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Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4 . LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans. Carotid intima-media thickness (cIMT) and plaque are associated with subclinical atherosclerosis and coronary heart disease (CHD). Here, the authors identify and prioritize genetic loci for cIMT and plaque by GWAS and colocalization approaches and further demonstrate genetic correlation with CHD and stroke.

Although hundreds of cytosolic or transmembrane molecules form the primary cilium, few secreted molecules are known to contribute to ciliogenesis. Here, homologous secreted metalloproteases ADAMTS9 and ADAMTS20 are identified as ciliogenesis regulators that act intracellularly. Secreted and furin-processed ADAMTS9 bound heparan sulfate and was internalized by LRP1, LRP2 and clathrin-mediated endocytosis to be gathered in Rab11 vesicles with a unique periciliary localization defined by super-resolution microscopy. CRISPR-Cas9 inactivation of ADAMTS9 impaired ciliogenesis in RPE-1 cells, which was restored by catalytically active ADAMTS9 or ADAMTS20 acting in trans , but not by their proteolytically inactive mutants. Their mutagenesis in mice impaired neural and yolk sac ciliogenesis, leading to morphogenetic anomalies resulting from impaired hedgehog signaling, which is transduced by primary cilia. In addition to their cognate extracellular proteolytic activity, ADAMTS9 and ADAMTS20 thus have an additional proteolytic role intracellularly, revealing an unexpected regulatory dimension in ciliogenesis. Ciliogenesis is a complex process requiring hundreds of molecules, although few secreted proteins have been implicated. Here, the authors show that the secreted metalloproteases ADAMTS9 and ADAMTS20 intracellularly regulate ciliogenesis from unique periciliary vesicles with proteolytic activity.

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. Summary Sentence Arrested primary ovarian follicles and female to male sex conversion in Adamts9 KO zebrafish are due to dysregulation of extracellular matrix. Graphical Abstract

TMEM67 mutations cause Meckel-Gruber syndrome and other related ciliopathies. 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 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 non-cleavable TMEM67 mouse model which develop severe ciliopathies phenocopying Tmem67 -/- mice, but in contrast, transduces normal Wnt signaling, substantiating the existence of two functional forms of TMEM67. How Meckel-Gruber syndrome protein TMEM67 functions in ciliogenesis and Wnt signaling simultaneously is unknown. Here the authors show that TMEM67 is proteolytically cleaved by the matrix metalloproteinase ADAMTS9 generating two functional isoforms.

Background Preterm prelabor rupture of membranes (pPROM) is a leading cause of neonatal morbidity and mortality. While intra-amniotic infection is a well-established driver of pPROM, the role of sterile intra-amniotic inflammation remains unclear. Recent evidence suggests that interleukin-1 beta (IL-1β) promotes extracellular matrix (ECM) remodeling via downstream effectors, a disintegrin-like and metalloproteinase domain with thrombospondin type 1 motif 9 (ADAMTS9), while protein O-fucosyltransferase 2 (POFUT2) facilitates its O-fucosylation and secretion, amplifying ECM degradation. This study investigates how IL-1β-triggered nuclear factor kappa-B (NF-κB) activation promotes ADAMTS9 and POFUT2 expression, ultimately driving fetal membrane ECM remodeling and weakening in pPROM without signs of intra-amniotic infection. Methods A nested case-control study included maternal serum and fetal membrane samples from 60 pregnant women (34 pPROM, 26 full-term births [FTB]). ELISA measured serum levels of IL-1β and ADAMTS9, and their correlations were analyzed. Mechanistic studies utilized primary human amniotic epithelial cells (hAECs) and fetal membrane-decidua explants with IL-1β treatment. The role of NF-κB was explored using chromatin immunoprecipitation (ChIP) and luciferase assays to assess NF-κB binding to the promoters of ADAMTS9 and POFUT2. A murine model of sterile intra-amniotic inflammation under ultrasound-guided IL-1β injection was used to validate in vitro findings and assess pregnancy outcomes. Results Serum IL-1β and ADAMTS9 levels at 16 weeks of gestation were significantly higher in pPROM cases compared to FTB controls ( P  < 0.001). A combined model of these biomarkers demonstrated high predictive accuracy for pPROM (AUC = 0.83). Mechanistically, IL-1β activated NF-κB, leading to its binding to the promoters of ADAMTS9 and POFUT2. NF-κB activation promoted ADAMTS9 expression, while POFUT2 enhanced its secretion. Together, these processes drove versican degradation and ECM weakening. Intra-amniotic administration of IL-1β in mice induced fetal membrane weakening, preterm birth, and adverse neonatal outcomes, which were mitigated by the NF-κB inhibitor BAY 11-7082 treatment. Conclusion Maternal serum ADAMTS9 levels at mid-gestation are promising non-invasive biomarkers for pPROM risk stratification. Mechanistically, IL-1β-induced NF-κB activation promotes ADAMTS9 expression and POFUT2-dependent secretion, contributing to fetal membrane weakening. These findings provide new insights into the role and potential therapeutic target for sterile intra-amniotic inflammation in pPROM.

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.

Ischemic stroke is a common disease threatening human health. ADAMTS9-AS2 is a lncRNA that has been widely studied in tumors, but not in ischemic stroke. The purpose of this study was to investigate the role and potential molecular mechanism of ADAMTS9-AS2 in endothelial cell function after ischemic stroke in vivo and in vitro. The results showed that ADAMTS9-AS2 was decreased in the plasma of acute ischemic stroke (AIS) patients and in the brain tissue and plasma of MCAO mice, and the low expression of ADAMTS9-AS2 was associated with the increase in infarct size. Besides, compared with the control group, MCAO treatment slightly promoted angiogenesis, which was enhanced by the overexpression of ADAMTS9-AS2. Molecular mechanism results indicated that ADAMTS9-AS2 and miR-185-5p affected the pathological process of ischemic stroke through ceRNA mechanism, and IGFBP-2 was a downstream target gene of miR-185-5p. These findings demonstrated that ADAMTS9-AS2 promoted angiogenesis through regulating miR-185-5p/IGFBP-2 axis, suggesting that ADAMTS9-AS2 may be a potential marker for the diagnosis and treatment of neurological diseases.

Glioma is a malignancy of the central nervous system with a poor prognosis. Therefore, the elaboration of its molecular features creates therapeutic opportunities. Looking for the regulatory non-coding RNAs (lncRNAs and miRNAs) that are involved in glioma incidence/progression, RNA-seq analysis introduced upregulated ADAMTS9-AS1 as a bona fide candidate that sponges miR-128 and miR-150 and shows the negative correlation of expression with them. Then, RT-qPCR verified the upregulation of ADAMTS9-AS1 in glioma tissues and cell lines. Furthermore, dual-luciferase assay supported that cytoplasmic ADAMTS9-AS1 is capable of sponging miR-128 and miR-150, which are known as regulators of Ras/MAPK, PI3K, and Wnt pathways. Following the overexpression of ADAMTS9-AS1 in 1321N1 and U87 glioma cells, tyrosine kinase receptors (IGF1R and TrkC), as well as Wnt receptors (Lrp6 and Fzd) were upregulated, detected by RT-qPCR. Furthermore, downstream genes of both Ras/MAPK and Wnt pathways were upregulated. Finally following the ADAMTS9-AS1 overexpression, upregulation of Ras/MAPK and Wnt signaling pathways was verified through western blotting and Top/Fop flash assay, respectively. At the cellular level, ADAMTS9-AS1 overexpression brought about reduced sub-G1 cell population, increased proliferation rate, reduced apoptosis level, increased migration rate, shortened Bax/Bcl2 ratio, induced EMT, and stemness characteristics of transfected cells, detected by flow cytometry, MTT assay, scratch test, and RT-qPCR. Overall, these results introduced ADAMTS9-AS1 as an oncogene that upregulates Ras/MAPK and Wnt pathways through sponging of the miR-128 and miR-150 in glioma cells. The outcome of ADAMTS9-AS1 expression is more aggression of the glioma cells through increased EMT and stemness characteristics. These features candidate ADAMTS9 - AS1 locus for glioma therapy. Graphical Abstract As a result, we discovered the oncogenic properties of ADAMTS9-AS1 in glioma cancer. It sponges miR-128 and miR-150 and subsequently overstimulates RAS/MAPK and Wnt signaling pathways, particularly at the receptors level. Thus, ADAMTS9-AS1 increases proliferation, migration, and stemness in glioma cell lines. A schematic representation showing the functional effect of ADAMTS9-AS1

Background Laryngeal squamous cell carcinoma (LSCC) is recognized as the second most common malignant tumor of the respiratory tract. The study aimed to identify the roles of FOXO1, hsa-miR-96-5p, and lncRNA ADAMTS9-AS2 in the molecular pathogenesis of LSCC patients based on the systems biology data. Methods The LSCC patient tissue samples ( n  = 50) and the same individual’s adjacent normal tissues ( n  = 50) were collected from the candidates (aged 57.75 ± 9.3 years) of surgery. The miR-96-5p and lncRNA ADAMTS9-AS2 were predicted using the specific servers. The Kaplan Meier analysis was employed using TCGA data. The FOXO1and ncRNA gene expression levels were measured with the RT-qPCR technique. The Western blot technique was applied to estimate FOXO1/pFOXO1 protein values. Results A FOXO1/miR-96-5p/ADAMTS9-AS2 gene network was constructed and enriched using the bioinformatics data. The FOXO1 (p 0.037) correlated with ADAMTS9-AS2 (p 0.04) gene expression levels and was reduced in the LSCC patient tissue samples despite the elevated miR-96-5p expression levels (p 0.047). Moreover, the FOXO1 ( p  < 0.01) and pFOXO1 ( p  < 0.0001) protein values were reduced in the LSCC. The high FOXO1 and ADAMTS9-AS2 gene expression levels significantly increased the survival probability (HR 0.61 and 0.65, respectively). Conclusion The FOXO1 and ADAMTS9-AS2 genes might act as molecular suppressors in the cell growth pathways. Furthermore, miR-96-5p is suggested as an oncogenic miRNA in the LSCC.

Alterations in the methylation of genetic material can influence carcinogenesis by the downregulation or overexpression of ADAMTS (a disintegrin-like and metalloprotease with thrombospondin motifs) protease genes. Through their proteolytic activity, these enzymes are also capable of promoting angiogenesis. Consequently, ADAMTS proteases can either facilitate or inhibit cancer progression. This study aimed to evaluate the methylation levels of the ADAMTS6, ADAMTS9, and ADAMTS12 genes in non-small-cell lung cancer (NSCLC) using data from bioinformatics databases. The focus was on differences between lung adenocarcinoma (LUAD) and lung squamous-cell carcinoma (LUSC) subtypes and their impact on patient overall survival (OS). ADAMTS6 gene expression is significantly reduced in LUSC, and analysis of ADAMTS9 gene expression showed a significantly reduced gene transcript level in LUAD and LUSC, while both NSCLC subtypes demonstrated ADAMTS12 upregulation. In LUSC, significantly elevated promoter methylation was found in all of the aforementioned genes, while in LUAD, higher promoter methylation was observed only for ADAMTS9 and ADAMTS12. The differential methylation region (DMR) pattern demonstrated by ADAMTS6, ADAMTS9, and ADAMTS12 is a useful tool for distinguishing normal from cancer cells. The areas under the curve (AUCs) ranged from 0.86 to 0.99 for both LUAD and LUSC subtypes. The methylation level of different CpG sites among selected ADAMTS members is related to patient survival, suggesting it may have value as a prognostic marker. The methylation degree of promoter regions in genes encoding ADAMTS family proteins could significantly influence LUSC and LUAD. Increased promoter methylation could also reduce certain gene expression, contributing to cancer progression. The expression levels and specific DMRs of ADAMTS genes may serve as prognostic markers correlating with patient OS. Assessing ADAMTS gene methylation could become a diagnostic tool for differentiating NSCLC subtypes and potentially guide therapeutic strategies. Further research is needed to fully understand the activity and mechanisms of ADAMTS family proteins.