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In sturgeon aquaculture, oocyte maturation and ovulation are induced by the administration of hormones such as luteinizing hormone–releasing hormone analog (LHRHa). However, ovulation often fails to occur, probably as a result of inappropriate hormone injection timing. It is thus necessary to understand the molecular mechanisms of sturgeon ovulation responsible for producing good-quality eggs. In this study, we investigated the proteolytic genes and their inhibitory genes in a de novo transcriptome constructed using RNA samples of ovarian follicles from Amur sturgeon (Acipenser schrenckii). We subsequently identified 14 mmp, nine adam, ten adamts, nine cathepsins, and three timp contigs by a homology search with BLASTx. We compared the messenger RNA (mRNA) levels of these genes in the ovarian follicles of anovulated and ovulated Amur sturgeons using RNA sequencing and quantitative PCR analysis. The results showed that the mRNA levels of mmp16, adam23, adamts9, and timp2 were significantly increased by LHRHa injection only in ovulated sturgeons. We also examined the expression patterns in sterlet (Acipenser ruthenus) ovarian follicles in in vitro culture. adamts9 mRNA levels were drastically upregulated by the administration of 17α-hydroxyprogesterone, suggesting that Adamts9 is a key factor in successfully inducing ovulation in sturgeons. Clarifying the functions of these four genes during ovulation will lead to improved sturgeon seedling production technologies. [ABSTRACT FROM AUTHOR]

Atherosclerosis is an inflammatory disease of arterial stenosis caused by the imbalance of lipid metabolism and atherosclerotic plaques clustered on the arterial wall. It is the main pathological process of vascular diseases， such as stroke and coronary heart disease， etc. Atherosclerotic diseases yield high disability and death rates. Recent relevant studies have reported that ADAMTS9 is closely correlated with vascular pathophysiological processes. ADAMTS9 can degrade and assemble extracellular matrix， enhance vascular smooth muscle cell proliferation and migration， provoke pro-inflammatory response， promote intimal thickening， accelerate plaque rupture， and exert anti-angiogenesis effect. In this article， the role and mechanism of ADAMTS9 in the incidence and development of atherosclerosis were mainly summarized.

Abstract The lack of efficacious treatments for clear cell renal cell carcinoma (ccRCC) has led to a poor 5-year survival rate. Here, we found that the expression of ADAM metallopeptidase with thrombospondin type 1 motif 9 (ADAMTS9) antisense RNA 1 (ADAMTS9-AS1) is commonly decreased in ccRCC tissues. Decreased ADAMTS9-AS1 is associated with advanced stages and poor prognosis in ccRCC patients. Additionally, we found that promoter hypermethylation contributes to the suppression of ADAMTS9-AS1 expression in ccRCC that contained relatively low levels of ADAMTS9-AS1. Further functional studies demonstrated that ADAMTS9-AS1 inhibits cell growth and drug resistance through enhancing mRNA stability of ADAMTS9 in ccRCC. Mechanistically, ADAMTS9-AS1 directly bound to Human Antigen R (HuR). Then, the ADAMTS9-AS1-HuR complex was guided to the ADAMTS9 3’UTR through specific RNA–RNA interaction. Moreover, ADAMTS9-AS1 expression is positively correlated with ADAMTS9 expression in ccRCC tissues. In summary, our data not only highlight the important role of ADAMTS9-AS1 in ccRCC progression, but also reveal new regulatory mechanisms of ADAMTS9, which provides important insights into novel treatment strategies targeting ADAMTS9-AS1-HuR- ADAMTS9 axis in ccRCC.

Atherosclerosis is an inflammatory disease of arterial stenosis caused by the imbalance of lipid metabolism and atherosclerotic plaques clustered on the arterial wall. It is the main pathological process of vascular diseases, such as stroke and coronary heart disease, etc. Atherosclerotic diseases yield high disability and death rates. Recent relevant studies have reported that ADAMTS9 is closely correlated with vascular pathophysiological processes. ADAMTS9 can degrade and assemble extracellular matrix, enhance vascular smooth muscle cell proliferation and migration, provoke pro-inflammatory response, promote intimal thickening, accelerate plaque rupture, and exert anti-angiogenesis effect. In this article, the role and mechanism of ADAMTS9 in the incidence and development of atherosclerosis were mainly summarized. [ABSTRACT FROM AUTHOR]

The lack of efficacious treatments for clear cell renal cell carcinoma (ccRCC) has led to a poor 5-year survival rate. Here, we found that the expression of ADAM metallopeptidase with thrombospondin type 1 motif 9 (ADAMTS9) antisense RNA 1 (ADAMTS9-AS1) is commonly decreased in ccRCC tissues. Decreased ADAMTS9-AS1 is associated with advanced stages and poor prognosis in ccRCC patients. Additionally, we found that promoter hypermethylation contributes to the suppression of ADAMTS9-AS1 expression in ccRCC that contained relatively low levels of ADAMTS9-AS1. Further functional studies demonstrated that ADAMTS9-AS1 inhibits cell growth and drug resistance through enhancing mRNA stability of ADAMTS9 in ccRCC. Mechanistically, ADAMTS9-AS1 directly bound to Human Antigen R (HuR). Then, the ADAMTS9-AS1-HuR complex was guided to the ADAMTS9 3'UTR through specific RNA–RNA interaction. Moreover, ADAMTS9-AS1 expression is positively correlated with ADAMTS9 expression in ccRCC tissues. In summary, our data not only highlight the important role of ADAMTS9-AS1 in ccRCC progression, but also reveal new regulatory mechanisms of ADAMTS9, which provides important insights into novel treatment strategies targeting ADAMTS9-AS1-HuR- ADAMTS9 axis in ccRCC. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective: In this study, we aimed to evaluate subclinical atherosclerosis in patients with obesity who had cardiovascular disease risk indicators such as arterial stiffness, which is evaluated using pulse wave velocity (PWV), carotid intima-media thickness (CIMT), and biomarkers of endothelial dysfunction such as endocan, ADAMTS97, and ADAMTS9. Subjects and methods: Sixty obese subjects, including 23 subjects with body mass index (BMI) ≥ 40, 37 subjects with BMI ≥ 30 but < 40, and 60 age-and sex-matched control subjects, were included in our study. Serum endocan, ADAMTS97, and ADAMTS9 levels as well as PWV and CIMT measurements of the subjects in the obese and control groups were performed. Results: In the obesity group, PWV levels were significantly higher than they were in the control group and endocan levels were significantly lower than they were in the control group. When we compared the obese group with BMI ≥ 40 and the control group, the BMI ≥ 40 group had significantly higher PWV and CIMT levels than the control group had, whereas endocan, ADAMTS7, and ADAMTS9 levels were similar to those of the control group. When we compared the obese group with BMI ≥ 30 < 40 to the control group, endocan levels were lower in the group with BMI ≥ 30 < 40, and PWV and CIMT levels were similar to the control group. Conclusions: We found that arterial stiffness and CIMT increased in obese patients with BMI ≥ 40 and that increased arterial stiffness was associated with age, systolic blood pressure, and HBA1C. In addition, we found that the endocan levels were lower in obese patients than they were in nonobese control individuals.

IntroductionMutations in ADAMTS9 cause nephronophthisis-related ciliopathies (NPHP-RC), which are characterized by multiple developmental defects and kidney diseases. Patients with NPHP-RC usually have normal glomeruli and negligible or no proteinuria. Herein, we identified novel compound-heterozygous ADAMTS9 variants in two siblings with NPHP-RC who had glomerular manifestations, including proteinuria.MethodsTo investigate whether ADAMTS9 dysfunction causes NPHP and glomerulopathy, we differentiated ADAMTS9 knockout human induced pluripotent stem cells (hiPSCs) into kidney organoids. Single-cell RNA sequencing was utilized to elucidate the gene expression profiles from the ADAMTS9 knockout kidney organoids.ResultsADAMTS9 knockout had no effect on nephron differentiation; however, it reduced the number of primary cilia, thereby recapitulating renal ciliopathy. Single-cell transcriptomics revealed that podocyte clusters express the highest levels of ADAMTS9, followed by the proximal tubules. Loss of ADAMTS9 increased the activity of multiple signaling pathways, including the Wnt/PCP signaling pathway, in podocyte clusters.ConclusionsMutations in ADMATS9 cause a glomerulotubular nephropathy in kidney and our study provides insights into the functional roles of ADMATS9 in glomeruli and tubules.

Osteoarthritis (OA) is a type of common degenerative joint disorder, in which adipose mesenchymal stem cells (ADSCs) and the secreted exosomes play an important role. The purpose of this study was to investigate the role and mechanism of exosomes derived from ADSCs (ADSC-exos) in OA. The gradient of IL-1β concentration was designed to construct the articular chondrocyte model of arthritic mice. The expression of miR-93-5p and ADAMTS9 in articular chondrocytes was detected by reverse transcription quantitative polymerase chain reaction. Dual luciferase reporter gene assay was performed to verify the interaction between them. Monodansylcadaverine staining was used to visualize the autophagosome formation and cell apoptosis was analyzed by flow cytometry. ADSC-exos were authenticated by transmission electron microscope and western blot assay. miR-93-5p was found to be downregulated in IL-1β-treated articular chondrocytes compared with OA cartilage while ADAMTS9 was upregulated, which was identified as a direct target gene of miR93-5p. Silencing of ADAMTS9 attenuated the effects of miR-93-5p. Exosomal miR-93-5p can reduce the release of inflammatory factors in mouse arthritis cell models. This study first described the mechanism under that ADSCexos inhibited inflammation and alleviated OA through the innovative targets miR-93-5p/ADAMTS9 signal axis. This provided a new method for the treatment of OA. [ABSTRACT FROM AUTHOR]

Background: In this study, we aimed to investigate the mRNA expression levels of ADAMTS9 and ADAMTS15 in peripheral blood mononuclear cells (PBMCs) of psoriasis (PsO) and psoriatic arthritis (PsA) patients and the effects of TNF-α/MAPK and IL-1β/NFkB signaling pathways on the regulation of the expression of these genes. Materials and Methods: 15 PsO and 15 PsA patients and 15 healthy individuals (control) were included in the study. After PBMCs were isolated from venous blood, ADAMTS9 and ADAMTS15 mRNA expression levels were measured by Real-Time Quantitative PCR (RT-qPCR). Results: It was found that ADAMTS9 mRNA expression in PBMCs did not change between groups, while the level of ADAMTS15 mRNA expression increased significantly in the PsA group compared to the control and PsO groups. ADAMTS9 expression was observed not changed in the control and PsA groups in response to TNF-α stimulation, but decreased in the PsO group. However; TNF-α stimulation led to an increase in ADAMTS15 expression in the control group but did not change in the PsO and PsA groups. It has been revealed that the formation of TNF-α response and related changes in ADAMTS9 and ADAMTS15 expressions were regulated by MAP kinase genes (Erk1/2, p38 and JNK). ADAMTS9 expression was determined not affected by IL-1β stimulation, however; ADAMTS15 mRNA expression was decreased only in the PsA group. In addition, NFkB signaling molecule was involved in the formation of the IL-1β response and the regulation of ADAMTS15 expression. Conclusions: ADAMTS15 expression increased in PBMCs of PsA patients is regulated by the IL-1β/NFkB signaling pathway. An increase in ADAMTS15 mRNA expressin level may play a role in PsA pathogenesis. Furthermore, the expression level of ADAMTS15 has a potential to be used as an important biomarker in monitoring the risk of PsA development for PsO patients. [ABSTRACT FROM AUTHOR]

TMEM67 mutations are the major cause of Meckel-Gruber syndrome. TMEM67 is involved in both ciliary transition zone assembly, and non-canonical Wnt signaling mediated by its extracellular domain. How TMEM67 performs these two separate functions is not known. We identify a novel cleavage motif in the extracellular domain of TMEM67 cleaved by the extracellular matrix metalloproteinase ADAMTS9. This cleavage regulates the abundance of two functional forms: A C-terminal portion which localizes to the ciliary transition zone regulating ciliogenesis, and a non-cleaved form which regulates Wnt signaling. By characterizing three TMEM67 ciliopathy patient variants within the cleavage motif utilizing mammalian cell culture and C. elegans, we show the cleavage motif is essential for cilia structure and function, highlighting its clinical significance. We generated a novel non-cleavable TMEM67 mouse model which develop severe ciliopathies phenocopying Tmem67 -/- mice, but in contrast, undergo normal Wnt signaling, substantiating the existence of two functional forms of TMEM67.

The role of methyltransferase-like 3 (METTL3), which participates in catalyzing N-methyladenosine (m6A) RNA modification, in gastric cancer (GC) is unclear. Here, we found that METTL3 was overexpressed in human GC. Functionally, we verified that METTL3 promoted tumor cell proliferation and angiogenesis through a series of phenotypic experiments. Subsequently, ADAMTS9 was identified as the downstream effector of METTL3 in GC, which could be degraded by the YTHDF2-dependent pathway. Finally, the data suggested that METTL3 might facilitate GC progression through the ADAMTS9-mediated PI3K/AKT pathway. Our study unveiled the fundamental mechanisms of METTL3 in GC progression. The clinical value of METTL3 in GC deserves further exploration. [ABSTRACT FROM AUTHOR]

The role of methyltransferase-like 3 (METTL3), which participates in catalyzing N-methyladenosine (m6A) RNA modification, in gastric cancer (GC) is unclear. Here, we found that METTL3 was overexpressed in human GC. Functionally, we verified that METTL3 promoted tumor cell proliferation and angiogenesis through a series of phenotypic experiments. Subsequently, ADAMTS9 was identified as the downstream effector of METTL3 in GC, which could be degraded by the YTHDF2-dependent pathway. Finally, the data suggested that METTL3 might facilitate GC progression through the ADAMTS9-mediated PI3K/AKT pathway. Our study unveiled the fundamental mechanisms of METTL3 in GC progression. The clinical value of METTL3 in GC deserves further exploration.

Previous studies have suggested that adamts9 (a disintegrin and metalloprotease with thrombospondin type-1 motifs, member 9), an extracellular matrix (ECM) metalloprotease, participates in primordial germ cell (PGC) migration and is necessary for female fertility. In this study, we found that adamts9 knockout (KO) led to reduced body size, and female-to-male sex conversion in late juvenile or adult zebrafish; however, primary sex determination was not affected in early juveniles of adamts9 KO. Overfeeding and lowering the rearing density rescued growth defects in female adamts9 KO fish but did not rescue defects in ovarian development in adamts9 KO. Delayed PGC proliferation, significantly reduced number and size of Stage IB follicles (equivalent to primary follicles) in early juveniles of adamts9 KO, and arrested development at Stage IB follicles in mid- or late-juveniles of adamts9 KO are likely causes of female infertility and sex conversion. Via RNAseq, we found significant enrichment of differentially expressed genes involved in ECM organization during sexual maturation in ovaries of wildtype fish; and significant dysregulation of these genes in adamts9 KO ovaries. RNAseq analysis also showed enrichment of inflammatory transcriptomic signatures in adult ovaries of these adamts9 KO. Taken together, our results indicate that adamts9 is critical for development of primary ovarian follicles and maintenance of female sex, and loss of adamts9 leads to defects in ovarian follicle development, female infertility, and sex conversion in late juveniles and mature adults. These results show that the ECM and extracellular metalloproteases play major roles in maintaining ovarian follicle development in zebrafish., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Long non-coding RNAs (lncRNAs), as competitive endogenous RNAs (ceRNAs), play a critical role in biological processes of cancer. However, the roles of specific lncRNAs in ceRNA network of lung adenocarcinoma (LUAD) remains largely unclear. Herein, we identified the roles of lncRNA ADAMTS9-AS1/AS2 (ADAMTS-AS1/AS2) in lung adenocarcinoma by bioinformatics analyses and functional verification. First, differentially expressed genes ADAMTS9-AS1, ADAMTS9-AS2 and ADAMTS9 were screened out from GSE130779. Then the expression correlation of these three genes was analyzed. The results showed that ADAMTS9-AS1, ADAMTS9-AS2 and ADAMTS9 were down-regulated in LUAD, and were positively correlated with each other. After that, miRcode was used to find miR-150 which binds to ADAMTS9-AS1/ADAMTS9-AS2/ADAMTS9. Next, co-expression analysis and functional enrichment analyses were performed to further analyze differentially expressed genes. The results showed that the differentially expressed genes were mainly enriched in Beta3 integrin cell surface interactions and epithelial-to-mesenchymal transition. Finally, the cell functions of ADAMTS9-AS1 and ADAMTS9-AS2 in A549 and NCI-H1299 cell lines were verified. In vitro cell studies confirmed that ADAMTS9-AS1 and ADAMTS9-AS2 play an inhibitory role in LUAD cells.

Long non-coding RNAs (lncRNAs), as competitive endogenous RNAs (ceRNAs), play a critical role in biological processes of cancer. However, the roles of specific lncRNAs in ceRNA network of lung adenocarcinoma (LUAD) remains largely unclear. Herein, we identified the roles of lncRNA ADAMTS9-AS1/AS2 (ADAMTS-AS1/AS2) in lung adenocarcinoma by bioinformatics analyses and functional verification. First, differentially expressed genes ADAMTS9-AS1, ADAMTS9-AS2 and ADAMTS9 were screened out from GSE130779. Then the expression correlation of these three genes was analyzed. The results showed that ADAMTS9-AS1, ADAMTS9-AS2 and ADAMTS9 were down-regulated in LUAD, and were positively correlated with each other. After that, miRcode was used to find miR-150 which binds to ADAMTS9-AS1/ADAMTS9-AS2/ADAMTS9. Next, co-expression analysis and functional enrichment analyses were performed to further analyze differentially expressed genes. The results showed that the differentially expressed genes were mainly enriched in Beta3 integrin cell surface interactions and epithelial-to-mesenchymal transition. Finally, the cell functions of ADAMTS9-AS1 and ADAMTS9-AS2 in A549 and NCI-H1299 cell lines were verified. In vitro cell studies confirmed that ADAMTS9-AS1 and ADAMTS9-AS2 play an inhibitory role in LUAD cells. [ABSTRACT FROM AUTHOR]

Osteoarthritis is a progressive disease characterized by cartilage destruction in the joints. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) play key roles in osteoarthritis progression. In this study, we screened a chemical compound library to identify new drug candidates that target MMP and ADAMTS using a cytokine-stimulated OUMS-27 chondrosarcoma cells. By screening PCR-based mRNA expression, we selected 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide as a potential candidate. We found that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated IL-1β-induced MMP13 mRNA expression in a dose-dependent manner, without causing serious cytotoxicity. Signaling pathway analysis revealed that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated ERK- and p-38-phosphorylation as well as JNK phosphorylation. We then examined the additive effect of 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide in combination with low-dose betamethasone on IL-1β-stimulated cells. Combined treatment with 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide and betamethasone significantly attenuated MMP13 and ADAMTS9 mRNA expression. In conclusion, we identified a potential compound of interest that may help attenuate matrix-degrading enzymes in the early osteoarthritis-affected joints.

Background/aim: This study aims to identify the role of synovial fluid levels of a disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9) and a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) for the prediction of intraarticular steroid injection success in knee osteoarthritis (OA). Material and methods: A total of eighty-four advanced stage knee OA patients (42 with stage 3 OA and 42 with stage 4 OA) were enrolled in the study. Baseline and posttreatment outcomes were determined using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Pretreatment synovial fluid ADAMTS9 and ADAMTS4 levels were measured by enzyme linked immunosorbent assay (ELISA). ‘’Total WOMAC score regression of 18% and above’’ was taken as a minimal clinically important difference (MCID) to indicate improvement. Determining the best predictors of intraarticular steroid injection success in both groups was evaluated by multiple logistic regression analyses. Results: Synovial fluid ADAMTS9 levels were significantly lower in the stage 4 OA group when compared with the stage 3 group. The level of synovial fluid ADAMTS9 was statistically significantly lower in the WOMAC score percent change ≥18% than the WOMAC score percent change <18% group in Stage 3 OA group (P = 0.026). Decreasing synovial fluid ADAMTS9 levels (odds ratio (OR): 0.625, 95% confidence interval (CI): 0.437–0.893) were found to be predictive for the WOMAC score percent change ≥18 in all OA patients (P = 0.010). Decreasing ADAMTS9 levels in synovial fluid (OR: 0.602; 95% CI = 0.372–0.974) were predictive for MCID in stage 3 OA patients (P = 0.039). Conclusion: The lower levels of ADAMTS9 in synovial fluid may be used in conjunction with high WOMAC scores in the prediction of intraarticular steroid injection success and advanced stage knee OA patients. [ABSTRACT FROM AUTHOR]

Background/Aims: ADAMTS (disintegrin-like and metalloproteinase with thrombospondin motifs) proteins are extracellular zinc metalloproteinases that play an important role in extracellular matrix assembly and degradation, connective tissue structuring, angiogenesis, and cell migration. Multiple studies suggest that ADAMTS proteins (e.g. ADAMTS9) can act as tumor suppressors. In gastric, esophageal, and nasopharyngeal carcinomas ADAMTS9 is frequently down-regulated by promoter methylation. Whether ADAMTS9 can function as a tumor suppressor gene (TSG) in colorectal cancer is still unclear. Methods: We performed immunohistochemistry, RT-PCR, and qRT-PCR, to examine the expression of ADAMTS9 in colorectal cancer cell lines and primary colorectal cancer tissues. Methylation-specific PCR was also carried out to investigate the promoter methylation status of ADAMTS9. We also explored the functions of ADAMTS9 in colorectal cancer cell lines through in vitro experiments. Results: ADAMTS9 expression was down-requlated or silenced in 83.3% (5/6) of colorectal cancer cell lines, and frequently repressed in 65.6% (21/32) of colorectal cancer tissues. Down-regulation of ADAMTS9 was partially due to promoter methylation. Exogenous expression of ADAMTS9 in colorectal cancer cell lines inhibited cell proliferation and migration through the regulation of cell cycle and apoptosis. In addition, ADAMTS9 prevented the activation of Akt, and its downstream targets in colorectal cancer cell lines. Conclusion: Our findings suggest ADAMTS9 is a TSG in colorectal cancer.

• First established and characterized adult phenotypes of adamts9 knockout in vertebrates. • Male biased sexual development in adamts9−/−. • Female-like adamts9−/− had empty ovarian sac with well-developed spermatozoa. • Female adamts9−/− unable to ovulate. Expression of adamts9 (A disintegrin and metalloprotease with thrombospondin type-1 motif, member 9) increases dramatically in the somatic cells surrounding oocytes during ovulation in vertebrates from zebrafish to human. However, the function of Adamts9 during ovulation has not been determined due to the embryonic lethality of knockouts in mice and Drosophila. To identify the role of Adamts9 during ovulation we generated knockout (adamts9−/−) zebrafish using CRISPR/Cas9 and characterized the effects of the mutation. From 1047 fish generated by crossing adamts9+/− pairs, we found significantly fewer adult adamts9−/− fish (4%) than predicted by Mendelian ratios (25%). Of the mutants found, there was a significant male bias (82%). Only 3 female mutants were identified (7%), and they had small ovaries with few stage III and IV oocytes compared to wildtype (wt) counterparts of comparable size and age. Astoundingly, the remaining mutants (11%) did not appear to have normal testis or ovaries. Instead there was a pair of transparent, ovarian-like membranous shells that filled the abdominal cavity. Histological examination confirmed that shells were largely empty with no internal structure. Surprisingly, seminiferous tubules and various spermatocytes including mature spermatozoa were observed on the periphery of these transparent shells. No female or female like knockouts were observed to release eggs, and no ovulated oocytes were observed in histological sections. To our knowledge, this is the first report of an adamts9 global knockout model in any adult vertebrates and the first description of how gonadal sex and structure are affected- highlighting the importance of Adamts9 during gonadal development and the value of zebrafish as a model organism. [ABSTRACT FROM AUTHOR]

Ovulation requires proteinases to promote the rupture of ovarian follicles. However, the identity of these proteinases remains unclear. In our previous studies using RNA-seq analysis of differential expressed genes, we found significant down-regulation of five metalloproteinases: adam8b (a disintegrin and metalloproteinase domain 8b), adamts8a (a disintegrin and metalloproteinase with thrombospondin motif 8a), adamts9, mmp2 (matrix metalloproteinase 2), and mmp9 in the nuclear progestin receptor knockout (pgr−/−) zebrafish that have failed to ovulate. We hypothesize that these metalloproteinases are responsible for ovulation and are regulated by progestin and Pgr. In this study, we first determined the expression of these five metalloproteinases and adamts1 in preovulatory follicles at different times within the spawning cycle in pgr−/− and wildtype (wt) zebrafish and under varying hormonal treatments. We found that transcripts of adam8b, adamts1, adamts9, and mmp9 increased drastically in the preovulatory follicular cells of wt female zebrafish, while changes of adamts8a and mmp2 were not significant. This increase of adam8b, adamts9, and mmp9 was significantly reduced in pgr−/−, whereas expression of adamts1 was not affected in pgr−/− zebrafish. Among upregulated metalloproteinases, adamts9 mRNA was found to be expressed specifically in follicular cells. Strong immunostaining of Adamts9 protein was observed in the follicular cells of wt fish, and this expression was reduced drastically in pgr−/−. Interestingly, about an hour prior to the increase of metalloproteinases in wt fish, both Pgr transcript and protein increased transiently in preovulatory follicular cells. The results from in vitro experiments showed that adamts9 expression markedly increased in a dose, time and Pgr-dependent manner when preovulatory follicles were exposed to a progestin, 17α,20β-dihydroxy-4-pregnen-3-one (DHP). Taken together, our results provide the first evidence that upregulation of adamts9 occurs specifically in preovulatory follicular cells of zebrafish prior to ovulation. Progestin and its receptor (Pgr) are essential for the upregulation of metalloproteinases.

Ovulation requires proteinases to promote the rupture of ovarian follicles. However, the identity of these proteinases remains unclear. In our previous studies using RNA-seq analysis of differential expressed genes, we found significant down-regulation of five metalloproteinases: adam8b (a disintegrin and metalloproteinase domain 8b), adamts8a (a disintegrin and metalloproteinase with thrombospondin motif 8a), adamts9, mmp2 (matrix metalloproteinase 2), and mmp9 in the nuclear progestin receptor knockout (pgr −/−) zebrafish that have failed to ovulate. We hypothesize that these metalloproteinases are responsible for ovulation and are regulated by progestin and Pgr. In this study, we first determined the expression of these five metalloproteinases and adamts1 in preovulatory follicles at different times within the spawning cycle in pgr −/− and wildtype (wt) zebrafish and under varying hormonal treatments. We found that transcripts of adam8b, adamts1, adamts9 , and mmp9 increased drastically in the preovulatory follicular cells of wt female zebrafish, while changes of adamts8a and mmp2 were not significant. This increase of adam8b, adamts9 , and mmp9 was significantly reduced in pgr −/−, whereas expression of adamts1 was not affected in pgr −/− zebrafish. Among upregulated metalloproteinases, adamts9 mRNA was found to be expressed specifically in follicular cells. Strong immunostaining of Adamts9 protein was observed in the follicular cells of wt fish, and this expression was reduced drastically in pgr −/−. Interestingly, about an hour prior to the increase of metalloproteinases in wt fish, both Pgr transcript and protein increased transiently in preovulatory follicular cells. The results from in vitro experiments showed that adamts9 expression markedly increased in a dose, time and Pgr-dependent manner when preovulatory follicles were exposed to a progestin, 17α,20β-dihydroxy-4-pregnen-3-one (DHP). Taken together, our results provide the first evidence that upregulation of adamts9 occurs specifically in preovulatory follicular cells of zebrafish prior to ovulation. Progestin and its receptor (Pgr) are essential for the upregulation of metalloproteinases. [ABSTRACT FROM AUTHOR]

Extracellular matrix (ECM) remodeling by metalloproteinases is crucial during development. The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin type I motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling. The human family includes 19 members. In this study we identified the 19 members of the ADAMTS family in Xenopus laevis and Xenopus tropicalis . Gene identification and a phylogenetic study revealed strong conservation of the ADAMTS family and contributed to a better annotation of the Xenopus genomes. Expression of the entire ADAMTS family was studied from early stages to tadpole stages of Xenopus , and detailed analysis of ADAMTS9 revealed expression in many structures during organogenesis such as neural crest (NC) derivative tissues, the pronephros and the pancreas. Versican, a matrix component substrate of ADAMTS9 shows a similar expression pattern suggesting a role of ADAMTS9 in the remodeling of the ECM in these structures by degradation of versican. [ABSTRACT FROM AUTHOR]

Abstract: Chromosome region 3p12‐14 is an important tumour suppressor gene (TSG) locus for multiple cancers. ADAMTS9, a member of the metalloprotease large family, has been identified as a candidate 3p14.2 TSG inactivated by aberrant promoter CpG methylation in several carcinomas, but little known about its expression and function in breast cancer. In this report, ADAMTS9 expression and methylation was analysed in breast cancer cell lines and tissue samples. ADAMTS9 RNA was significantly down‐regulated in breast cancer cell lines (6/8). After treating the cells with demethylation agent Aza and TSA, ADAMTS9 expression was dramatically increased. Bisulphite genomic sequencing and methylation‐specific PCR detected promoter methylation, which was associated with decreased ADAMTS9 expression. Hypermethylation was also detected in 130/219 (59.4%) of primary tumours but only in 4.5% (2/44) of paired surgical margin tissues. Ectopic expression of ADAMTS9 in tumor cells induced significant growth suppression, cell cycle arrest at the G0/G1 phase, enhanced apoptosis and reduced cell migration and invasion. Conditioned culture medium from ADAMTS9‐transfected BT549 cells markedly disrupted tube formation ability of human umbilical vein endothelial cell (HUVEC) in Matrigel. Furthermore, ADAMTS9 inhibited AKT signaling and its downstream targets (MDM2, p53, p21, p27, E‐cadherin, VIM, SNAIL, VEGFA, NFκB‐p65 and MMP2). In addition, we demonstrated, for the first time, that ADAMTS9 inhibits AKT signaling, through suppressing its upstream activators EGFR and TGFβ1/TβR(I/II) in breast cancer cells. Our results suggest that ADAMTS9 is a TSG epigenetically inactivated in breast cancer, which functions through blocking EGFR‐ and TGFβ1/TβR(I/II)‐activated AKT signaling. [ABSTRACT FROM AUTHOR]

Background/Aims: ADAMTS (disintegrin-like and metalloproteinase with thrombospondin motifs) proteins are extracellular zinc metalloproteinases that play an important role in extracellular matrix assembly and degradation, connective tissue structuring, angiogenesis, and cell migration. Multiple studies suggest that ADAMTS proteins (e.g. ADAMTS9) can act as tumor suppressors. In gastric, esophageal, and nasopharyngeal carcinomas ADAMTS9 is frequently down-regulated by promoter methylation. Whether ADAMTS9 can function as a tumor suppressor gene (TSG) in colorectal cancer is still unclear. Methods: We performed immunohistochemistry, RT-PCR, and qRT-PCR, to examine the expression of ADAMTS9 in colorectal cancer cell lines and primary colorectal cancer tissues. Methylation-specific PCR was also carried out to investigate the promoter methylation status of ADAMTS9. We also explored the functions of ADAMTS9 in colorectal cancer cell lines through in vitro experiments. Results: ADAMTS9 expression was down-regulated or silenced in 83.3% (5/6) of colorectal cancer cell lines, and frequently repressed in 65.6% (21/32) of colorectal cancer tissues. Down-regulation of ADAMTS9 was partially due to promoter methylation. Exogenous expression of ADAMTS9 in colorectal cancer cell lines inhibited cell proliferation and migration through the regulation of cell cycle and apoptosis. In addition, ADAMTS9 prevented the activation of Akt, and its downstream targets in colorectal cancer cell lines. Conclusion: Our findings suggest ADAMTS9 is a TSG in colorectal cancer. [ABSTRACT FROM AUTHOR]

• Significant association of six coding variants across five genes have been identified in familial cases of Schizophrenia. • Glycosylation processes has been found to be involved using pathway analysis. • Novel association of ADAMTS9 gene has been demonstrated with Schizophrenia. • MD simulation study on ADAMTS9 variant revealed a damaging effect on structural stability of the protein. Schizophrenia is a complex neuropsychiatric disorder and heritability is as high as 80 % making it the most heritable mental disorder. Although GWAS has identified numerous variants, the pathophysiology is still elusive. Here, an attempt was made to identify genetic risk factors in familial cases of schizophrenia that are associated with a common causative pathway. To achieve this objective, exome sequencing was done in 4 familial cases and identified six unique coding variants in five genes. Among these genes, PIGQ gene has two pathogenic variants, one nonsense and in-frame deletion. One missense variant in GALNT16 and one in GALNT5 have variable damaging score, however, the other variants, in ADAMTS9 and in LTBP4 have the highest damaging score. Further analysis showed that the variant of LTBP4 was not present in the functional domain. The other missense variant in the ADAMTS9 gene was found to be significant and was present in the thrombospondin repeat motif, one of the important motifs. Detailed molecular dynamics simulation study on this variant showed a damaging effect on structural stability. Since, all these genes culminated into the glycosylation process, it was evident that an aberrant glycosylation process may be one of the risk factors. Although, extracellular matrix formation through glycosylation have been shown to be associated, the involvement of ADAMTS9 and PIGQ gene mediated glycosylation has not been reported. In this paper, a novel link between ADAMTS9 and PIGQ gene with schizophrenia have been reported. Therefore, this novel observation has contributed immensely to the existing knowledge on risk factor of Schizophrenia. [ABSTRACT FROM AUTHOR]

Orofacial clefts include cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP), which combined represent the largest group of craniofacial malformations in humans with an overall prevalence of one per 1,000 live births. Each of these birth defects shows strong familial aggregation, suggesting a major genetic component to their etiology. Genetic studies of orofacial clefts extend back centuries, but it has proven difficult to define any single etiologic mechanism because many genes appear to influence risk. Both linkage and association studies have identified several genes influencing risk, but these differ across families and across populations. Genome-wide association studies have identified almost two dozen different genes achieving genome-wide significance, and there are broad classes of ‘causal genes’ for orofacial clefts: a few genes strongly associated with risk and possibly directly responsible for Mendelian syndromes which include orofacial clefts as a key phenotypic feature of the syndrome, and multiple genes with modest individual effects on risk but capable of disrupting normal craniofacial development under the right circumstances (which may include exposure to environmental risk factors). Genomic sequencing studies are now underway which will no doubt reveal additional genes/regions where variants (sequence and structural) can play a role in controlling risk to orofacial clefts. The real challenge to medicine and public health is twofold: to identify specific genes and other etiologic factors in families with affected members and then to devise effective interventions for these different biological mechanisms controlling risk to complex and heterogeneous birth defects such as orofacial clefts.

Objective: In this study, we aimed to evaluate subclinical atherosclerosis in patients with obesity who had cardiovascular disease risk indicators such as arterial stiffness, which is evaluated using pulse wave velocity (PWV), carotid intima-media thickness (CIMT), and biomarkers of endothelial dysfunction such as endocan, ADAMTS97, and ADAMTS9., Subjects and Methods: Sixty obese subjects, including 23 subjects with body mass index (BMI) ≥ 40, 37 subjects with BMI ≥ 30 but < 40, and 60 age-and sex-matched control subjects, were included in our study. Serum endocan, ADAMTS97, and ADAMTS9 levels as well as PWV and CIMT measurements of the subjects in the obese and control groups were performed., Results: In the obesity group, PWV levels were significantly higher than they were in the control group and endocan levels were significantly lower than they were in the control group. When we compared the obese group with BMI ≥ 40 and the control group, the BMI ≥ 40 group had significantly higher PWV and CIMT levels than the control group had, whereas endocan, ADAMTS7, and ADAMTS9 levels were similar to those of the control group. When we compared the obese group with BMI ≥ 30 < 40 to the control group, endocan levels were lower in the group with BMI ≥30 < 40, and PWV and CIMT levels were similar to the control group., Conclusion: We found that arterial stiffness and CIMT increased in obese patients with BMI ≥ 40 and that increased arterial stiffness was associated with age, systolic blood pressure, and HBA1C. In addition, we found that the endocan levels were lower in obese patients than they were in nonobese control individuals.

Introduction: Mutations in ADAMTS9 cause nephronophthisis-related ciliopathies (NPHP-RC), which are characterized by multiple developmental defects and kidney diseases. Patients with NPHP-RC usually have normal glomeruli and negligible or no proteinuria. Herein, we identified novel compound-heterozygous ADAMTS9 variants in two siblings with NPHP-RC who had glomerular manifestations, including proteinuria., Methods: To investigate whether ADAMTS9 dysfunction causes NPHP and glomerulopathy, we differentiated ADAMTS9 knockout human induced pluripotent stem cells (hiPSCs) into kidney organoids. Single-cell RNA sequencing was utilized to elucidate the gene expression profiles from the ADAMTS9 knockout kidney organoids., Results: ADAMTS9 knockout had no effect on nephron differentiation; however, it reduced the number of primary cilia, thereby recapitulating renal ciliopathy. Single-cell transcriptomics revealed that podocyte clusters express the highest levels of ADAMTS9, followed by the proximal tubules. Loss of ADAMTS9 increased the activity of multiple signaling pathways, including the Wnt/PCP signaling pathway, in podocyte clusters., Conclusions: Mutations in ADMATS9 cause a glomerulotubular nephropathy in kidney and our study provides insights into the functional roles of ADMATS9 in glomeruli and tubules., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yu, Choi, Rim, Kim, Bekheirnia, Swartz, Dai, Gu, Lee, Nishinakamura, Hildebrandt, Bekheirnia and Gee.)

Protein O -fucosyltransferase 2 (POFUT2) adds O- linked fucose to Thrombospondin Type 1 Repeats (TSR) in 49 potential target proteins. Nearly half the POFUT2 targets belong to the A Disintegrin and Metalloprotease with ThromboSpondin type-1 motifs (ADAMTS) or ADAMTS-like family of proteins. Both the mouse Pofut2 RST434 gene trap allele and the Adamts9 knockout were reported to result in early embryonic lethality, suggesting that defects in Pofut2 mutant embryos could result from loss of O- fucosylation on ADAMTS9. To address this question, we compared the Pofut2 and Adamts9 knockout phenotypes and used Cre-mediated deletion of Pofut2 and Adamts9 to dissect the tissue-specific role of O- fucosylated ADAMTS9 during gastrulation. Disruption of Pofut2 using the knockout ( LoxP ) or gene trap ( RST434 ) allele, as well as deletion of Adamts9, resulted in disorganized epithelia (epiblast, extraembryonic ectoderm, and visceral endoderm) and blocked mesoderm formation during gastrulation. The similarity between Pofut2 and Adamts9 mutants suggested that disruption of ADAMTS9 function could be responsible for the gastrulation defects observed in Pofut2 mutants. Consistent with this prediction, CRISPR/Cas9 knockout of POFUT2 in HEK293T cells blocked secretion of ADAMTS9. We determined that Adamts9 was dynamically expressed during mouse gastrulation by trophoblast giant cells, parietal endoderm, the most proximal visceral endoderm adjacent to the ectoplacental cone, extraembryonic mesoderm, and anterior primitive streak. Conditional deletion of either Pofut2 or Adamts9 in the epiblast rescues the gastrulation defects, and identified a new role for O- fucosylated ADAMTS9 during morphogenesis of the amnion and axial mesendoderm. Combined, these results suggested that loss of ADAMTS9 function in the extra embryonic tissue is responsible for gastrulation defects in the Pofut2 knockout. We hypothesize that loss of ADAMTS9 function in the most proximal visceral endoderm leads to slippage of the visceral endoderm and altered characteristics of the extraembryonic ectoderm. Consequently, loss of input from the extraembryonic ectoderm and/or compression of the epiblast by Reichert's membrane blocks gastrulation. In the future, the Pofut2 and Adamts9 knockouts will be valuable tools for understanding how local changes in the properties of the extracellular matrix influence the organization of tissues during mammalian development. [ABSTRACT FROM AUTHOR]

Objective: Recent studies performed in the central nervous system highlight the pathophysiological relevance of A disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTS) genes and their protein products. The determination of alterations in expression profiles of ADAMTS family genes in Alzheimer's disease (AD) patients may contribute to the explanation of tissue pathology and also new ideas for remedial approaches for this incurable but preventable disease. Therefore, the goal of this study was to describe and identify the distribution, characteristics, and any changes in the expression, in other words, immunoreactivity, for aggrecanases (ADAMTS4, 5, 9, and 15) proteins in AD brain. Methods: Nine cases that were autopsied in the Council of Forensic Medicine, Bursa Morgue Department in 2013, were selected. All of the cases were sent for autopsy to the institution within 8 hours after death. At autopsy, tissue samples were obtained for histopathological examination of organs for determining the cause of death. Out of these, two cases were diagnosed with AD by neurologists when they were alive. Immunohistochemical staining was performed on the brain slides by using relevant primary and secondary antibodies against aggrecanase proteins. All images were acquired using a X200 objective of a microscope (Olympus BX53) and evaluated by the staining intensity using a semi-quantitative scoring system. Results: ADAMTS4 and 5 were slightly under-expressed in the brains from autopsied AD cases compared to those of control brains and suggested that extracellular matrix (ECM) degradation was not endorsed in AD brain. On the other hand, ADAMTS9 and 15 aggrecanases were not found to be expressed in correspondent brain sections of AD and control cases. Conclusion: The current study demonstrated that some aggrecanases were found to be under-expressed in AD brains. Additional studies in which all ADAMTS enzymes will be studied in terms of mRNA and protein levels are needed to understand the relative contributions of ADAMTS genes and proteins in AD brains. [ABSTRACT FROM AUTHOR]

The pathways involved in the regulation of a disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9) expression have not yet been elucidated. Therefore, the aim of this study was to investigate the involvement of nuclear factor- κB (NF- κB), mitogen activated protein kinases (MAPK) and Phosphatidylinositol 3-kinase (PI3 kinase) in ADAMTS9 gene regulation, with special focus on the involvement of NF- κB in IL-1 β-induced ADAMTS9 expression. The OUMS-27 chondrosarcoma cells were exposed to IL-1 β. They were pretreated with 20 μM PD98059 (specific inhibitor of p44/42 kinase), 10 μM SB203580 (specific inhibitor of p38 kinase), 20 μM SB600125 (MAPK inhibitor), and 1 μM Wortmannin and 10 μM LY294002 (specific inhibitors of PI3 kinase) for 30 min and subsequently incubated with IL-1 β. For the effects of NF- κB and I κB inhibitors, cells were pretreated with curcumin or BAY117085 for 30 min and subsequently incubated with IL-1 β. BAY117085 and different concentrations of curcumin were applied to the cells just after the first experiment to determine their concentration effect on ADAMTS9 gene expression. After total RNA was extracted, they were reversely transcribed with random primers and then real-time polymerase chain reaction (PCR) was performed on cDNA samples. There was a significant difference between control and stimulated cells in terms of ADAMTS9/ β-actin ratio. Wortmannin and LY294002 did not have any repressive effect on the OUMS-27 whereas SB203580 and SP600125 were found to decrease the expression of ADAMTS9 gene. BAY 117085 and curcumin, which are two NF- κB inhibitors, led to a decrease in the ratio of ADAMTS9/ β-actin. As a conclusion, the pathways MAPK and NF- κB were thought to be responsible pathways for the induction of ADAMTS9 gene. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We investigated cross-sectionally whether the type 2 diabetes (T2DM) risk alleles of rs1801282 ( PPARG2) and rs4607103 ( ADAMTS9) were associated with T2DM and/or insulin sensitivity (IS) and beta cell function (βF) in Italians without and with newly diagnosed T2DM. In 676 nondiabetic subjects (336 NGR and 340 IGR) from the GENFIEV study and in 597 patients from the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS), we (1) genotyped rs1801282 and rs4607103, (2) assessed βF by C-peptide/glucose modeling after OGTT, and (3) assessed IS by HOMA-IR in both studies and by euglycemic insulin clamp in VNDS only. Logistic, linear, and two-stage least squares regression analyses were used to test (a) genetic associations with T2DM and with pathophysiological phenotypes, (b) causal relationships of the latter ones with T2DM by a Mendelian randomization design. Both SNPs were associated with T2DM. The rs4607103 risk allele was associated to impaired βF ( p < 0.01) in the GENFIEV study and in both cohorts combined. The rs1801282 genotype was associated with IS both in the GENFIEV study ( p < 0.03) and in the VNDS ( p < 0.03), whereas rs4607103 did so in the VNDS only ( p = 0.01). In a Mendelian randomization design, both HOMA-IR (instrumental variables: rs1801282, rs4607103) and βF (instrumental variable: rs4607103) were related to T2DM ( p < 0.03-0.01 and p < 0.03, respectively). PPARG2 and ADAMTS9 variants are both associated with T2DM and with insulin resistance, whereas only ADAMTS9 may be related to βF. Thus, at least in Italians, they may be considered bona fide 'insulin resistance genes'. [ABSTRACT FROM AUTHOR]

Gastric cancer is believed to result in part from the accumulation of multiple genetic and epigenetic alterations leading to oncogene overexpression and tumor suppressor loss. Tumor suppressor genes are inactivated more frequently by promoter methylation than by mutation in gastric cancer. Identification of genes inactivated by promoter methylation is a powerful approach to discover novel tumor suppressor genes. We have previously identified tumor suppressor genes in gastric cancer by genome-wide methylation screening. The biological functions of these genes are related to cell adhesion, ubiquitination, transcription, p53 regulation and diverse signaling pathways. Some of the tumor suppressor genes are of particular clinical importance as they can be used as predictive biomarkers for early diagnosis or ongoing prognosis of gastric cancer. [ABSTRACT FROM AUTHOR]

AIM: To investigate the effects of hypericin which is obtained from the plant Hypericum perforatum on the expression and the regulation of ADAMTS8 and ADAMTS9 genes in MCF7 breast cancer cells and on the viability of these cells. MATERIALS AND METHODS: MCF7 cells were cultured and were separately exposed to 2, 10 and 50 µl/mL of hypericin. After 24 hours, RNA was isolated from these cells and converted to cDNA. The expression levels of ADAMTS8 and ADAMTS9 genes were evaluated using the Reverse Transcription Polymerase Chain Reaction. XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium- 5-carboxanilide, disodium salt) cell viability assay was used to determine cytotoxicity. RESULTS: ADAMTS9 expression in MCF7 cells were increased 1.8 and 3.6 fold with the use of 2 and 10 µl/mL of hypericin, respectively; and decreased 0.7 fold with the use of 50 µl/mL of hypericin. There was no significant change in the ADAMTS8 expression. Rapid cell death was observed in the cancer cells when hypericin was used at a dose of ≥ 50 µl/mL. CONCLUSIONS: The increase in ADAMTS9 expression can be a useful factor in the prevention of possible metastasis in breast cancer and for the occurrence of a tumor suppressive effect. Hypericin increases the expression of ADAMTS9, therefore, it may show its antitumoral and antiapoptotic effects by means of ADAMTS9. [ABSTRACT FROM AUTHOR]

A gene critical to esophageal cancer has been identified. Functional studies using microcell-mediated chromosome transfer of intact and truncated donor chromosomes 3 into an esophageal cancer cell line and nude mouse tumorigenicity assays were used to identify a 1.61 Mb tumor suppressive critical region (CR) mapping to chromosome 3p14.2. This CR is bounded by D3S1600 and D3S1285 microsatellite markers. One candidate tumor suppressor gene, ADAMTS9, maps to this CR. Further studies showed normal expression levels of this gene in tumor-suppressed microcell hybrids, levels that were much higher than observed in the recipient cells. Complete loss or downregulation of ADAMTS9 gene expression was found in 15 out of 16 esophageal carcinoma cell lines. Promoter hypermethylation was detected in the cell lines that do not express this gene. Re-expression of ADAMTS9 was observed after demethylation drug treatment, confirming that hypermethylation is involved in gene downregulation. Downregulation of ADAMTS9 was also found in 43.5 and 47.6% of primary esophageal tumor tissues from Hong Kong and from the high-risk region of Henan, respectively. Thus, this study identifies and provides functional evidence for a CR associated with tumor suppression on 3p14.2 and provides the first evidence that ADAMTS9, mapping to this region, may contribute to esophageal cancer development.Oncogene (2007) 26, 148–157. doi:10.1038/sj.onc.1209767; published online 26 June 2006 [ABSTRACT FROM AUTHOR]

Abstract: ADAMTS metalloproteases constitute a family of 19 secreted protein or proteoglycan processing enzymes. ADAMTS9 and its closest mammalian relative, ADAMTS20, are related to gon-1, a metalloprotease required for gonadal morphogenesis in Caenorhabditis elegans. Although expressed at generally low levels in embryonic subectodermal mesenchyme, ADAMTS20 is required for melanoblast colonization of skin. Mutations in Adamts20 cause Belted, one of several white spotting alleles in the mouse. In contrast to Adamts20, we previously showed by Northern blotting that Adamts9 was expressed highly throughout mouse development. Using RNA in situ hybridization, we determined the spatial and temporal regulation of Adamts9 during mouse embryogenesis. At 7.5 dpc Adamts9 is expressed in the allantois, trophoblast, parietal endoderm and decidual tissue. At 9.5 dpc it is expressed in head mesoderm and in the developing heart. From 11.5 to 12.5 dpc, Adamts9 is strongly expressed in posterior mesoderm, in the craniofacial region, ventral body wall and diaphragm. After 14.5 dpc, Adamts9 was highly expressed in the mesenchyme of developing lung, kidney, and mesentery. It is expressed during skeletogenesis, being present from 13.5 dpc in perichondrium, in the proliferation zone of growth plates after 15.5 dpc and it is highly expressed in newly formed bone. It is expressed in vascular endothelium and during formation of the pituitary and cochlea, but expression in the central nervous system is limited to the floor plate of the diencephalon, to the ventricular zone of the cerebral cortex and to the choroid plexus. [Copyright &y& Elsevier]

Objective: Cardiovascular complications such as cardiomyopathy and endothelial dysfunction, which are frequently seen in patients with acromegaly, are among the most important causes of morbidity and mortality. In this study, we aimed to investigate arterial stiffness, carotid intima-media thickness, endocan level, and A disintegrin and metalloproteinase with thrombospondin type I motif 9 level and their relationship with disease activity in patients with acromegaly with and without cardiovascular risk factors., Methods: A total of 60 patients with acromegaly-25 with active disease, 26 with well-controlled disease, and 9 with newly diagnosed disease-and 60 age-, sex-, and body mass index (BMI)-matched healthy control subjects were enrolled in this study. All the subjects' height, weight, BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose (FPG) level, insulin, hemoglobin A1C (HbA1C), C-reactive protein , lipid, endocan, A disintegrin and metalloproteinase with thrombospondin type I motif 9 levels, pulse wave velocity (PWV), and carotid intima-media thickness were measured., Results: The SBP, DBP, FPG level, HbA1C level, and PWV of the acromegaly group were higher than those of the control group. In patients with acromegaly with cardiovascular disease (CVD) risk factors, the PWV was higher than that in the control group, and in patients with acromegaly without CVD risk factors, the PWV was similar to that in the control group. In a correlation analysis, a positive correlation was found between PWV and age, BMI, SBP, DBP, FPG level, and HbA1C level in the acromegaly group., Conclusion: In our study, we found that arterial stiffness increased in patients with acromegaly with CVD risk factors and that increased arterial stiffness was associated with hemodynamic (SBP and DBP) and metabolic (BMI, FPG level, and HbA1C level) parameters., (Copyright © 2021 AACE. Published by Elsevier Inc. All rights reserved.)

Osteoarthritis is a progressive disease characterized by cartilage destruction in the joints. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) play key roles in osteoarthritis progression. In this study, we screened a chemical compound library to identify new drug candidates that target MMP and ADAMTS using a cytokine-stimulated OUMS-27 chondrosarcoma cells. By screening PCR-based mRNA expression, we selected 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide as a potential candidate. We found that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated IL-1β-induced MMP13 mRNA expression in a dose-dependent manner, without causing serious cytotoxicity. Signaling pathway analysis revealed that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated ERK- and p-38-phosphorylation as well as JNK phosphorylation. We then examined the additive effect of 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide in combination with low-dose betamethasone on IL-1β-stimulated cells. Combined treatment with 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide and betamethasone significantly attenuated MMP13 and ADAMTS9 mRNA expression. In conclusion, we identified a potential compound of interest that may help attenuate matrix-degrading enzymes in the early osteoarthritis-affected joints.

To investigate the role of thrombospondin motifs 9 (ADAMTS9) in preterm premature rupture of membranes (pPROM). ADAMTS9 levels were measured in amnion cells from 24 patients of different groups (preterm vs. full-term birth, with vs. without PROM). ADAMTS9 was suppressed in human amnioblasts to investigate its effects on embryonic membrane cells and inflammation-induced cell damage. Pregnant mouse models were used to assess whether inflammation regulates ADAMTS9 by upregulating TNF-α and IL-6, contributing to the preterm birth occurrence. We found that ADAMTS9 protein and gene expression levels significantly differed among various groups (pPROM > full-term PROM > preterm non-PROM > full-term non-PROM). After ADAMTS9 suppression in human amnioblast WISH cells, TNF-α- and IL-6-induced apoptosis was decreased. In addition, TNF-α, IL-6, and ADAMTS9 protein and gene expression levels were increased in the embryos of mice treated with LPS compared with controls. In agreement, the rate of preterm birth was higher in the LPS group compared with controls. Taken together, these in vitro and in vivo findings suggest that TNF-α and IL-6 secreted by macrophages during inflammation regulate ADAMTS9 and induce pPROM. • ADAMTS9 expression levels significantly differed：pPROM > full-term PROM > preterm non-PROM > full-term non-PROM. • After ADAMTS9 suppression in human amnioblast WISH cells, TNF-α and IL-6-induced apoptosis was decreased. • TNF-α, IL-6, and ADAMTS9 expression levels were increased in mice embryos treated with LPS. [ABSTRACT FROM AUTHOR]