Metabolic properties of the osteoclast

Osteoclasts are defined as cells capable of excavating 3-dimensional resorption pits in bone and other mineralised tissues. They are derived from the differentiation/fusion of promonocytic precursors, and are usually large, multinucleated cells. In common with other cells from this myeloid lineage such as macrophages and dendritic cells, they are adapted to function in hypoxic, acidic environments. The process of bone resorption is rapid and is presumably highly energy-intensive, since osteoclasts must actively extrude protons to dissolve hydroxyapatite mineral, whilst secreting cathepsin K to degrade collagen, as well as maintaining a high degree of motility. Osteoclasts are well known to contain abundant mitochondria but they are also able to rely on glycolytic (anaerobic) metabolism to generate the ATP needed to power their activity. Their primary extracellular energy source appears to be glucose. Excessive accumulation of mitochondrial reactive oxygen species in osteoclasts during extended periods of high activity in oxygen-poor environments may promote apoptosis and help to limit bone resorption — a trajectory that could be termed “live fast, die young”. In general, however, the metabolism of osteoclasts remains a poorly-investigated area, not least because of the technical challenges of studying actively resorbing cells in appropriate conditions

Acidosis Is a Key Regulator of Osteoblast Ecto-Nucleotidase Pyrophosphatase/Phosphodiesterase 1 (NPP1) Expression and Activity

Previous work has shown that acidosis prevents bone nodule formation by osteoblasts in vitro by inhibiting mineralisation of the collagenous matrix. The ratio of phosphate (Pi) to pyrophosphate (PPi) in the bone microenvironment is a fundamental regulator of bone mineralisation. Both Pi and PPi, a potent inhibitor of mineralisation, are generated from extracellular nucleotides by the actions of ecto‐nucleotidases. This study investigated the expression and activity of ecto‐nucleotidases by osteoblasts under normal and acid conditions. We found that osteoblasts express mRNA for a number of ecto‐nucleotidases including NTPdase 1–6 (ecto‐nucleoside triphosphate diphosphohydrolase) and NPP1‐3 (ecto‐nucleotide pyrophosphatase/phosphodiesterase). The rank order of mRNA expression in differentiating rat osteoblasts (day 7) was Enpp1 > NTPdase 4 > NTPdase 6 > NTPdase 5 > alkaline phosphatase > ecto‐5‐nucleotidase > Enpp3 > NTPdase 1 > NTPdase 3 > Enpp2 > NTPdase 2. Acidosis (pH 6.9) upregulated NPP1 mRNA (2.8‐fold) and protein expression at all stages of osteoblast differentiation compared to physiological pH (pH 7.4); expression of other ecto‐nucleotidases was unaffected. Furthermore, total NPP activity was increased up to 53% in osteoblasts cultured in acid conditions (P < 0.001). Release of ATP, one of the key substrates for NPP1, from osteoblasts, was unaffected by acidosis. Further studies showed that mineralised bone formation by osteoblasts cultured from NPP1 knockout mice was increased compared with wildtypes (2.5‐fold, P < 0.001) and was partially resistant to the inhibitory effect of acidosis. These results indicate that increased NPP1 expression and activity might contribute to the decreased mineralisation observed when osteoblasts are exposed to acid conditions

Activation of the P2Y2 receptor regulates bone cell function by enhancing ATP release

Bone cells constitutively release ATP into the extracellular environment where it acts locally via P2 receptors to regulate bone cell function. Whilst P2Y2 receptor stimulation regulates bone mineralisation, the functional effects of this receptor in osteoclasts remain unknown. This investigation used the P2Y2 receptor knockout (P2Y2R−/−) mouse model to investigate the role of this receptor in bone. MicroCT analysis of P2Y2R−/− mice demonstrated age-related increases in trabecular bone volume (≤48%), number (≤30%) and thickness (≤17%). In vitro P2Y2R−/− osteoblasts displayed a 3-fold increase in bone formation and alkaline phosphatase activity, whilst P2Y2R−/− osteoclasts exhibited a 65% reduction in resorptive activity. Serum cross-linked C-telopeptide levels (CTX, resorption marker) were also decreased (≤35%). The resorption defect in P2Y2R−/− osteoclasts was rescued by the addition of exogenous ATP, suggesting that an ATP deficit could be a key factor in the reduced function of these cells. In agreement, we found that basal ATP release was reduced up to 53% in P2Y2R−/− osteoclasts. The P2Y2 receptor agonists, UTP and 2-thioUTP, increased osteoclast activity and ATP release in wild-type but not in P2Y2R−/− cells. This indicates that the P2Y2 receptor may regulate osteoclast function indirectly by promoting ATP release. UTP and 2-thioUTP also stimulate ATP release from osteoblasts suggesting that the P2Y2 receptor exerts a similar function in these cells. Taken together, our findings are consistent with the notion that the primary action of P2Y2 receptor signalling in bone is to regulate extracellular ATP levels

Pyrophosphate: a key inhibitor of mineralisation

Inorganic pyrophosphate has long been known as a by-product of many intracellular biosynthetic reactions, and was first identified as a key endogenous inhibitor of biomineralisation in the 1960s. The major source of pyrophosphate appears to be extracellular ATP, which is released from cells in a controlled manner. Once released, ATP can be rapidly hydrolysed by ecto-nucleotide pyrophosphatase/phosphodiesterases to produce pyrophosphate. The main action of pyrophosphate is to directly inhibit hydroxyapatite formation thereby acting as a physiological 'water-softener'. Evidence suggests pyrophosphate may also act as a signalling molecule to influence gene expression and regulate its own production and breakdown. This review will summarise our current understanding of pyrophosphate metabolism and how it regulates bone mineralisation and prevents harmful soft tissue calcification

Stellar Hydrodynamics in Radiative Regions

We present an analysis of the response of a radiative region to waves generated by a convective region of the star; this wave treatment of the classical problem of ``overshooting'' gives extra mixing relative to the treatment traditionally used in stellar evolutionary codes. The interface between convectively stable and unstable regions is dynamic and nonspherical, so that the nonturbulent material is driven into motion, even in the absence of ``penetrative overshoot.'' These motions may be described by the theory of nonspherical stellar pulsations, and are related to motion measured by helioseismology. Multi-dimensional numerical simulations of convective flow show puzzling features which we explain by this simplified physical model. Gravity waves generated at the interface are dissipated, resulting in slow circulation and mixing seen outside the formal convection zone. The approach may be extended to deal with rotation and composition gradients. Tests of this description in the stellar evolution code TYCHO produce carbon stars on the asymptotic giant branch (AGB), an isochrone age for the Hyades and three young clusters with lithium depletion ages from brown dwarfs, and lithium and beryllium depletion consistent with observations of the Hyades and Pleiades, all without tuning parameters. The insight into the different contributions of rotational and hydrodynamic mixing processes could have important implications for realistic simulation of supernovae and other questions in stellar evolution.Comment: 27 pages, 5 figures, accepted to the Astrophysical Journa

Observational Tests and Predictive Stellar Evolution II: Non-standard Models

We examine contributions of second order physical processes to results of stellar evolution calculations amenable to direct observational testing. In the first paper in the series (Young et al. 2001) we established baseline results using only physics which are common to modern stellar evolution codes. In the current paper we establish how much of the discrepancy between observations and baseline models is due to particular elements of new physics. We then consider the impact of the observational uncertainties on the maximum predictive accuracy achievable by a stellar evolution code. The sun is an optimal case because of the precise and abundant observations and the relative simplicity of the underlying stellar physics. The Standard Model is capable of matching the structure of the sun as determined by helioseismology and gross surface observables to better than a percent. Given an initial mass and surface composition within the observational errors, and no additional constraints for which the models can be optimized, it is not possible to predict the sun's current state to better than ~7%. Convectively induced mixing in radiative regions, seen in multidimensional hydrodynamic simulations, dramatically improves the predictions for radii, luminosity, and apsidal motions of eclipsing binaries while simultaneously maintaining consistency with observed light element depletion and turnoff ages in young clusters (Young et al. 2003). Systematic errors in core size for models of massive binaries disappear with more complete mixing physics, and acceptable fits are achieved for all of the binaries without calibration of free parameters. The lack of accurate abundance determinations for binaries is now the main obstacle to improving stellar models using this type of test.Comment: 33 pages, 8 figures, accepted for publication in the Astrophysical Journa

Role Salience and Anticipated Work–Family Relations Among Young Adults With and Without Hearing Loss

This study examined the effect of hearing status on role salience and anticipated work–family relations among 101 unmarried young adults aged 20–33 years: 35 with hearing loss (19 hard of hearing and 16 deaf) and 66 hearing. Participants completed the Life Role Salience scale, anticipated conflictual relations scale, anticipated facilitory relations scale, and a background questionnaire. The deaf participants demonstrated a significantly higher level of commitment to work but anticipated the significantly lowest level of conflict. Hearing status was a significant variable in predicting anticipated conflictual relations among all participants. Mode of communication was a significant predictor of conflictual relations among the hearing loss group. Implications for theory and practice were discussed

Neutrino-driven Explosions

The question why and how core-collapse supernovae (SNe) explode is one of the central and most long-standing riddles of stellar astrophysics. A solution is crucial for deciphering the SN phenomenon, for predicting observable signals such as light curves and spectra, nucleosynthesis, neutrinos, and gravitational waves, for defining the role of SNe in the evolution of galaxies, and for explaining the birth conditions and properties of neutron stars (NSs) and stellar-mass black holes. Since the formation of such compact remnants releases over hundred times more energy in neutrinos than the SN in the explosion, neutrinos can be the decisive agents for powering the SN outburst. According to the standard paradigm of the neutrino-driven mechanism, the energy transfer by the intense neutrino flux to the medium behind the stagnating core-bounce shock, assisted by violent hydrodynamic mass motions (sometimes subsumed by the term "turbulence"), revives the outward shock motion and thus initiates the SN blast. Because of the weak coupling of neutrinos in the region of this energy deposition, detailed, multidimensional hydrodynamic models including neutrino transport and a wide variety of physics are needed to assess the viability of the mechanism. Owing to advanced numerical codes and increasing supercomputer power, considerable progress has been achieved in our understanding of the physical processes that have to act in concert for the success of neutrino-driven explosions. First studies begin to reveal observational implications and avenues to test the theoretical picture by data from individual SNe and SN remnants but also from population-integrated observables. While models will be further refined, a real breakthrough is expected through the next Galactic core-collapse SN, when neutrinos and gravitational waves can be used to probe the conditions deep inside the dying star. (abridged)Comment: Author version of chapter for 'Handbook of Supernovae,' edited by A. Alsabti and P. Murdin, Springer. 54 pages, 13 figure

Inclusive Masculinity and Facebook Photographs Among Early Emerging Adults at a British University

Central to debates about the construction of masculinity in sociology is the influence of culture and what constitutes acceptable displays of masculinity. This article adopts a novel approach in examining this question. It adopts a summative content analysis, combined with a semiotic analysis, of 1,100 Facebook photographs, in order to explore the underlying meanings within the photos and the performances of masculinity. Facebook photographs from 44, straight, White, male, early emerging adults attending the same university are used as a representation of an individual’s ideal self. These are then analyzed in order to determine the behaviors endorsed by peer culture. It was found that the sample overwhelmingly adopted inclusive behaviors (including homosocial tactility, dancing, and kissing each other), and inclusive masculinity theory was utilized to contextualize participants’ constructions of masculinity. Thus, this research shows that emerging adult males at this university construct their masculine identities away from previous orthodox archetypes. It is argued that the reducing importance of gendered behavior patterns may represent an adoption of what are perceived as wider cultural norms and act as a symbol of adulthood to these early emerging adults

Effective one-body approach to general relativistic two-body dynamics

We map the general relativistic two-body problem onto that of a test particle moving in an effective external metric. This effective-one-body approach defines, in a non-perturbative manner, the late dynamical evolution of a coalescing binary system of compact objects. The transition from the adiabatic inspiral, driven by gravitational radiation damping, to an unstable plunge, induced by strong spacetime curvature, is predicted to occur for orbits more tightly bound than the innermost stable circular orbit in a Schwarzschild metric of mass M = m1 + m2. The binding energy, angular momentum and orbital frequency of the innermost stable circular orbit for the time-symmetric two-body problem are determined as a function of the mass ratio.Comment: 52 pages, RevTex, epsfig, 8 figure