A model of inflammatory arthritis highlights a role for oncostatin M in pro-inflammatory cytokine-induced bone destruction via RANK/RANKL

Oncostatin M is a pro-inflammatory cytokine previously shown to promote marked cartilage destruction both in vitro and in vivo when in combination with IL-1 or tumour necrosis factor alpha. However, the in vivo effects of these potent cytokine combinations on bone catabolism are unknown. Using adenoviral gene transfer, we have overexpressed oncostatin M in combination with either IL-1 or tumour necrosis factor alpha intra-articularly in the knees of C57BL/6 mice. Both of these combinations induced marked bone damage and markedly increased tartrate-resistant acid phosphatase-positive multinucleate cell staining in the synovium and at the front of bone erosions. Furthermore, there was increased expression of RANK and its ligand RANKL in the inflammatory cells, in inflamed synovium and in articular cartilage of knee joints treated with the cytokine combinations compared with expression in joints treated with the cytokines alone or the control. This model of inflammatory arthritis demonstrates that, in vivo, oncostatin M in combination with either IL-1 or tumour necrosis factor alpha represents cytokine combinations that promote bone destruction. The model also provides further evidence that increased osteoclast-like, tartrate-resistant acid phosphatase-positive staining multinucleate cells and upregulation of RANK/RANKL in joint tissues are key factors in pathological bone destruction

Metalloproteinase and inhibitor expression profiling of resorbing cartilage reveals pro-collagenase activation as a critical step for collagenolysis

Excess proteolysis of the extracellular matrix (ECM) of articular cartilage is a key characteristic of arthritis. The main enzymes involved belong to the metalloproteinase family, specifically the matrix metalloproteinases (MMPs) and a group of proteinases with a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS). Chondrocytes are the only cell type embedded in the cartilage ECM, and cell-matrix interactions can influence gene expression and cell behaviour. Thus, although the use of monolayer cultures can be informative, it is essential to study chondrocytes encapsulated within their native environment, cartilage, to fully assess cellular responses. The aim of this study was to profile the temporal gene expression of metalloproteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), reversion-inducing cysteine-rich protein with Kazal motifs (RECK), and α(2)-macroglobulin (α(2)M), in actively resorbing cartilage. The addition of the pro-inflammatory cytokine combination of interleukin-1 (IL-1) + oncostatin M (OSM) to bovine nasal cartilage induces the synthesis and subsequent activation of pro-metalloproteinases, leading to cartilage resorption. We show that IL-1+OSM upregulated the expression of MMP-1, -2, -3, -9, 12, -13, -14, TIMP-1, and ADAMTS-4, -5, and -9. Differences in basal expression and the magnitude of induction were observed, whilst there was no significant modulation of TIMP-2, -3, RECK, or ADAMTS-15 gene expression. IL-1+OSM downregulated MMP-16,TIMP-4, and α(2)M expression. All IL-1+OSM-induced metalloproteinases showed marked upregulation early in the culture period, whilst inhibitor expression was reduced throughout the stimulation period such that metalloproteinase production would be in excess of inhibitors. Moreover, although pro-collagenases were upregulated and synthesized early (by day 5), collagenolysis became apparent later with the presence of active collagenases (day 10) when inhibitor levels were low. These findings indicate that the activation cascades for pro-collagenases are delayed relative to collagenase expression, further confirm the coordinated regulation of metalloproteinases in actively resorbing cartilage, and support the use of bovine nasal cartilage as a model system to study the mechanisms that promote cartilage degradation

Defining and Exploring Animal Sentience

One of the commentaries on the target article notes that animal sentience is difficult to define operationally. This response to the commentaries develops a working, usable definition of animal sentience and examines the relationships between animal emotions and sentience

A z=5.34 Galaxy Pair in the Hubble Deep Field

We present spectrograms of the faint V-drop (V(606) = 28.1, I(814) = 25.6) galaxy pair HDF3-951.1 and HDF3-951.2 obtained at the Keck II Telescope. Fernandez-Soto, Lanzetta, & Yahil (1998) derive a photometric redshift of z(ph) = 5.28 (+0.34,-0.41; 2 sigma) for these galaxies; our integrated spectrograms show a large and abrupt discontinuity near 7710 (+- 5) Angstroms. This break is almost certainly due to the Lyman alpha forest as its amplitude (1 - fnu(short) / fnu(long) > 0.87; 95% confidence limit) exceeds any discontinuities observed in stellar or galaxian rest-frame optical spectra. The resulting absorption-break redshift is z=5.34 (+- 0.01). Optical/near-IR photometry from the HDF yields an exceptionally red (V(606)-I(814)) color, consistent with this large break. A more accurate measure of the continuum depression blueward of Lyman alpha utilizing the imaging photometry yields D(A) = 0.88. The system as a whole is slightly brighter than L*(1500) relative to the z~3 Lyman break population and the total star formation rate inferred from the UV continuum is ~22 h(50)^-2 M(sun) yr^-1 (q(0) = 0.5) assuming the absence of dust extinction. The two individual galaxies are quite small (size scales < 1 h(50)^-1 kpc). Thus these galaxies superficially resemble the Pascarelle etal (1996) ``building blocks''; if they comprise a gravitationally bound system, the pair will likely merge in a time scale ~100 Myr.Comment: 18 pages, 4 figures; accepted to A

High-resolution evidence for dynamic transitional geomagnetic field behaviour from a Miocene reversal, McMurdo Sound, Ross Sea, Antarctica

We report a high-resolution record of a Miocene polarity transition (probably the Chron C6r-C6n transition) from glacimarine sediments in McMurdo Sound, Ross Sea, Antarctica, which is the first transition record reported from high southern latitudes. The transition is recorded in two parallel cores through a 10.7 m stratigraphic thickness. The sediments are interpreted as having been deposited in a marine environment under the influence of floating ice or seaward of a glacier terminus from which a large sediment load was delivered to the drill site. The core was recovered using rotary drilling, which precludes azimuthal orientation of the core and determination of a vector record of the field during the transition. However, constraints on transitional field behaviour are provided by the exceptional resolution of this record. Large-scale paleomagnetic inclination fluctuations in the two cores can be independently correlated with each other using magnetic susceptibility data, which suggests that the sediments are reliable recorders of geomagnetic field variations. Agreement between the two parallel transition records provides evidence for highly dynamic field behaviour, as suggested by numerous large-scale inclination changes (∼90◦) throughout the transition. These large-scale changes occur across stratigraphically narrow intervals, which is consistent with the suggestion of rapid field changes during transitions. In one intact portion of the core, where there is no apparent relative core rotation between samples, declinations and inclinations are consistent with the presence of a stable cluster of virtual geomagnetic poles within the transition (although the possibility that this cluster represents a rapid depositional event cannot be precluded). These observations are consistent with those from other high-resolution records and provide a rare detailed view of transitional field behaviour compared to most sedimentary records, which are not as thick and which appear to have been smoothed by sedimentary remanence acquisition processes

Systems biology reveals how altered TGF beta signalling with age reduces protection against pro-inflammatory stimuli

<div><p>Osteoarthritis (OA) is a degenerative condition caused by dysregulation of multiple molecular signalling pathways. Such dysregulation results in damage to cartilage, a smooth and protective tissue that enables low friction articulation of synovial joints. Matrix metalloproteinases (MMPs), especially MMP-13, are key enzymes in the cleavage of type II collagen which is a vital component for cartilage integrity. Transforming growth factor beta (TGFβ) can protect against pro-inflammatory cytokine-mediated MMP expression. With age there is a change in the ratio of two TGFβ type I receptors (Alk1/Alk5), a shift that results in TGFβ losing its protective role in cartilage homeostasis. Instead, TGFβ promotes cartilage degradation which correlates with the spontaneous development of OA in murine models. However, the mechanism by which TGFβ protects against pro-inflammatory responses and how this changes with age has not been extensively studied. As TGFβ signalling is complex, we used systems biology to combine experimental and computational outputs to examine how the system changes with age. Experiments showed that the repressive effect of TGFβ on chondrocytes treated with a pro-inflammatory stimulus required Alk5. Computational modelling revealed two independent mechanisms were needed to explain the crosstalk between TGFβ and pro-inflammatory signalling pathways. A novel meta-analysis of microarray data from OA patient tissue was used to create a Cytoscape network representative of human OA and revealed the importance of inflammation. Combining the modelled genes with the microarray network provided a global overview into the crosstalk between the different signalling pathways involved in OA development. Our results provide further insights into the mechanisms that cause TGFβ signalling to change from a protective to a detrimental pathway in cartilage with ageing. Moreover, such a systems biology approach may enable restoration of the protective role of TGFβ as a potential therapy to prevent age-related loss of cartilage and the development of OA.</p></div

Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology

Objective Proteinase-activated receptor 2 (PAR2) deficiency protects against cartilage degradation in experimental osteoarthritis (OA). The wider impact of this pathway upon OA-associated pathologies such as osteophyte formation and pain is unknown. Herein, we investigated early temporal bone and cartilage changes in experimental OA in order to further elucidate the role of PAR2 in OA pathogenesis. Methods OA was induced in wild-type (WT) and PAR2-deficient (PAR2−/−) mice by destabilisation of the medial meniscus (DMM). Inflammation, cartilage degradation and bone changes were monitored using histology and microCT. In gene rescue experiments, PAR2−/− mice were intra-articularly injected with human PAR2 (hPAR2)-expressing adenovirus. Dynamic weight bearing was used as a surrogate of OA-related pain. Results Osteophytes formed within 7 days post-DMM in WT mice but osteosclerosis was only evident from 14 days post induction. Importantly, PAR2 was expressed in the proliferative/hypertrophic chondrocytes present within osteophytes. In PAR2−/− mice, osteophytes developed significantly less frequently but, when present, were smaller and of greater density; no osteosclerosis was observed in these mice up to day 28. The pattern of weight bearing was altered in PAR2−/− mice, suggesting reduced pain perception. The expression of hPAR2 in PAR2−/− mice recapitulated osteophyte formation and cartilage damage similar to that observed in WT mice. However, osteosclerosis was absent, consistent with lack of hPAR2 expression in subchondral bone. Conclusions This study clearly demonstrates PAR2 plays a critical role, via chondrocytes, in osteophyte development and subchondral bone changes, which occur prior to PAR2-mediated cartilage damage. The latter likely occurs independently of OA-related bone changes

The Sloan Digital Sky Survey: The Cosmic Spectrum and Star-Formation History

We present a determination of the `Cosmic Optical Spectrum' of the Universe, i.e. the ensemble emission from galaxies, as determined from the red-selected Sloan Digital Sky Survey main galaxy sample and compare with previous results of the blue-selected 2dF Galaxy Redshift Survey. Broadly we find good agreement in both the spectrum and the derived star-formation histories. If we use a power-law star-formation history model where star-formation rate $\propto (1+z)^\beta$ out to z=1, then we find that $\beta$ of 2 to 3 is still the most likely model and there is no evidence for current surveys missing large amounts of star formation at high redshift. In particular `Fossil Cosmology' of the local universe gives measures of star-formation history which are consistent with direct observations at high redshift. Using the photometry of SDSS we are able to derive the cosmic spectrum in absolute units (i.e.$W \AA$^{-1}$Mpc$^{-3}$) at 2--5\AA resolution and find good agreement with published broad-band luminosity densities. For a Salpeter IMF the best fit stellar mass/light ratio is 3.7--7.5$\Msun/\Lsun$in the r-band (corresponding to$\omstars h = 0.0025$--0.0055) and from both the stellar emission history and the H$\alpha$luminosity density independently we find a cosmological star-formation rate of 0.03--0.04 h$\Msun$yr$^{-1}$Mpc$^{-3}$ today.Comment: 17 pages, 11 figures, ApJ in press (April 10th 2003

Differential expression, function and response to inflammatory stimuli of 11β-hydroxysteroid dehydrogenase type 1 in human fibroblasts: a mechanism for tissue-specific regulation of inflammation

Stromal cells such as fibroblasts play an important role in defining tissue-specific responses during the resolution of inflammation. We hypothesized that this involves tissue-specific regulation of glucocorticoids, mediated via differential regulation of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Expression, activity and function of 11β-HSD1 was assessed in matched fibroblasts derived from various tissues (synovium, bone marrow and skin) obtained from patients with rheumatoid arthritis or osteoarthritis. 11β-HSD1 was expressed in fibroblasts from all tissues but mRNA levels and enzyme activity were higher in synovial fibroblasts (2-fold and 13-fold higher mRNA levels in dermal and synovial fibroblasts, respectively, relative to bone marrow). Expression and activity of the enzyme increased in all fibroblasts following treatment with tumour necrosis factor-α or IL-1β (bone marrow: 8-fold and 37-fold, respectively, compared to vehicle; dermal fibroblasts: 4-fold and 14-fold; synovial fibroblasts: 7-fold and 31-fold; all P < 0.01 compared with vehicle). Treatment with IL-4 or interferon-γ was without effect, and there was no difference in 11β-HSD1 expression between fibroblasts (from any site) obtained from patients with rheumatoid arthritis or osteoarthritis. In the presence of 100 nmol/l cortisone, IL-6 production – a characteristic feature of synovial derived fibroblasts – was significantly reduced in synovial but not dermal or bone marrow fibroblasts. This was prevented by co-treatment with an 11β-HSD inhibitor, emphasizing the potential for autocrine activation of glucocorticoids in synovial fibroblasts. These data indicate that differences in fibroblast-derived glucocorticoid production (via the enzyme 11β-HSD1) between cells from distinct anatomical locations may play a key role in the predeliction of certain tissues to develop persistent inflammation