Diverse Functions of a Disintegrin and Metalloproteinase with Thrombospondin Motif-1

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

Download Full-text

Diagnostic relevance of ADAMTS13 activity: Evaluation of 28 patients with thrombotic thrombocytopenic purpura - hemolytic uremic syndrome clinical diagnosis

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh1308466v ◽

2013 ◽

Vol 141 (7-8) ◽

pp. 466-474

Author(s):

Dragica Vucelic ◽

Danijela Mikovic ◽

Zoran Rajic ◽

Nebojsa Savic ◽

Zivko Budisin ◽

...

Keyword(s):

Hemolytic Uremic Syndrome ◽

Thrombotic Thrombocytopenic Purpura ◽

Binding Activity ◽

Adamts13 Activity ◽

Activity Assay ◽

Thrombocytopenic Purpura ◽

Uremic Syndrome ◽

Adamts13 Deficiency ◽

A Disintegrin And Metalloproteinase ◽

Thrombospondin Motif

Introduction. The significance of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif-13) activity for diagnosis and therapy of thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) is still a controversial issue. Objective. The aim of this report was to analyze the value of ADAMTS13 measurements in the diagnosis of TTP and HUS. Methods. At presentation, we analyzed patients with idiopathic TTP (n=18), secondary TTP (n=4), diarrhea positive HUS (n=3) and diarrhea negative HUS (n=3) treated in Belgrade, Serbia from 2004 to 2010. ADAMTS13 activity from acute phase samples was measured using the residual collagen binding activity assay at the Haemophilia and Thrombosis Centre, Milan, Italy. Results. There was a significant correlation between reduced ADAMTS13 activity and idiopathic TTP diagnosis (p=0.000) as well as between lower ADAMTS13 activities and higher reticulocytes (p=0.017) and lactate dehydrogenase levels (p=0.027). Significant correlation was also found between higher protease activity and diagnosis of HUS (p=0.000). There was a statistically significant correlation between higher ADAMTS13 activities and higher platelets count (p=0.002), blood urea nitrogen (p=0.000), and creatinine level (p=0.000). Conclusion. Severe ADAMTS13 deficiency points at the diagnosis of idiopathic TTP and it is present in the secondary TTP but not in HUS.

Download Full-text

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

Bioscience Reports ◽

10.1042/bsr20181619 ◽

2018 ◽

Vol 38 (6) ◽

Cited By ~ 1

Author(s):

Jian-Zhong Huo ◽

Xing-Hua Ji ◽

Zhong-Yi Su ◽

Peng Shang ◽

Fei Gao

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Nucleotide Polymorphisms ◽

Degenerative Diseases ◽

Single Nucleotide ◽

Data Collection Sheet ◽

A Disintegrin And Metalloproteinase ◽

Meta Analyses ◽

Thrombospondin Motif ◽

Allelic Model

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.

Download Full-text

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

10.1101/2020.06.12.146324 ◽

2020 ◽

Author(s):

Santamaria Salvatore ◽

Doretta Cuffaro ◽

Elisa Nuti ◽

Lidia Ciccone ◽

Tiziano Tuccinardi ◽

...

Keyword(s):

Active Site ◽

Targeted Mutagenesis ◽

Inhibitor Binding ◽

New Class ◽

Cross Domain ◽

Novel Approach ◽

Docking Calculations ◽

A Disintegrin And Metalloproteinase ◽

Dynamics Simulations ◽

Thrombospondin Motif

AbstractADAMTS-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.

Download Full-text

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

Neural Plasticity ◽

10.1155/2016/1305801 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 23

Author(s):

Shinji Miyata ◽

Hiroshi Kitagawa

Keyword(s):

Extracellular Matrix ◽

Chondroitin Sulfate ◽

Neural Plasticity ◽

Adult Brain ◽

Chondroitin Sulfate Proteoglycans ◽

Perineuronal Nets ◽

Perineuronal Net ◽

A Disintegrin And Metalloproteinase ◽

The Stability ◽

Thrombospondin Motif

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.

Download Full-text

Designing TIMP (tissue inhibitor of metalloproteinases) variants that are selective metalloproteinase inhibitors

Biochemical Society Symposium ◽

10.1042/bss0700201 ◽

2003 ◽

Vol 70 ◽

pp. 201-212 ◽

Cited By ~ 51

Author(s):

Hideaki Nagase ◽

Keith Brew

Keyword(s):

Three Dimensional ◽

Therapeutic Interventions ◽

Tissue Inhibitors Of Metalloproteinases ◽

Structural Basis ◽

Structural Elements ◽

Ridge Structure ◽

Extracellular Matrix Components ◽

Metalloproteinase Inhibitors ◽

The Matrix ◽

A Disintegrin And Metalloproteinase

The tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of the matrix metalloproteinases (MMPs), enzymes that play central roles in the degradation of extracellular matrix components. The balance between MMPs and TIMPs is important in the maintenance of tissues, and its disruption affects tissue homoeostasis. Four related TIMPs (TIMP-1 to TIMP-4) can each form a complex with MMPs in a 1:1 stoichiometry with high affinity, but their inhibitory activities towards different MMPs are not particularly selective. The three-dimensional structures of TIMP-MMP complexes reveal that TIMPs have an extended ridge structure that slots into the active site of MMPs. Mutation of three separate residues in the ridge, at positions 2, 4 and 68 in the amino acid sequence of the N-terminal inhibitory domain of TIMP-1 (N-TIMP-1), separately and in combination has produced N-TIMP-1 variants with higher binding affinity and specificity for individual MMPs. TIMP-3 is unique in that it inhibits not only MMPs, but also several ADAM (a disintegrin and metalloproteinase) and ADAMTS (ADAM with thrombospondin motifs) metalloproteinases. Inhibition of the latter groups of metalloproteinases, as exemplified with ADAMTS-4 (aggrecanase 1), requires additional structural elements in TIMP-3 that have not yet been identified. Knowledge of the structural basis of the inhibitory action of TIMPs will facilitate the design of selective TIMP variants for investigating the biological roles of specific MMPs and for developing therapeutic interventions for MMP-associated diseases.

Download Full-text

Requirement for C-mannosylation to be secreted and activated a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4)

Biochimica et Biophysica Acta (BBA) - General Subjects ◽

10.1016/j.bbagen.2020.129833 ◽

2021 ◽

Vol 1865 (3) ◽

pp. 129833

Author(s):

Kazuki Miura ◽

Takehiro Suzuki ◽

Hongkai Sun ◽

Haruka Takada ◽

Yudai Ishizawa ◽

...

Keyword(s):

A Disintegrin And Metalloproteinase

Download Full-text

Expression of VEGF-A Signaling Pathway in Cartilage of ACLT-induced Osteoarthritis Mouse Model

Journal of Orthopaedic Surgery and Research ◽

10.1186/s13018-021-02528-w ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Jia-jia Qian ◽

Qi Xu ◽

Wei-min Xu ◽

Ren Cai ◽

Gui-cheng Huang

Keyword(s):

Signaling Pathway ◽

Cruciate Ligament ◽

Time Dependent ◽

Pathological Changes ◽

The Matrix ◽

Vegfr2 Signaling ◽

Cox 2 ◽

Anterior Cruciate ◽

A Disintegrin And Metalloproteinase ◽

Safranin O

Abstract Background Anterior cruciate ligament transection surgery (ACLT)-induced OA model was often used to investigate the molecular mechanism of knee osteoarthritis (KOA). Researches have shown that vascular endothelial growth factor (VEGF) played an important role in OA. The present study aimed to investigate the pathological changes after ACLT surgery and reveal the expression characteristics of the VEGF-A/VEGFR2 signaling pathway in this model. Methods Moderate KOA model was established by ACLT, and 1, 2, 4, 8, and 12 weeks after surgery, hematoxylin-eosin (HE) and Safranin-O(S-O) staining were used to detect the pathological changes in mouse knee cartilage, and the matrix biomarkers A Disintegrin and Metalloproteinase with Thrombospondin Motifs 5(ADAMTS5), Collagen II (COL-II) were detected using immunohistochemistry (IHC), CD31 was detected by immunofluorescence (IF) to show the vascular invasion in cartilage, and proteins expression of VEGF-A pathway were detected by Western blot (WB). Meanwhile, the inflammatory biomarkers cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in cartilage were detected by WB. Results ACLT surgery can lead to degeneration of cartilage in mice, and the characteristics of the lesion were time-dependent. The ADAMTS5-positive cells increased while COL-II decreased in OA cartilage with time, and new blood vessels labeled by CD31 can be seen from 1 week in OA cartilage, and increased in 8 and 12 weeks. The expression of VEGF-A, VEGFR2, COX-2, and iNOS were higher than control groups, which were basically consistent with the degree of osteoarthritis. Conclusions The degenerative degree of articular cartilage was time-dependent; angiogenesis and inflammation were important pathological changes of cartilage in KOA. The expression of the VEGF-A/VEGFR2 signaling pathway was basically correlated with the degree of KOA.

Download Full-text