ADAMTS proteases in cardiovascular physiology and disease

The a disintegrin-like and metalloproteinase with thrombospondin motif (ADAMTS) family comprises 19 proteases that regulate the structure and function of extracellular proteins in the extracellular matrix and blood. The best characterized cardiovascular role is that of ADAMTS-13 in blood. Moderately low ADAMTS-13 levels increase the risk of ischeamic stroke and very low levels (less than 10%) can cause thrombotic thrombocytopenic purpura (TTP). Recombinant ADAMTS-13 is currently in clinical trials for treatment of TTP. Recently, new cardiovascular roles for ADAMTS proteases have been discovered. Several ADAMTS family members are important in the development of blood vessels and the heart, especially the valves. A number of studies have also investigated the potential role of ADAMTS-1, -4 and -5 in cardiovascular disease. They cleave proteoglycans such as versican, which represent major structural components of the arteries. ADAMTS-7 and -8 are attracting considerable interest owing to their implication in atherosclerosis and pulmonary arterial hypertension, respectively. Mutations in the ADAMTS19 gene cause progressive heart valve disease and missense variants in ADAMTS6 are associated with cardiac conduction. In this review, we discuss in detail the evidence for these and other cardiovascular roles of ADAMTS family members, their proteolytic substrates and the potential molecular mechanisms involved.

Kelainan Matriks Ekstraseluler Agrekan pada Osteoarthritis

Abstrak Osteoarthritis (OA) merupakan penyakit sendi dengan prevalensi paling tinggi yang menyebabkan nyeri kronis dan disabilitas. Berbagai faktor antara lain faktor mekanik, biokimia dan faktor enzimatik berperan dalam perkembangan OA. Perkembangan OA dicirikan oleh degradasi berlebihan pada agrekan dalam matriks ekstraseluler tulang rawan sendi. Agrekan berfungsi menyediakan fleksibilitas, viskoelastisitas dan kompresibilitas jaringan. Struktur agrekan tidak konstan sepanjang hidup, namun mengalami perubahan yang disebabkan oleh aktivitas sintesis maupun degradasi. Degradasi agrekan merupakan penanda awal kerusakan tulang rawan sendi pada OA, yang diikuti oleh kerusakan kolagen tipe II. Sejauh ini mekanisme molekulernya belum diketahui pasti, sehingga diperlukan penelitian lebih lanjut mengenai mekanisme dan penyebab kerusakan agrekan. Tulisan ini merupakan suatu kajian naratif berdasarkan artikel dari jurnal nasional dan internasional yang bertujuan untuk memberikan informasi mengenai agrekan meliputi struktur, fungsi, dan faktor-faktor yang berperan pada perubahan struktur agrekan yang menginduksi terjadinya OA. Hasil kajian menunjukkan bahwa perubahan struktur agrekan erat kaitannya dengan perubahan fungsi mekanik tulang rawan sendi. Perubahan ini terjadi terutama karena degradasi yang disebabkan oleh aktivitas enzim, dari keluarga matriks metalloprotease (MMP) dan a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS). Dari kajian ini disimpulkan bahwa degradasi agrekan karena aktivitas enzim berperan penting dalam perkembangan OA, sehingga perlu dilakukan penelitian untuk mencari inhibitor enzim MMP dan ADAMTS sebagai agen terapeutik untuk menghambat perkembangan dan progresivitas OA. Kata kunci: osteoarthritis, matriks ektraseluler, agrekan, degradasi. Abstract Osteoarthritis (OA) is a joint disease with the highest prevalence and a major cause of chronic pain and disability. Many factors such as mechanical, biochemical, and enzymatic factors are involved in OA development. The development of OA is characterized by excessive degradation of aggrecan in the extracellular matrix of articular cartilage, which functions to provide flexibility, viscoelasticity, and tissue compressibility. The structure of aggrecan is not constant throughout life but undergoes changes caused by synthesis and degradation activities. Aggrecan degradation is an early marker of joint cartilage damage in OA, followed by type II collagen damage. However, the molecular mechanisms are not completely understood, so further research is needed on the mechanisms and causes of aggrecan damage. Here we provide a narrative review based on articles from national and international journals to describe the structure, function, and factors that contribute to the degradation of aggrecan. The results of the study show that changes in the structure of aggrecan are closely related to changes in the mechanical function of joint cartilage. This change occurs mainly due to degradation caused by enzyme activity, a family of matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS). The present study concludes that aggrecan degradation caused by enzyme activity was very crucial in the development of OA, it was needed to find MMP and ADAMTS inhibitors as a therapeutic agent to prevent the development and progression of OA. Keywords: osteoarthritis, extracellular matrix, aggrecan, degradation

Exosite inhibition of A Disintegrin And Metalloproteinase with Thrombospondin motif (ADAMTS)-5 by a glycoconjugated arylsulfonamide

ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Its aggrecanase activity has been directly linked to the etiology of osteoarthritis (OA), identifying ADAMTS-5 as a pharmaceutical target for OA treatment. However, most existing ADAMTS-5 inhibitors target its active site and therefore suffer from poor selectivity. Here, using a novel approach, we have designed a new class of sugar-based arylsulfonamide inhibitors, which are selective for ADAMTS-5 through binding to a previously unknown substrate-binding site (exosite). Docking calculations combined with molecular dynamics simulations demonstrated that our lead compound is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Targeted mutagenesis identified disintegrin-like domain residues K532 and K533 as an exosite which is critical for substrate recognition. Furthermore, we show that this exosite acts as major determinant for inhibitor binding and, therefore, can be targeted for development of selective ADAMTS-5 inhibitors.

Effect of Acute Myocardial Infarction on a Disintegrin and Metalloprotease with Thrombospondin Motif 13 and Von Willebrand Factor and Their Relationship with Markers of Inflammation

Objectives. Coagulation mechanisms and fibrinolytic assembly are important components role players of acute myocardial infarction (AMI) progression. Our study objective was to see the serial variations in the levels of Von Willebrand factor (VWF) and A Disintegrin and Metalloprotease with ThromboSpondin motif (ADAMTS13) over the course of AMI and to determine their relationship with the cardiovascular risk markers and the patient’s clinical characteristics. Methods. This project was done at the departments of Emergency Medicine, Physiology and Cardiac sciences of King Saud University Medical City. We studied ADAMTS13, VWF, fibrinogen, and CRP levels in 80 patients with AMI when patients were admitted; post AMI by 3-4 days and at follow-up of 3 months. We compared them with a control group consisting of 36 subjects. Results. AMI had significantly lower levels of ADAMTS13 at AMI and after 3-4 days; at follow-up the difference in levels was nonsignificant, when compared with controls. Similarly, VWF levels were significantly higher in AMI and remained high even at follow-up compared to control subjects. VWF/ADAMTS13 ratio was also significantly higher at AMI and 3-4 days while at follow-up difference was nonsignificant compared to control subjects. Regression analysis between hsCRP and ADAMTS13 showed an inverse relationship (r=0.376,p<0.01), while correlation with VWF was significantly positive (r=0.337,p<0.01). Conclusions. Increased levels of VWF and reduced levels of ADAMTS13 activity may contribute to the pathogenesis of acute myocardial infarction and might prove to be important mediators of AMI progression.

ADAM and ADAMTS Proteases in Hepatic Disorders

Proteolysis is an irreversible post-translational modification that regulates protein function and signal transduction. This includes remodelling of the extracellular matrix, release of membrane-bound cytokines and receptor ectodomains, as well as the initiation of intracellular signalling cues. Members of the adamalysin protease subfamily, in particular the ADAM (a disintegrin and metalloprotease) and ADAMTS (the ADAM containing thrombospondin motif) families, are involved in these processes. This review presents an overview of how ADAM and ADAMTS proteins are involved in liver physiology and pathophysiology.

Association of ADAMTS4 and ADAMTS5 polymorphisms with musculoskeletal degenerative diseases: a systematic review and meta-analysis

Objective: This meta-analysis and systematic review was performed with the aim of investigating the association between a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)4, AMDMTS5 polymorphisms and risk of musculoskeletal degenerative diseases.Methods: PubMed, EMBASE, ISI Web of Science, Wanfang and CNKI were searched from their inception until May 2018 to identify eligible studies. Data from individual studies were extracted using a standardized data collection sheet. The estimate of association between ADAMTS4, AMDMTS5 polymorphisms and risk of musculoskeletal degenerative diseases was expressed as odds ratio (OR) along with its related 95% confidence interval (95%CI) under an allelic model of inheritance. Meta-analysis was conducted using RevMan 5.3 software. Subgroup-analyses by ethnicity and type of diseases were performed.Results: Eight studies including ten cohorts were included in this meta-analysis. The meta-analyses results based on seven studies showed that rs226794 in ADAMTS5 gene was not associated with risk of musculoskeletal degenerative diseases (A vs. G: OR 1.07; 95%CI 0.97–1.19; P=0.16). Rs2830585 in ADAMTS5 was significantly associated with musculoskeletal degenerative diseases in only Asians (OR 1.41, 95%CI 1.18–1.68; P=0.0001), but not in Caucasians. Since only two of the collected studies referred to ADAMTS4, we did not perform meta-analysis for these comparisons.Conclusion: Taken together, rs226794 and rs2830585 in ADAMTS5 gene were not associated with musculoskeletal degenerative diseases in overall population, but there seemed to be an ethnicity-dependent effect of rs2830585 in the risk of musculoskeletal degenerative diseases. Insufficient evidence was found to support the association of other single nucleotide polymorphisms and musculoskeletal degenerative diseases.

Chondroitin 6-Sulfation Regulates Perineuronal Net Formation by Controlling the Stability of Aggrecan

Perineuronal nets (PNNs) are lattice-like extracellular matrix structures composed of chondroitin sulfate proteoglycans (CSPGs). The appearance of PNNs parallels the decline of neural plasticity, and disruption of PNNs reactivates neural plasticity in the adult brain. We previously reported that sulfation patterns of chondroitin sulfate (CS) chains on CSPGs influenced the formation of PNNs and neural plasticity. However, the mechanism of PNN formation regulated by CS sulfation remains unknown. Here we found that overexpression of chondroitin 6-sulfotransferase-1 (C6ST-1), which catalyzes 6-sulfation of CS chains, selectively decreased aggrecan, a major CSPG in PNNs, in the aged brain without affecting other PNN components. Both diffuse and PNN-associated aggrecans were reduced by overexpression of C6ST-1. C6ST-1 increased 6-sulfation in both the repeating disaccharide region and linkage region of CS chains. Overexpression of 6-sulfation primarily impaired accumulation of aggrecan in PNNs, whereas condensation of other PNN components was not affected. Finally, we found that increased 6-sulfation accelerated proteolysis of aggrecan by a disintegrin and metalloproteinase domain with thrombospondin motif (ADAMTS) protease. Taken together, our results indicate that sulfation patterns of CS chains on aggrecan influenced the stability of the CSPG, thereby regulating formation of PNNs and neural plasticity.