ADAMTS-12 Metalloprotease Is Necessary for Normal Inflammatory Response

Moncada-Pazos, Ángela; Obaya, Álvaro J.; Llamazares, María; Heljasvaara, Ritva; Suárez, María Fernanda; Colado, Enrique; Noël, Agnès; Cal, Santiago; López-Otı́n, Carlos

doi:10.1074/jbc.m112.408625

Cited by 40 publications

(38 citation statements)

References 36 publications

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“…Tumor necrosis factor-a and IL-1b increase ADAMTS 7 and 12 mRNA in cartilage explants, 64 whereas ADAMTS-12 is not induced in human fetal fibroblasts. 57 We report, for the first time in SF, that IL-1b and Fn-fs promoted significant increases in ADAMTS-7 transcripts and protein levels, being greater in OA-than in HD-SF.…”

Section: Q18mentioning

confidence: 99%

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Healthy and Osteoarthritic Synovial Fibroblasts Produce a Disintegrin and Metalloproteinase with Thrombospondin Motifs 4, 5, 7, and 12

Pérez‐García

Gutiérrez‐Cañas

Seoane

et al. 2016

The American Journal of Pathology

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Current description of osteoarthritis includes the involvement of synovial inflammation. Studies contributing to understanding the mechanisms of cross-talk and feedback among the joint tissues could be relevant to the development of therapies that block disease progression. During osteoarthritis, synovial fibroblasts exposed to anomalous mechanical forces and an inflammatory microenvironment release factors such as a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) metalloproteinases that mediate tissue damage and perpetuate inflammation. We therefore studied the production of ADAMTS by synovial fibroblasts and their contribution to cartilage degradation. Moreover, we analyzed the implication of two mediators present in the osteoarthritis joint, IL-1b as proinflammatory cytokine, and 45-kDa fibronectin fragments as products of matrix degradation. We reported that synovial fibroblasts constitutively express and release ADAMTS 4, 5, 7, and 12. Despite the contribution of both mediators to the stimulation of Runx2 and Wnt/b-catenin signaling pathways, as well as to ADAMTS expression, promoting the degradation of aggrecan and cartilage oligomeric matrix protein from cartilage, fibronectin fragments rather than IL-1b played the major pathological role in osteoarthritis, contributing to the maintenance of the disease. Moreover, higher levels of ADAMTS 4 and 7 and a specific regulation of ADAMTS-12 were observed in osteoarthritis, suggesting them as new potential therapeutic targets. Therefore, synovial fibroblasts provide the biochemical tools to the chronicity and destruction of the osteoarthritic joints. (Am J Pathol 2016, -: 1e13; http:// dx

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Section: Q18mentioning

confidence: 99%

“…Those facts are important for the development of combined therapies on the basis of the blockade of these ADAMTS. Emergent data indicate that ADAMTS-12 has multiple functions in the inflammatory response, 64 angiogenesis, and apoptosis.…”

Section: Q18mentioning

confidence: 99%

Healthy and Osteoarthritic Synovial Fibroblasts Produce a Disintegrin and Metalloproteinase with Thrombospondin Motifs 4, 5, 7, and 12

Pérez‐García

Gutiérrez‐Cañas

Seoane

et al. 2016

The American Journal of Pathology

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“…25 Furthermore, subsequent analysis suggested an important role for ADAMTS12ininflammatory processes. 22 Inflammation has been frequently connected to CA pathogenesis. 3,8,15,33 This is primarily because extensive inflammatoryandimmunologicalreactionsarecommon in unruptured CAs and may be related to aneurysm formation and rupture.…”

Section: 38mentioning

confidence: 99%

“…27 Members of the ADAMTS family play a role in extracellularmatrixdegradationandareinvolvedinseveral other biological processes, including coagulation, angiogenesis, and cell migration. 13 Variations within several ADAMTSgeneshavebeenimplicatedinprothrombotic, 13 inflammatory, 22,28 and connective tissue diseases, 42 suggesting a potential role in CA pathogenesis. 18 Together, thesefindingssuggestthatADAMTS genes may be excellentscreeningcandidatesforCApathogenesis;however, to our knowledge, it remains unknown if and where these genes act on disease susceptibility.…”

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confidence: 99%

ADAMTS genes and the risk of cerebral aneurysm

Arning

Jeibmann²,

Köhnemann

et al. 2016

JNS

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C erebral aneurysms (CAs) are dilations of cerebral arteries that affect 2%-5% of the population. 35 Although most of these lesions are clinically unapparent, CA rupture and subarachnoid hemorrhage usually occur between 40 and 60 years of age. Therefore, early identi fication of a CA is essential for preventing subsequent bleeding events, which often lead to substantial morbidity and mortality. 4,16 The pathogenesis of CA formation and rupture is complex and seems to arise from multiple factors. A familial predispositionisthestrongestriskfactorforthedevelopment of a CA; siblings of patients with CA are at a 4-fold increased risk of hemorrhage, 40 suggesting a significant genetic component to CA pathogenesis. 37Environmental factors,suchassmoking,hypertension,andextensivealcohol intake, appear to play a more important role in the abbreviatioNs CA = cerebral aneurysm; FDR = false discovery rate; GWAS = genome-wide association study; HWE = Hardy-Weinberg equilibrium; ICB = intracerebral bleeding; IS = ischemic stroke; MI = myocardial infarction; MMP = matrix metalloproteinase; PS = pediatric stroke; SAB = subarachnoidal bleeding; SNP = single nucleotide polymorphism; TSR = thrombospondin Type 1 sequence repeat motif. submitted January 2, 2015. methods To identify susceptible genetic variants, the authors investigated 8 single nucleotide polymorphisms (SNPs) in 4 genes from the ADAMTS family (ADAMTS2, -7, -12, and -13) known to be associated with vascular diseases. The study included 353 patients with CAs and 1055 healthy adults. results The authors found significant associations between CA susceptibility and genetic variations in 3 members of the ADAMTS family. The largest risk for CA (OR 1.32, p = 0.006) was observed in carriers of the ADAMTS2 variant rs11750568, which has been previously associated with pediatric stroke. Three SNPs under investigation are associated with a protective effect in CA pathogenesis (ADAMTS12 variant rs1364044: OR 0.65, p = 0.0001; and ADAMTS13 variants rs739469 and rs4962153: OR 0.77 and 0.63, p = 0.02 and 0.0006, respectively), while 2 other ADAMTS13 variants may confer a significant risk (rs2301612: OR 1.26, p = 0.011; rs2285489: OR 1.24, p = 0.02). coNclusioNs These results suggest that reduced integrity of the endothelial wall, as conferred by ADAMTS variants, together with inflammatory processes and defective vascular remodeling plays an important role in CA pathogenesis, although the mechanism of action remains unknown. The authors' findings may lead to specific screening of at-risk populations in the future.

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“…ADAMTS12 gene is found in skeletal muscles, cartilage, tendons and fetal lung. [7][8][9] ADAMTS12 was shown to be associated with arthritis, 10 intervertebral disc degeneration, 11,12 inflammation, 13,14 tumor invasion, and metastasis. [15][16][17] Also, high levels of ADAMTS12 messenger ribonucleic acid (mRNA) were detected in osteoarthritis and rheumatoid arthritis.…”

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confidence: 99%

ADAMTS12 Depletion by Insulin in OUMS-27 Human Chondrosarcoma Cells

et al. 2015

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Objectives:In this study, we aim to investigate the association between articular damage in diabetes and a disintegrin-like and metalloproteinase with thrombospondin motifs 12 (ADAMTS12) at gene expression and protein levels. Materials and methods: OUMS-27 human chondrosarcoma cells were used to investigate how ADAMTS12 levels changed in vitro condition in presence and absence of insulin. The study included three groups of cells treated with 10 μg/mL of insulin, and a control group. Cells were incubated with insulin in medium for one day, three days, and seven days. The effects of insulin on ADAMTS12 were investigated at both gene expression and protein levels. The relationships between the variables were tested by Mann-Whitney U test. Results: ADAMTS12 expression was significantly lower in the groups treated with insulin medium for one day and seven day periods (p=0.008 and p=0.008, respectively) compared to the control group. No significant difference was detected in the expression level between the groups kept in insulin medium for three days and the control group (p=0.55). In addition, protein amounts of the groups exposed to insulin medium for one, three, and seven day periods were lower. Conclusion: Insulin reduces the amount of ADAMTS12 which causes delayed recovery of cartilage tissue in the OUMS-27 cell lines utilized in our study for their chondrocytic properties. This reduction due to insulin treatment may contribute to recovery of cartilage tissue.

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ADAMTS-12 Metalloprotease Is Necessary for Normal Inflammatory Response

Cited by 40 publications

References 36 publications

Healthy and Osteoarthritic Synovial Fibroblasts Produce a Disintegrin and Metalloproteinase with Thrombospondin Motifs 4, 5, 7, and 12

Healthy and Osteoarthritic Synovial Fibroblasts Produce a Disintegrin and Metalloproteinase with Thrombospondin Motifs 4, 5, 7, and 12

ADAMTS genes and the risk of cerebral aneurysm

ADAMTS12 Depletion by Insulin in OUMS-27 Human Chondrosarcoma Cells

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