Matrix metalloproteinase (MMP)-19-deficient fibroblasts display a profibrotic phenotype

Jara, Paul; Calyeca, Jazmín; Romero, Yair; Plácido, Luis; Yu, Guoying; Kaminski, Naftali; Maldonado, Vilma; Cisneros, José; Selman, Moisés; Pardo, Annie

doi:10.1152/ajplung.00043.2014

Cited by 45 publications

(35 citation statements)

References 26 publications

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“…Supporting the notion that decreased autophagy activity contributes to fibrosis, we have found that knockout mice for MMP‐19, when exposed to bleomycin instillation, develop a stronger lung fibrotic response with the formation of fibroblasts foci. These fibroblasts exhibited a decrease in the expression of Atg4c, other member involved in autophagy stress response that has been associated with aging (Fernandez & Lopez‐Otin, ; Jara et al ., ).…”

Section: Discussionmentioning

confidence: 97%

mTORC 1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts

et al. 2016

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SummaryIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually lethal disease associated with aging. However, the molecular mechanisms of the aging process that contribute to the pathogenesis of IPF have not been elucidated. IPF is characterized by abundant foci of highly active fibroblasts and myofibroblasts resistant to apoptosis. Remarkably, the role of aging in the autophagy activity of lung fibroblasts and its relationship with apoptosis, as adaptive responses, has not been evaluated previously in this disease. In the present study, we analyzed the dynamics of autophagy in primary lung fibroblasts from IPF compared to young and age-matched normal lung fibroblasts. Our results showed that aging contributes for a lower induction of autophagy on basal conditions and under starvation which is mediated by mTOR pathway activation. Treatment with rapamycin and PP242, that target the PI3K/AKT/mTOR signaling pathway, modified starvation-induced autophagy and apoptosis in IPF fibroblasts. Interestingly, we found a persistent activation of this pathway under starvation that contributes to the apoptosis resistance in IPF fibroblasts. These findings indicate that aging affects adaptive responses to stress decreasing autophagy through activation of mTORC1 in lung fibroblasts. The activation of this pathway also contributes to the resistance to cell death in IPF lung fibroblasts.

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Section: Discussionmentioning

confidence: 97%

mTORC 1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts

et al. 2016

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“…It was recently found that MMP‐19 deficient mice develop an exaggerated bleomycin‐induced lung fibrosis. These findings suggest that, in lung fibroblasts, MMP‐19 has strong regulatory effects on the synthesis of key extracellular matrix components, on fibroblast to myofibroblast differentiation, and on fibroblast migration and proliferation (Jara et al, ). Additionally, MMP‐19 has been discovered to be significantly upregulated in hyperplastic epithelial cells overlying fibroblast foci in IPF.…”

Section: Matrix Metalloproteinase‐19mentioning

confidence: 99%

Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions

Mittal

Patel

Debs

et al. 2016

Journal Cellular Physiology

147

115

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Matrix metalloproteinases (MMPs) are a diverse group of proteolytic enzymes and play an important role in the degradation and remodeling of the extracellular matrix (ECM). In normal physiological conditions, MMPs are usually minimally expressed. Despite their low expression, MMPs have been implicated in many cellular processes ranging from embryological development to apoptosis. The activity of MMPs is controlled at three different stages: (1) transcription; (2) zymogen activation; and (3) inhibition of active forms by tissue inhibitor metalloproteinases (TIMPs). They can collectively degrade any component of ECM and basement membrane, and their excessive activity has been linked to numerous pathologies mainly including, but not limited to, tumor invasion and metastasis. The lack of information about several MMPs and the steady stream of new discoveries suggest that there is much more to be studied in this field. In particular, there is a need for controlling their expression in disease states. Various studies over the past 30 years have found that each MMP has a specific mode of activation, action, and inhibition. Drugs specifically targeting individual MMPs could revolutionize the treatment of a great number of health conditions and tremendously reduce their burden. In this review article, we have summarized the recent advances in understanding the role of MMPs in physiological and pathological conditions. J. Cell. Physiol. 231: 2599-2621, 2016. © 2016 Wiley Periodicals, Inc.

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“…Thus, in lung fibroblasts, MMP-19 has strong regulatory effects on the synthesis of key ECM components, on fibroblast to myofibroblast differentiation, and in migration and proliferation. 180 …”

Section: Special Attributes Of Specific Mmpsmentioning

confidence: 99%

Biochemical and Biological Attributes of Matrix Metalloproteinases

Cui

Khalil

2017

Progress in Molecular Biology and Translational Science

1,008

891

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Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are involved in the degradation of various proteins in the extracellular matrix (ECM). Typically, MMPs have a propeptide sequence, a catalytic metalloproteinase domain with catalytic zinc, a hinge region or linker peptide, and a hemopexin domain. MMPs are commonly classified on the basis of their substrates and the organization of their structural domains into collagenases, gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs, and other MMPs. MMPs are secreted by many cells including fibroblasts, vascular smooth muscle (VSM) and leukocytes. MMPs are regulated at the level of mRNA expression and by activation of their latent zymogen form. MMPs are often secreted as inactive proMMP form which is cleaved to the active form by various proteinases including other MMPs. MMPs cause degradation of ECM proteins such as collagen and elastin, but could influence endothelial cell function as well as VSM cell migration, proliferation, Ca2+ signaling and contraction. MMPs play a role in tissue remodeling during various physiological processes such as angiogenesis, embryogenesis, morphogenesis and wound repair, as well as in pathological conditions such as myocardial infarction, fibrotic disorders, osteoarthritis, and cancer. Increases in specific MMPs could play a role in arterial remodeling, aneurysm formation, venous dilation and lower extremity venous disorders. MMPs also play a major role in leukocyte infiltration and tissue inflammation. MMPs have been detected in cancer, and elevated MMP levels have been associated with tumor progression and invasiveness. MMPs can be regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP ratio often determines the extent of ECM protein degradation and tissue remodeling. MMPs have been proposed as biomarkers for numerous pathological conditions and are being examined as potential therapeutic targets in various cardiovascular and musculoskeletal disorders as well as cancer.

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Matrix metalloproteinase (MMP)-19-deficient fibroblasts display a profibrotic phenotype

Cited by 45 publications

References 26 publications

mTORC 1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts

mTORC 1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts

Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions

Biochemical and Biological Attributes of Matrix Metalloproteinases

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