A Role for MMP-10 (Matrix Metalloproteinase-10) in Calcific Aortic Valve Stenosis

Matilla, Lara; Roncal, Carmen; Ibarrola, Jaime; Arrieta, Vanessa; García-Peña, Amaia; Fernández‐Celis, Amaya; Navarro, Adela; Álvarez, Virginia; Gainza, Alicia; Orbe, Josune; Cachofeiro, Victoria; Zalba, Guillermo; Sádaba, Rafael; Rodríguez, José Antonio; López‐Andrés, Natalia

doi:10.1161/atvbaha.120.314143

Cited by 41 publications

(35 citation statements)

References 47 publications

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“…Data from in vitro studies have demonstrated that inhibition of NF‐κB prevents up‐regulation of MMP1, MMP3 and MMP9 production from fibroblasts and vascular smooth muscle cells 77 . The valvular expression of several MMPs has been shown within aortic stenotic valves 78,79 . An in vitro study by Matilla et al 79 revealed that MMP‐10 in VIC cultures increased expression of inflammatory (IL‐1β), fibrotic (α‐smooth muscle actin, vimentin, collagen) and osteogenic (BMP‐4, BMP‐9, osteopontin, Sox9 and Smad1/5/8) markers.…”

Section: Resultsmentioning

confidence: 99%

“…The valvular expression of several MMPs has been shown within aortic stenotic valves 78,79 . An in vitro study by Matilla et al 79 revealed that MMP‐10 in VIC cultures increased expression of inflammatory (IL‐1β), fibrotic (α‐smooth muscle actin, vimentin, collagen) and osteogenic (BMP‐4, BMP‐9, osteopontin, Sox9 and Smad1/5/8) markers. The addition of a physiological MMP inhibitor (the tissue inhibitor of metalloproteinases type 1) to cultured human VICs prevented the release of pro‐inflammatory and osteogenic factors.…”

Section: Resultsmentioning

confidence: 99%

“…The addition of a physiological MMP inhibitor (the tissue inhibitor of metalloproteinases type 1) to cultured human VICs prevented the release of pro‐inflammatory and osteogenic factors. Moreover, monoclonal antibodies against MMP‐10 inhibited the osteogenesis, resulting in much lower rate of VIC calcification 79 . Thus, it might be hypothesized that MMPs are potential therapeutic targets for delaying the progression of aortic valve calcification in AS.…”

Section: Resultsmentioning

confidence: 99%

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Aortic valvular stenosis: Novel therapeutic strategies

Natorska

Kopytek

Undas

2021

Eur J Clin Investigation

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Background Aortic stenosis (AS) prevalence is estimated to reach 4.5 million cases worldwide by the year 2030. AS is a progressive disease without a pharmacological treatment. In the current review, we aimed to investigate novel therapeutic approaches for non‐surgical AS treatment, at least in patients with mild‐to‐moderate AS. Materials and Methods The most recent and relevant papers concerned with novel molecular pathways that have potential as therapeutic targets in AS were selected from searches of PubMed and Web of Science up to February 2021. Results Growing evidence indicates that therapies using proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, simvastatin/ezetimibe combination, cholesteryl ester transfer protein inhibitors or antisense oligonucleotides targeting apolipoprotein(a) reduce the risk of AS progression. It has been shown that enhanced valvular lipid oxidation may drive AS development by leading to the activation of valvular interstitial cells (VICs), the most abundant valvular cells having a major contribution to valve calcification. Since VICs are able to release pro‐inflammatory cytokines, clotting factors and proteins involved in calcification, strategies targeting these cell activations seem promising as therapeutic interventions. Recently, non‐vitamin K antagonist oral anticoagulants (NOACs) have been shown to inhibit activation of VICs. Conclusion Several novel molecular pathways of AS development have been identified over the past few years. Therapies using PCSK9 inhibitors, simvastatin/ezetimibe combination, lipoprotein(a)‐lowering therapy are highly promising candidates as therapeutics in the prevention of mild AS progression, while preclinical studies show that NOACs may inhibit valvular inflammation and coagulation activation and slower the rate of AS progression.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Aortic valvular stenosis: Novel therapeutic strategies

Natorska

Kopytek

Undas

2021

Eur J Clin Investigation

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“…Of note, among the genes selectively upregulated in Gata4KD , Il11 is a key mediator of organ fibrosis, possible downstream effector of TGF β [39]. Among genes upregulated in Tbx20KD, Heyl , downstream effector of Notch, is involved in cardiogenesis and is thought to repress Gata4 expression [40], Mmp10 is upregulated in patients with end-stage HF [41], and it is involved in valve ossification [42]. KEGG pathway analyses ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Adult fibroblasts retain organ-specific transcriptomic identity

Forte

Ramialison

et al. 2021

Preprint

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Organ fibroblasts are essential components of homeostatic and diseased tissues. They participate in sculpting the extracellular matrix, sensing the microenvironment and communicating with other resident cells. Recent studies have revealed transcriptomic heterogeneity among fibroblasts within and between organs. To dissect the basis of interorgan heterogeneity, we compare the gene expression of fibroblasts from different tissues (tail, skin, lung, liver, heart, kidney, gonads) and show that they display distinct positional and organ-specific transcriptome signatures that reflect their embryonic origins. We demonstrate that fibroblasts′ expression of genes typically attributed to the surrounding parenchyma is established in embryonic development and largely maintained in culture, bioengineered tissues, and ectopic transplants. Targeted knockdown of key organ-specific transcription factors affects fibroblasts functions, with modulation of genes related to fibrosis and inflammation. Our data open novel opportunities for the treatment of fibrotic diseases in a more precise, organ-specific manner.

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“…OPN is also a pivotal intrinsic factor for regulating cartilage degradation due to its effects on the expression of MMP-13 and proteoglycan loss [ 9 ]. Several MMPs have been reported to regulate OPN expression; for example, MMP-9 can cleave an OPN fragment to mediate tumor immune escape, while the MMP-10 can induce the overexpression of OPN in calcific aortic valve stenosis [ 10 , 11 ]. The elevated expression of OPN, which was found in the joints of OA, is deemed to be correlated with the severity of joint lesions in OA [ 12 – 16 ].…”

Section: Introductionmentioning

confidence: 99%

OPN Deficiency Increases the Severity of Osteoarthritis Associated with Aberrant Chondrocyte Senescence and Apoptosis and Upregulates the Expression of Osteoarthritis-Associated Genes

Tian

Chen

Kuang

et al. 2020

Pain Research and Management

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Objectives. A recent work has reported that the elevated osteopontin (OPN) levels in the articular cartilage and synovial fluid are correlated with the progressive osteoarthritis (OA) joint damage, and OPN has a protective effect against OA by suppressing the expressions of OA-associated genes. The present study examined whether the OPN deficiency was susceptible to OA through the regulation of chondrocyte senescence and apoptosis and the expressions of OA-associated genes. Methods. The mRNA levels of COL2A1 and OPN were compared between human OA chondrocytes and normal chondrocytes. The effects of OPN siRNA on the SA-β-Gal expressions and the percentage of apoptotic chondrocytes were examined by using SA-β-Gal staining and apoptosis assay, and the effects on the expressions of COL2A1 and OA-associated genes (COL10A1, IL-1β, TNF-ɑ, MMP-13, and ADAMTS5) were examined by western blot analysis and quantitative real-time RT-PCR. Furthermore, an in vivo OA model was established to examine the effects of OPN siRNA on the senescence and apoptosis of OA chondrocytes and the expressions of OA-associated genes. Results. The mRNA levels of COL2A1 and OPN were decreased in knee OA chondrocytes in comparison with those in normal chondrocytes. The OPN deficiency enhanced the senescence and apoptosis of OA chondrocytes and increased the expressions of COL10A1, IL-1β, TNF-ɑ, MMP-13, and ADAMTS5 but decreased the expression of COL2A1. Meanwhile, OPN deficiency could result in severe, accelerated OA in vivo, which was also associated with enhanced senescence and apoptosis of chondrocytes and elevated expressions of OA-associated genes. Conclusions. The findings of this study suggest that the OPN deficiency can result in accelerated OA, which is associated with enhanced senescence and apoptosis of OA chondrocytes and the upregulated expressions of OA-associated genes.

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A Role for MMP-10 (Matrix Metalloproteinase-10) in Calcific Aortic Valve Stenosis

Cited by 41 publications

References 47 publications

Aortic valvular stenosis: Novel therapeutic strategies

Aortic valvular stenosis: Novel therapeutic strategies

Adult fibroblasts retain organ-specific transcriptomic identity

OPN Deficiency Increases the Severity of Osteoarthritis Associated with Aberrant Chondrocyte Senescence and Apoptosis and Upregulates the Expression of Osteoarthritis-Associated Genes

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