The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defects in certain family members give rise to inherited genetic disorders, while the aberrant expression or function of others is associated with arthritis, cancer and cardiovascular disease. In particular, ADAMTS4 and 5 have emerged as therapeutic targets in arthritis. Multiple ADAMTSs from different sub-groupings exert either positive or negative effects on tumorigenesis and metastasis, with both metalloproteinase-dependent and -independent actions known to occur. The basic ADAMTS structure comprises a metalloproteinase catalytic domain and a carboxy-terminal ancillary domain, the latter determining substrate specificity and the localization of the protease and its interaction partners; ancillary domains probably also have independent biological functions. Focusing primarily on the aggrecanases and proteoglycanases, this review provides a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future

PGF2α-F-prostanoid receptor signalling via ADAMTS1 modulates epithelial cell invasion and endothelial cell function in endometrial cancer

<p>Abstract</p> <p>Background</p> <p>An increase in cancer cell invasion and microvascular density is associated with a poorer prognosis for patients with endometrial cancer. In endometrial adenocarcinoma F-prostanoid (FP) receptor expression is elevated, along with its ligand prostaglandin (PG)F_2α, where it regulates expression and secretion of a host of growth factors and chemokines involved in tumorigenesis. This study investigates the expression, regulation and role of a disintegrin and metalloproteinase with thrombospondin repeat 1 (ADAMTS1) in endometrial adenocarcinoma cells by PGF_2αvia the FP receptor.</p> <p>Methods</p> <p>Human endometrium and adenocarcinoma tissues were obtained in accordance with Lothian Research Ethics Committee guidance with informed patient consent. Expression of ADAMTS1 mRNA and protein in tissues was determined by quantitative RT-PCR analysis and immunohistochemistry. Signal transduction pathways regulating ADAMTS1 expression in Ishikawa cells stably expressing the FP receptor to levels seen in endometrial cancer (FPS cells) were determined by quantitative RT-PCR analysis. In vitro invasion and proliferation assays were performed with FPS cells and human umbilical vein endothelial cells (HUVECs) using conditioned medium (CM) from PGF_2α-treated FPS cells from which ADAMTS1 was immunoneutralised and/or recombinant ADAMTS1. The role of endothelial ADAMTS1 in endothelial cell proliferation was confirmed with RNA interference. The data in this study were analysed by T-test or ANOVA.</p> <p>Results</p> <p>ADAMTS1 mRNA and protein expression is elevated in endometrial adenocarcinoma tissues compared with normal proliferative phase endometrium and is localised to the glandular and vascular cells. Using FPS cells, we show that PGF2α-FP signalling upregulates ADAMTS1 expression via a calmodulin-NFAT-dependent pathway and this promotes epithelial cell invasion through ECM and inhibits endothelial cell proliferation. Furthermore, we show that CM from FPS cells regulates endothelial cell ADAMTS1 expression in a rapid biphasic manner. Using RNA interference we show that endothelial cell ADAMTS1 also negatively regulates cellular proliferation.</p> <p>Conclusions</p> <p>These data demonstrate elevated ADAMTS1 expression in endometrial adenocarcinoma. Furthermore we have highlighted a mechanism whereby FP receptor signalling regulates epithelial cell invasion and endothelial cell function via the PGF_2α-FP receptor mediated induction of ADAMTS1.</p

Expression of VEGF and semaphorin genes define subgroups of triple negative breast cancer.

PMC3648524Triple negative breast cancers (TNBC) are difficult to treat due to a lack of targets and heterogeneity. Inhibition of angiogenesis is a promising therapeutic strategy, but has had limited effectiveness so far in breast cancer. To quantify heterogeneity in angiogenesis-related gene expression in breast cancer, we focused on two families--VEGFs and semaphorins--that compete for neuropilin co-receptors on endothelial cells. We compiled microarray data for over 2,600 patient tumor samples and analyzed the expression of VEGF- and semaphorin-related ligands and receptors. We used principal component analysis to identify patterns of gene expression, and clustering to group samples according to these patterns. We used available survival data to determine whether these clusters had prognostic as well as therapeutic relevance. TNBC was highly associated with dysregulation of VEGF- and semaphorin-related genes; in particular, it appeared that expression of both VEGF and semaphorin genes were altered in a pro-angiogenesis direction. A pattern of high VEGFA expression with low expression of secreted semaphorins was associated with 60% of triple-negative breast tumors. While all TNBC groups demonstrated poor prognosis, this signature also correlated with lower 5-year survival rates in non-TNBC samples. A second TNBC pattern, including high VEGFC expression, was also identified. These pro-angiogenesis signatures may identify cancers that are more susceptible to VEGF inhibition.JH Libraries Open Access Fun

Personal attributes as determinants of timely care in rheumatoid arthritis

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EULAR evidence‐based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases

Objective: To develop evidence-based recommendations for the management of systemic glucocorticoid ( GC) therapy in rheumatic diseases. Methods: The multidisciplinary guideline development group from 11 European countries, Canada and the USA consisted of 15 rheumatologists, 1 internist, 1 rheumatologist-epidemiologist, 1 health professional, 1 patient and 1 research fellow. The Delphi method was used to agree on 10 key propositions related to the safe use of GCs. A systematic literature search of PUBMED, EMBASE, CINAHL, and Cochrane Library was then used to identify the best available research evidence to support each of the 10 propositions. The strength of recommendation was given according to research evidence, clinical expertise and perceived patient preference. Results: The 10 propositions were generated through three Delphi rounds and included patient education, risk factors, adverse effects, concomitant therapy ( ie, non-steroidal anti-inflammatory drugs, gastroprotection and cyclo-oxygenase-2 selective inhibitors, calcium and vitamin D, bisphosphonates) and special safety advice ( ie, adrenal insufficiency, pregnancy, growth impairment). Conclusion: Ten key recommendations for the management of systemic GC-therapy were formulated using a combination of systematically retrieved research evidence and expert consensus. There are areas of importance that have little evidence ( ie, dosing and tapering strategies, timing, risk factors and monitoring for adverse effects, perioperative GC-replacement) and need further research; therefore also a research agenda was composed

The Biology of the Presenilin Complexes

APP proteolytic processing Alzheimer's Disease (AD) is characterized by the deposition of two kinds of abnormal protein aggregates, senile plaques and neurofibrillary tangles, and by neuronal dysfunction and cell loss in the brain. Senile plaques are primarily composed of extracellular deposits of hydrophobic 37-43 amino acid Aβ peptides. Aβ peptides are derived by successive enzymatic cleavages of the type I membrane protein, β-amyloid precursor protein (APP) (Haass and Selkoe 1993). APP is first cleaved close to the membrane in the extracellular domain by either α-or β-secretase, resulting in a release of soluble APP ectodomains, and residual membrane-tethered C-terminal protein stubs, termed C83 or C99, respectively (The numbers indicate the length of each carboxylterminal fragment). C83 and C99 are substrates for γ-secretase, an activity that generates p3 and Aβ peptides, respectively. γ-Secretase processes substrates at different positions within the membrane domain and thus, both Aβ and p3 have "ragged" termini. Aβ has been best studied in this regard and species between 37 and 43 amino acid residues have been identified. γ-Secretase cleavage of APP also releases the intracellular carboxy-terminal "APP intracellular domain" or "AICD". The function of both Aβ and AICD is the subject of intense investigations. Because Aβ42 is the primary constituent of the amyloid fibrils deposited in the AD brains, and mutations in APP and presenilin enhance the production of this peptide, γ-secretase cleavage of APP is a pivotal step in AD pathogenesis. It is striking that this proteolytic reaction occurs within the highly hydrophobic environment of the membrane. Identification of presenilin Genetic studies in familial AD (FAD) cases have identified disease-linked mutations in three genes that contribute to AD. The first pathogenic mutations in early-onset FAD families were found in the APP gene on chromosome 21 (Chartier-Harlin et al. 1991; Goate et al. 1991; Murrell et al. 1991). However, subsequent studies indicated that mutations in APP account only for a small fraction of FAD cases. Several genetic studies indicated a major locus for FAD on chromosome 14 in early onset autosomal dominant AD, and in 1995, the Presenilin1 (PS1) gene on chromosome 14 (14q24.3) was identified by positional cloning (Sherrington et al. 1995). Shortly thereafter, it was shown that mutations in the closely related PS2 gene on chromosome 1 (1q42.2) could cause FAD as well (Levy-Lahad et al. 1995; Rogaev et al. 1995). Studies in transgenic mice (Borchelt et al. 1996; Duff et al. 1996) and cultured cells (Citron et al. 1997; Scheuner et al. 1996; Tomita et al. 1997) have revealed that expression of FAD-linked PS variants elevates Aβ42/Aβ40 ratios. Moreover, transgenic mice that co-express FAD-mutant PS1 and APP develop amyloid plaques much earlier than age-matched mutant APP mice (Borchelt et al. 1997). Therefore, PS mutations cause a change in the Aβ42/40 ratio, but whether PS is directly involved in γ-secretase processing of APP was unclear. However, in PS-deficient neurons and fibroblasts, APP processing was greatly impaired, leading to the accumulation of the C83 and C99 APP fragments, the direct substrates of γ-secretase, and inhibition of Aβ (and p3) generation (De Strooper et al. 1998; Xia et al. 1998). Thus, PS are directly required for γ-secretase cleavage of APP. Overall, the findings imply that mutations in the substrate (APP) or in the proteolytic machinery (PS) result in similar changes in Aβ42 generation (Scheuner et al. 1996). This provides very strong support for the "amyloid cascade hypothesis". © 2007 Springer Science+Business Media, LLC. All rights reserved