-menopausal women is associated with altered BMD and fracture risk. Thus, thyroid status at the upper end of the euthyroid reference range is associated with low BMD and increased risk of osteoporotic fragility fracture. Overall, extensive data demonstrate that euthyroid status is required for normal post-natal growth and bone mineral accrual, and is fundamental for maintenance of adult bone structure and strength

Quantitative X-ray microradiography for high-throughput phenotyping of osteoarthritis in mice

Objective To investigate and validate digital X-ray microradiography as a novel, high-throughput and cost-effective screening approach to identify abnormal joint phenotypes in mice. Method Digital X-ray microradiography was used to quantify the subchondral bone mineral content (BMC) in the medial tibial plateau. Accuracy and reproducibility of the method were determined in 22 samples from C57BL/6(B6Brd;B6Dnk;B6N-Tyrc-Brd) wild-type mice. The method was then validated in wild-type mice that had undergone surgical destabilisation of medial meniscus (DMM) and in a genetically modified mouse strain with an established increase in trabecular bone mass. Results The measurement of subchondral BMC by digital X-ray microradiography had a coefficient of variation of 3.6%. Digital X-ray microradiography was able to demonstrate significantly increased subchondral BMC in the medial tibial plateau of male mice 4 and 8 weeks after DMM surgery and in female mice 8 weeks after surgery. Furthermore, digital X-ray microradiography also detected the increase in subchondral BMC in a genetically modified mouse strain with high trabecular bone mass. Conclusion Quantitation of subchondral BMC by digital X-ray microradiography is a rapid, sensitive and cost-effective method to identify abnormal joint phenotypes in mice of both genders at several ages

Evidence for post-nebula volatilisation in an exo-planetary body

The loss and gain of volatile elements during planet formation is key for setting their subsequent climate, geodynamics, and habitability. Two broad regimes of volatile element transport in and out of planetary building blocks have been identified: that occurring when the nebula is still present, and that occurring after it has dissipated. Evidence for volatile element loss in planetary bodies after the dissipation of the solar nebula is found in the high Mn to Na abundance ratio of Mars, the Moon, and many of the solar system's minor bodies. This volatile loss is expected to occur when the bodies are heated by planetary collisions and short-lived radionuclides, and enter a global magma ocean stage early in their history. The bulk composition of exo-planetary bodies can be determined by observing white dwarfs which have accreted planetary material. The abundances of Na, Mn, and Mg have been measured for the accreting material in four polluted white dwarf systems. Whilst the Mn/Na abundances of three white dwarf systems are consistent with the fractionations expected during nebula condensation, the high Mn/Na abundance ratio of GD362 means that it is not (>3 sigma). We find that heating of the planetary system orbiting GD362 during the star's giant branch evolution is insufficient to produce such a high Mn/Na. We, therefore, propose that volatile loss occurred in a manner analogous to that of the solar system bodies, either due to impacts shortly after their formation or from heating by short-lived radionuclides. We present potential evidence for a magma ocean stage on the exo-planetary body which currently pollutes the atmosphere of GD362

Are exoplanetesimals differentiated?

Metals observed in the atmospheres of white dwarfs suggest that many have recently accreted planetary bodies. In some cases, the compositions observed suggest the accretion of material dominantly from the core (or the mantle) of a differentiated planetary body. Collisions between differentiated exoplanetesimals produce such fragments. In this work, we take advantage of the large numbers of white dwarfs where at least one siderophile (core-loving) and one lithophile (rock-loving) species have been detected to assess how commonly exoplanetesimals differentiate. We utilise N-body simulations that track the fate of core and mantle material during the collisional evolution of planetary systems to show that most remnants of differentiated planetesimals retain core fractions similar to their parents, whilst some are extremely core-rich or mantle-rich. Comparison with the white dwarf data for calcium and iron indicates that the data are consistent with a model in which $66^{+4}_{-6}\%$ have accreted the remnants of differentiated planetesimals, whilst $31^{+5}_{-5}\%$ have Ca/Fe abundances altered by the effects of heating (although the former can be as high as $100\%$, if heating is ignored). These conclusions assume pollution by a single body and that collisional evolution retains similar features across diverse planetary systems. These results imply that both collisions and differentiation are key processes in exoplanetary systems. We highlight the need for a larger sample of polluted white dwarfs with precisely determined metal abundances to better understand the process of differentiation in exoplanetary systems

Automatic Quantification of Epidermis Curvature in H&E Stained Microscopic Skin Image of Mice

Changes in the curvature of the epidermis layer is often associated with many skin disorders, such as ichthyoses and generic effects of ageing. Therefore, methods to quantify changes in the curvature are of a scientific and clinical interest. Manual methods to determine curvature are both laborious and intractable to large scale investigations. This paper proposes an automatic algorithm to quantify curvature of microscope images of H&E-stained murine skin. The algorithm can be divided into three key stages. First, skin layers segmentation based on colour deconvolution to separate the original image into three channels of different representations to facilitate segmenting the image into multiple layers, namely epidermis, dermis and subcutaneous layers. The algorithm then further segments the epidermis layer into cornified and basal sub-layers. Secondly, it quantifies the curvature of the epidermis layer by measuring the difference between the epidermis edge and a straight line (theoretical reference line) connecting the two far sides of the epidermis edge. Finally, the curvature measurements extracted from a large number of images of mutant mice are used to identify a list of genes responsible for changes in the epidermis curvature. A dataset of 5714 H&E microscopic images of mutant and wild type mice were used to evaluate the effectiveness of the algorithm

Genetic and pharmacological targeting of transcriptional repression in resistance to thyroid hormone alpha

Background Thyroid hormones act in bone and cartilage via thyroid hormone receptor α (TRα). In the absence of T3, TRα interacts with co-repressors, including nuclear receptor co-repressor-1 (NCoR1), which recruit histone deacetylases (HDACs) and mediate transcriptional repression. Dominant-negative mutations of TRα cause resistance to thyroid hormone α (RTHα; OMIM 614450), characterized by excessive repression of T3 target genes leading to delayed skeletal development, growth retardation and bone dysplasia. Treatment with thyroxine has been of limited benefit even in mildly affected individuals and there is a need for new therapeutic strategies. We hypothesized that (i) the skeletal manifestations of RTHα are mediated by the persistent TRα/NCoR1/HDAC repressor complex containing mutant TRα, and (ii) treatment with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) would ameliorate these manifestations. Methods We determined the skeletal phenotypes of (i) Thra1PV/+ mice, a well characterized model of RTHα, (ii) Ncor1ΔID/ΔID mice, which express an NCoR1 mutant that fails to interact with TRα, and (iii) Thra1PV/+Ncor1ΔID/ΔID double mutant adult mice. Wild-type, Thra1PV/+, Ncor1ΔID/ΔID, and Thra1PV/+Ncor1ΔID/ΔID double mutant mice were also treated with SAHA to determine whether HDAC inhibition results in amelioration of skeletal abnormalities. Results Thra1PV/+ mice had a severe skeletal dysplasia characterized by short stature, abnormal bone morphology and increased bone mineral content. Despite normal bone length, Ncor1ΔID/ΔID mice displayed increased cortical bone mass, mineralization and strength. Thra1PV/+Ncor1ΔID/ΔID double mutant mice displayed only a small improvement of skeletal abnormalities compared to Thra1PV/+ mice. Treatment with SAHA to inhibit histone deacetylation had no beneficial or detrimental effects on bone structure, mineralization or strength in wild-type or mutant mice. Conclusions These studies indicate treatment with SAHA is unlikely to improve the skeletal manifestations of RTHα. Nevertheless, the findings (i) confirm that TRα1 has a critical role in the regulation of skeletal development and adult bone mass, (ii) suggest a physiological role for alternative co-repressors that interact with TR in skeletal cells, and (iii) demonstrate a novel role for NCoR1 in the regulation of adult bone mass and strength

ELECTRONIC-STRUCTURE OF AMORPHOUS SI-N COMPOUNDS

We have measured valence-band photoemission spectra and dark conductivity of a-SiN(x):H compounds for compositions between x = 0 and x = 1.35. The photoemission spectra have been measured with Zr Mzeta and Al Kalpha radiation of 151.4 and 1486.6 eV, respectively. At hnu = 151.4 eV the spectra resemble directly the total density-of-states (DOS) of the system; the most important change with x is the shift of spectral weight from near the valence-band maximum (VBM) toward the center of the band, indicating the change from a band of Si-Si bonding states to a band of Si-N bonding states. At hnu = 1486.6 eV the spectra are dominated by the contribution of the Si-3s partial DOS; this contribution is located at the bottom of the band and shifts toward higher binding energies with increasing x. We compare our results at x = 0.36 and x = 1.35 with those of two recent calculations. Combining results of the dark-conductivity measurements and the photoemission spectra with a previous determination of the optical gaps we make a plot of the VBM, Fermi-level position, and conduction-band minimum (CBM) versus x. It is shown that the sudden opening of the gap at x approximately 1 is due mainly to the recession of the CBM.4919134461345

The secreted protein augurin is a novel modulator of canonical Wnt signalling involved in osteoblast differentiation

Background ECRG4/C2ORF40 is a tumour suppressor gene downregulated in several cancer types, which encodes the secreted protein augurin. A wide number of functions in health and disease have been assigned to augurin, but the signalling pathways it regulates are still poorly characterized. Augurin expression is strongly upregulated during in vitro differentiation of neonatal mouse osteoblasts. Methods In vitro differentiation assays of calvarial osteoblasts isolated from Ecrg4 -/- and wild-type mice; transient transfection assays using reporters activated by Wnt signalling and other signal transduction pathways; Real-time quantitative polymerase chain reaction for measurement of gene expression; protein expression in Chinese hamster ovary cells and Escherichia coli; in situ binding assays of proteins expressed as fusions to alkaline phosphatase with cells expressing various membrane receptors. Results Osteoblasts from Ecrg4 -/- mice have an accelerated differentiation compared to wild-type and upregulation of Wnt markers. Augurin is a specific repressor of Wnt-stimulated transcriptional activity, both when coexpressed together with the reporter and when added to the culture medium as a soluble protein. We confirmed the previously described binding of augurin to LOX1, a scavenger receptor, but an inhibitor of this molecule did not impair augurin repression of Wnt-stimulated transcription specifically. Genome-wide association studies showed an association of ECRG4 genomic variation with body height and osteoarthritis. Conclusions Our study sheds new light on the wide spectrum of functions previously ascribed to augurin in brain function, stem cell biology, inflammation/immunity and cancer. Furthermore, our discovery paves the way to further characterization of the mechanisms involved in augurin repression of Wnt signalling and the development of agonists and antagonists for this protein, which have a wide array of potential applications in the clinic