Expression Of ADAMTS2 Research Articles

Transcriptome Signatures for Cognitive Resilience Among Individuals with Pathologically Confirmed Alzheimer Disease.

Limited success to date in development of drugs that target hallmark Alzheimer disease (AD) proteins as a means to slow AD-related cognitive decline has sparked interest in approaches focused on cognitive resilience. We sought to identify transcriptome signatures among brain donors with neuropathologically confirmed AD that distinguish those with cognitive impairment from those that were cognitively intact. We compared gene expression patterns in brain tissue from donors in four cohorts who were cognitively and pathologically normal (controls), met clinical and pathological criteria for AD (SymAD), or were cognitively normal prior to death despite pathological evidence of AD (cognitively resilient or AsymAD). Differentially expressed genes (DEGs) at the transcriptome-wide significance (TWS) level (P<10 -6 ) in the total sample and nominally significant (P<0.05) in at least two datasets were further evaluated in analyses testing association of gene expression with co-calibrated and harmonized cognitive domain scores and AD-related neuropathological traits. We identified 52 TWS DEGs, including 14 that surpassed a significance threshold of P<5×10 -8 . The three most significant DEGs, ADAMTS2 (Log2 fold change [Log2FC]=0.46, P=2.94×10 -14 ), S100A4 (Log2FC=0.61, P=3.98×10 -11 ) and NRIP2 (Log2FC=0.32, P=9.52×10 -11 ) were up-regulated in SymAD compared to AsymAD brains. ADAMTS2 and SLC6A9 were also significantly and nominally differentially expressed between AsymAD cases and controls (FDR P=0.45 and FDR P=0.57, respectively). Significant associations (P<0.0038) were identified for executive function with expression of ADAMTS2 (P=4.15×10 -8 ) and ARSG (P=1.09×10 -3 ), and for memory with PRELP (P=3.92×10 -5 ) and EMP3 (P=7.75×10 -4 ), and for language with SLC38A2 (P=6.76×10 -5 ) and SLC6A9 (P=2.13 ×10 -3 ). Expression of ARSG and FHIP1B were associated with measures of Tau pathology (AT8: P=1.5×10 -3 , and pTau181: P=3.64×10 -3 , respectively), and SLC6A9 expression was associated with multiple pTau isoforms including pTau181 (P=1.5×10 -3 ) and pTau396 (P=2.05×10 -3 ). PRELP expression was associated with synaptic density (PSD.95: P=6.18 ×10 -6 ). DEGs were significantly enriched in pathways involving E2F targets, cholesterol homeostasis, and oxidative phosphorylation. We identified multiple DEGs that differentiate neuropathologically confirmed AD cases with and without cognitive impairment prior to death. Expression of several of these genes was also associated with measures of cognitive performance and AD-related neuropathological traits, thus providing important insights into cognitive resilience mechanisms and strategies for delaying clinical symptoms of AD.

Skeletal Class III Malocclusion Is Associated with ADAMTS2 Variants and Reduced Expression in a Familial Case.

Skeletal Class III malocclusion with maxillary deficiency is a severe maxillofacial disease with unclear pathogenic mechanisms. We recruited a Han Chinese family who was clinically diagnosed with skeletal Class III malocclusion and maxillary deficiency. Using whole exome sequencing, a missense variant in ADAMTS2 (NM_014244: c.3506G>T: p.G1169V) was identified and predicted as deleterious by in silico tools. We also found ADAMTS2 variants associated with deficient maxillary development in a cohort. ADAMTS2 expression in HEK293 cells showed significant decrease due to the variant, which was also consistent in dental pulp stem cells from the proband and a healthy control. In the adamts2-knockdown zebrafish model, the length and width of the ethmoid plate, as well as the length of the palatoquadrate became significantly shorter than the control group (p < 0.001), while there was no significant difference in the length and width of the mandible. The expression of Sox3, which was required in early embryonic craniofacial development, was significantly downregulated in the adamts2-knockdown zebrafish embryos. Bioinformatic and cellular studies showed that the decreased expression of ADAMTS2 may inhibit downstream ErbB signaling pathway transduction and restrain subsequent osteogenesis in human adult mesenchymal stromal cells. Collectively, these data showed that ADAMTS2 (c.3506G>T: p.G1169V) may confer susceptibility to risk of skeletal Class III malocclusion with maxillary deficiency.

Prognostic Values for the mRNA Expression of the ADAMTS Family of Genes in Gastric Cancer.

The “A Disintegrin and Metalloproteinase with Thrombospondin Motif” (ADAMTS) family of genes is involved in the occurrence and development of different cancers. However, the prognostic value of these genes in gastric cancer (GC) has not been revealed. The present study was thus conducted to determine the prognostic value for the ADAMTS family of genes in GC. First, we evaluated the mRNA expression levels of the ADAMTS family in GC patients using a GEPIA dataset. Thereafter, we determined the prognostic value of these genes by analyzing their mRNA level using the Kaplan–Meier Plotter database. The mRNA expression level of ADAMTS12 was randomly validated by qRT-PCR and meta-analysis while its coexpression genes were derived using Coexpedia. Finally, we performed Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses using the OmicShare Tools. Compared to normal tissues, expression of ADAMTS2 and 12 was significantly higher while that of ADAMTS1, 13, and 15 was significantly lower in GC tissues. According to the RNA-seq and gene chip data, the ADAMTS family (6, 7, 12, 15, and 18) of genes was closely related to the prognosis of GC, and their high expression levels were associated with poor prognosis and survival time. In addition, ADAMTS12 was highly expressed in 20 pairs of GC tissues based on RT-PCR (P=0.016) and meta-analysis (SMD: 0.73, 95% CI: 0.32–1.14, P < 0.001). GO and KEGG pathway analyses indicated that the ADAMTS12 coexpressed genes were enriched in the pathways of extracellular matrix organization, extracellular matrix structural constituent, extracellular matrix, and protein digestion and absorption. Herein, we discovered the prognostic values and biological roles of the ADAMTS genes in GC.

Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics

A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.

Overexpression of ADAMTS-2 in tumor cells and stroma is predictive of poor clinical prognosis in gastric cancer

ADAMTS-2 is a member of the ADAMTS family and is a procollagen N-proteinase. The objective of our research is to explore the prognostic significance of ADAMTS-2 in gastric carcinoma. A total of 655 samples with full clinicopathological data were investigated in this study. Tissue microarray immunohistochemistry analysis was used to analyze the relationship between clinicopathological characteristics and ADAMTS-2 expression. Oncomine and Kaplan-Meier plotters were performed for the relationship analysis between prognosis and ADAMTS-2 expression in patients with gastric cancer. Compared with that of normal tissues, the ADAMTS-2 protein expression was remarkably higher in gastric cancer cells and fibroblast cells. The results of univariate analysis indicated that the expression of ADAMTS-2 in tumor cells and fibroblast cells, Laurén classification, TNM grade, and carcinoembryonic antigen level in gastric cancer were all correlated with overall survival. The results of multivariate analysis indicated that the high expression of ADAMTS-2 in gastric cancer cells and fibroblast cells both were independent prognostic factors. Therefore, ADAMTS-2 may be a potential biomarker for assessing the prognosis of gastric carcinoma.

Expression of ADAMTS2 and ADAMTS5 in the salivary gland of rats after radioiodine therapy.

The aim of this study was to investigate the presence of ADAMTS2 and ADAMTS5 in the salivary gland (SG) of rats after high-dose radioiodine therapy. A total of 36 male Wistar albino rats were used for this study. Thirty-six male rats were divided randomly into six groups: control and five radioactive iodine (RAI) treatment groups of six rats each. All animals were killed. The evaluation of biodistribution and histopathological studies were carried out on the SGs removed. Real-time PCR and immunohistochemical analysis were carried out to determine mRNA and protein expression levels of ADAMTS genes. Differences between the groups were evaluated statistically. In RAI-treated groups, ADAMTS2 and ADAMTS5 gene expression was observed to increase, whereas there was no mRNA or protein expression in the control group. There were statistically significant increases in the mRNA expression of ADAMTS2 (all RAI-administered groups in parathyroid gland and at 4, 24, and 48 h in submandibular gland) and ADAMTS5 (all RAI-administered groups, except on the 30th day in the parathyroid gland and all RAI groups in submandibular gland). Through immunohistochemical analysis, the staining pattern in the extracellular source was also observed in the overexpressed ADAMTS2 and ADAMTS5 groups. Nuclear coarsening and partial focal subnuclei vacuolization were determined in all RAI-administered groups with histopathological examinations. An increase in the mRNA expression levels of ADAMTS2 and ADAMTS5 genes was detected in the RAI-administered groups. These results suggested that ADAMTS2 and ADAMTS5 genes might play a role in radiation exposure and radioiodine-induced SG changes.

Comparative analysis of gene expression in maternal peripheral blood and monocytes during spontaneous preterm labor

Preterm birth is the leading cause of newborn death worldwide, and is associated with significant cognitive and physiological challenges in later life. There is a pressing need to define the mechanisms that initiate spontaneous preterm labor, and for development of novel clinical biomarkers to identify high-risk pregnancies. Most preterm birth studies utilize fetal tissues, and there is limited understanding of the transcriptional changes that occur in mothers undergoing spontaneous preterm labor. Earlier work revealed that a specific population of maternal peripheral leukocytes (macrophages/monocytes) play an active role in the initiation of labor. Thus, we hypothesized that there are dynamic gene expression changes in maternal blood leukocytes during preterm labor. Using next-generation sequencing we aim to characterize the transcriptome in whole blood leukocytes and peripheral monocytes of women undergoing spontaneous preterm labor compared to healthy pregnant women who subsequently delivered at full term. RNA sequencing was performed in both whole blood and peripheral monocytes from women who underwent preterm labor (24-34 weeks of gestation, N= 20) matched for gestational age to healthy pregnant controls (N= 30). All participants were a part of the Ontario Birth Study cohort (Toronto, Ontario, Canada). We identified significant differences in expression of 262 genes in peripheral monocytes and 184 genes in whole blood of women who were in active spontaneous preterm labor compared to pregnant women of the same gestational age not undergoing labor, with 43 of these genes differentially expressed in both whole blood and peripheral monocytes. ADAMTS2 expression was significantly increased in women actively undergoing spontaneous preterm labor, which we validated through digital droplet reverse transcriptase polymerase chain reaction. Intriguingly, we have also identified a number of gene sets including signaling by stem cell factor-KIT, nucleotide metabolism, and trans-Golgi network vesicle budding, which exhibited changes in relative gene expression that was predictive of preterm labor status in both maternal whole blood and peripheral monocytes. This study is the first to investigate changes in both whole blood leukocytes and peripheral monocytes of women actively undergoing spontaneous preterm labor through robust transcript measurements from RNA sequencing. Our unique study design overcame confounding based on gestational age by collecting blood samples from women matched by gestational age, allowing us to study transcriptomic changes directly related to the active preterm parturition. We performed RNA profiling using whole genome sequencing, which is highly sensitive and allowed us to identify subtle changes in specific genes. ADAMTS2 expression emerged as a marker of prematurity within peripheral blood leukocytes, an accessible tissue that plays a functional role in signaling during the onset of labor. We identified changes in relative gene expression in a number of gene sets related to signaling in monocytes and whole blood of women undergoing spontaneous preterm labor compared to controls. These genes and pathways may help identify potential targets for the development of novel drugs for preterm birth prevention.

The relationships of collagen and ADAMTS2 expressionlevels with meat quality traits in cattle

Extracellular matrix (ECM) is the major macromolecule in skeletal muscle, and collagen is main component of ECM surrounding muscle fiber and adipocyte, which affect meat quality greatly. The remodeling of ECM is regulated by matrix metalloproteinases, such as ADAMTS2, which is essential for the maturation of triple helical collagen fibrils in body. The expression patterns of COL1A1, COL2A1, COL3A1 and ADAMTS2 in longissimus dorsi muscle were explored by qRT-PCR and results indicated that the expression levels of COL1A1, COL3A1 and ADAMTS2 were significantly higher at 3 and 24 month, while significantly lower at 12 and 30 month. The expression of ADAMTS2 and COL1A1 had significant positive relationships with intramuscular fat content, while expression of COL3A1 had significant positive relationship with shearing force and water holding capacity in cattle. The expression levels of collagen and ADAMTS2 were significantly higher in mesenteric fat, mammary fat pad and subcutaneous fat than in longissimus dorsi muscle, biceps femoris and infraspinitus tissues. The expressions levels of COL1A1, COL3A1 and ADAMTS2 were significantly lower in marbling fat than in other fat tissues. This study indicated that the expression of collagen and ADAMTS2 had important effects on postnatal skeletal muscle development and meat quality.

Induction of human ADAMTS-2 gene expression by IL-1α is mediated by a multiple crosstalk of MEK/JNK and PI3K pathways in osteoblast like cells

Up-regulation of ADAMTS genes with proinflammatory cytokines is important for some pathological conditions such as osteoarthritis (OA) that is a disease based on ECM degradation in cartilage. IL-1α is a proinflammatory cytokine and important both to normal and pathophysiologic conditions in cartilage and bone. Effects of some proinflammatory cytokines such as TNF-α and IL-1β on the some members of ADAMTS family have been investigated in some chondrocyte tissues or cell lines. However the effect of the IL-1α on the expression of ADAMTS-2 and ADAMTS-3 gene expression in osteoblast like cell lines, remains unclear. Therefore, the aim of this study is to investigate the effect of IL-1α on ADAMTS-2 and ADAMTS-3 gene expression in osteoblast like cells, Saos-2 and MG-63.The present study, for the first time, demonstrated that IL-1α increases ADAMTS-2 and ADAMTS-3 gene expressions in both Saos-2 and MG-63 cells. Having correlation to mRNA induction, the upregulation of ADAMTS-2,-3 protein levels by IL-1α stimulation is also observed. The inhibition studies showed that this upregulation occurred at the level of transcription, and there was no effect of IL-1α on ADAMTS-2 mRNA half-life in Saos-2 cells. Transactivation potential of IL-1α on ADAMTS-2 promoter was investigated by transient transfection assay. Specifically, IL-1α strongly increased −658/+112 and −530/+112 ADAMTS-2 promoter constructs. Further, we analyzed signaling pathways involved in ADAMTS-2 induction. Pathway inhibition studies revealed that this upregulation depends on the activation of MEK, JNK and PI3K pathways. These findings suggested that IL-1α is a strong positive regulator of ADAMTS-2 and ADAMTS-3 expression. These findings would provide novel insight into the pathophysiology of OA.

Gene Expression Profiling of Fibrous Dysplasia Reveals ADAMTS2 Overexpression as a Potential Marker

Fibrous dysplasia (FD) as an abnormal bone growth is one of the common fibro-osseous lesions (FOL) in oral and maxillofacial region; however, its etiology still remains unclear. Here, we performed gene expression profiling of FD using microarray analysis to explore the key molecule events in FD development, and develop potential diagnostic markers or therapeutic targets for FD. We found that 3,973 genes exhibited differential expression with more than twofold changes in FD compared with normal bone tissue, including 2,354 genes upregulated and 1,619 genes downregulated. Pathway analysis indicated that obviously overactivated pathways are ribosome and ECM-receptor interaction pathways; downregulated pathways are “Hepatitis C” and “cancer” signaling pathways. We further validated the expression of ADAMTS2, one of most differentiated expressed genes, by immunohistochemistry in 40 of the FD cases. We found that ADAMTS2 was significantly overexpressed in FD tissues, but rarely expressed in normal bone tissues, suggesting that ADAMTS2 could be a potential biomarker for FD. Thus, this study uncovered differentially expressed candidate genes in FD, which provides pilot data for understanding FD pathogenesis, and developing novel biomarkers for diagnosis and targeting of FD.

Expression of ADAMTS-2 and TGF-β1 in cirrhotic liver

To explore the expression and distribution of a disintegrin and metalloprotease with thrombospondin motif (ADAMTS)-2 and transforming growth factor (TGF) -β1 in patients with or without cirrhosis, and to determine their relation. The liver tissues from 16 patients with cirrhotic portal hypertensive and 8 patients with liver injury were collected in Wuhan General Hospital from March to June, 2010. Immunohistochemistry and Western blot were applied to detect the protein expression of ADAMTS-2 and TGF-β1. Immunohistochemistry showed that the expression of ADAMTS-2 and TGF-β1 was significantly higher in the cirrhotic tissues than that in normal tissues (P<0.05). Western blot also showed the expression of ADAMTS-2 and TGF-β1 in the cirrhosis tissues was significantly higher than that in normal tissues (P<0.05). There was a positive correlation between ADAMTS-2 and TGF-β1 (r=0.862, P<0.01). ADAMTS-2 and TGF-β1 may have a synergistic reaction in promoting liver cirrhosis.

Expression of ADAMTS-2, -3, -13, and -14 in culprit coronary lesions in patients with acute myocardial infarction or stable angina

ADAMTS (a disintegrin and metalloproteinase with thrombospondin type 1 motifs) proteases are emerging as key participants in the pathogenesis of vascular diseases. We studied the expression of ADAMTS-2, -3, -4 and -14 in the culprit plaques from patients presenting with acute myocardial infarction (AMI) versus stable angina. Tissue samples were gathered from 52 patients with AMI (n=35) or stable angina (n=17) who underwent directional coronary atherectomy. The specimens were stained with hematoxylin-eosin and analyzed immunohistochemically using antibodies specific to ADAMTS-2, -3, -13 and -14, and markers for endothelial cells, macrophages, and smooth muscle cells. Baseline characteristics of the groups were mostly similar. The proportion of smooth muscle α-actin-immunopositive area was smaller in the AMI group than in the stable angina group, but the areas immunopositive for CD31 or CD68 were higher in the AMI group. The relative areas immunopositive for ADAMTS-2, -3, and -13 in AMI were significantly larger than those in stable angina. However, the proportion of areas immunopositive for ADAMTS-14 did not differ between the two groups. Areas that stained for ADAMTS-2, -3, -13, and -14 largely overlapped with those positive for CD31 or CD68. The areas immunopositive for ADAMTS proteases were significantly correlated with CD31- or CD68-immunostained areas. In conclusions, ADAMTS-2, -3, and -13 expression, but not that of ADAMTS-14, are increased in plaques causing AMI compared those associated with stable angina. These results support a role for these enzymes in the pathogenesis of AMI.

Tissue-specific induction of ADAMTS2 in monocytes and macrophages by glucocorticoids

The regulated expression of ADAMTS2 (a disintegrin and metalloproteinase with thrombospondin motifs), a secreted metalloproteinase involved in the processing of procollagen to collagen, was studied in peripheral blood mononuclear cells (PBMC). Stimulation with glucocorticoids (GC) resulted in a pronounced dose- and time-dependent increase of ADAMTS2 mRNA levels in PBMC. The increase of ADAMTS2 expression was specific for CD14++ monocytes (440-fold) and alveolar macrophages (200-fold), whereas CD3+ (T lymphocytes), phytohemagglutinin-activated CD3+ (T lymphocytes), and CD19+ (B lymphocytes) showed no significant changes in ADAMTS2 mRNA after GC treatment. Treatment of monocyte-derived macrophages (MDM) with GC also resulted in an increase of ADAMTS2 protein in the culture tissue media. Using the GC analog RU486, GC-mediated induction of ADAMTS2 mRNA was blocked, implicating that GC acts specifically via the GC-receptor. In agreement with findings in blood monocytes, cell lines of the monocytic lineage (MM6, THP-1) showed significant GC-induced significant increases in ADAMTS2 mRNA, while in epithelial cells (A549, Calu-3, Colo320, BT-20) and fibroblast (MRC-5, WI-38, and two NHDF-c cell types from adult cheek and upper arm), they showed no or little responsiveness to GC. As macrophages have important functions in immune defense and tissue homeostasis, these findings suggest that GC-mediated specific induction of ADAMTS2 in these cells may play a crucial role in the resolution of inflammation and wound repair.