Metalloproteinases and Metalloproteinase Inhibitors in Age-Related Diseases

Gargiulo, Simona; Gamba, Paola; Poli, Giuseppe; Leonarduzzi, Gabriella

doi:10.2174/13816128113196660701

Cited by 23 publications

(20 citation statements)

References 497 publications

(552 reference statements)

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“…Similarly, matrix metalloproteinases (MMP) are involved in cartilage degradation [ 53 ]. MMP-3 serum levels decrease after mud therapy in OA patients [ 54 ]—either as a direct effect of the intervention or as a consequence of the reduction in pro-inflammatory mediators such as cytokines that promote MMP secretion—suggesting that mud therapy contributes to extracellular matrix integrity.…”

Section: Balneotherapy and Immune Systemmentioning

confidence: 99%

Balneotherapy, Immune System, and Stress Response: A Hormetic Strategy?

Gálvez

Torres-Piles

Ortega

2018

IJMS

123

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Balneotherapy is a clinically effective complementary approach in the treatment of low-grade inflammation- and stress-related pathologies. The biological mechanisms by which immersion in mineral-medicinal water and the application of mud alleviate symptoms of several pathologies are still not completely understood, but it is known that neuroendocrine and immunological responses—including both humoral and cell-mediated immunity—to balneotherapy are involved in these mechanisms of effectiveness; leading to anti-inflammatory, analgesic, antioxidant, chondroprotective, and anabolic effects together with neuroendocrine-immune regulation in different conditions. Hormesis can play a critical role in all these biological effects and mechanisms of effectiveness. The hormetic effects of balneotherapy can be related to non-specific factors such as heat—which induces the heat shock response, and therefore the synthesis and release of heat shock proteins—and also to specific biochemical components such as hydrogen sulfide (H2S) in sulfurous water and radon in radioactive water. Results from several investigations suggest that the beneficial effects of balneotherapy and hydrotherapy are consistent with the concept of hormesis, and thus support a role for hormesis in hydrothermal treatments.

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Section: Balneotherapy and Immune Systemmentioning

confidence: 99%

Balneotherapy, Immune System, and Stress Response: A Hormetic Strategy?

Gálvez

Torres-Piles

Ortega

2018

IJMS

123

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“…Recent advances also increased our understanding of how the loss of articular cartilage extracellular matrix (ECM) proteins characteristic of OA synovial joints results from the action of pro-inflammatory cytokines (e.g., interleukin-1β (IL-1β), IL-6, IL-15, IL-17, IL-21) and several other interleukin family members [ 7 , 8 , 9 ]. In addition to several of these interleukins, tumor necrosis factor-α (TNF-α) mediates the upregulation of matrix metalloproteinases (MMPs), and elevated levels of a family of enzymes termed a disintegrin and metalloproteinase with thrombospondin motif (e.g., ADAMTS-4,-5) with selective aggrecanase (i.e., aggrecanase-1 and aggrecanase-2) activities [ 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs and Osteoarthritis

Malemud

2018

Cells

101

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An imbalance in gene expressional events skewing chondrocyte anabolic and catabolic pathways toward the latter causes an aberrant turnover and loss of extracellular matrix proteins in osteoarthritic (OA) articular cartilage. Thus, catabolism results in the elevated loss of extracellular matrix proteins. There is also evidence of an increase in the frequency of chondrocyte apoptosis that compromises the capacity of articular cartilage to undergo repair. Although much of the fundamental OA studies over the past 20 years identified and characterized many genes relevant to pro-inflammatory cytokines, apoptosis, and matrix metalloproteinases (MMPs)/a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS), more recent studies focused on epigenetic mechanisms and the associated role of microRNAs (miRs) in regulating gene expression in OA cartilage. Thus, several miRs were identified as regulators of chondrocyte signaling pathways, apoptosis, and proteinase gene expression. For example, the reduced expression of miR-146a was found to be coupled to reduced type II collagen (COL2) in OA cartilage, whereas MMP-13 levels were increased, suggesting an association between MMP-13 gene expression and COL2A1 gene expression. Results of these studies imply that microRNAs could become useful in the search for diagnostic biomarkers, as well as providing novel therapeutic targets for intervention in OA.

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“…The inflammatory component of OA, as evidenced by chronic synovitis, is associated with a modulation of the chondrogenic phenotype. These changes include the upregulation of pro-inflammatory cytokine gene expression [ 16 ]; the upregulation of matrix metalloproteinase (MMP) gene expression [ 9 , 17 , 18 ] combined with a skewing of the ratio of the level of tissue inhibitor of metalloproteinases (TIMPs) to MMPs towards MMPs has also been considered as relevant; elevated expression of a disintegrin and metalloproteinases with thrombospondin motif (ADAMTS) genes [ 19 ]; and a disintegrin and metalloproteinase (ADAM) genes [ 20 ], the production of alarmins and Toll-like receptors [ 21 ], and an increased frequency of chondrocyte apoptosis [ 22 ]. These changes are likely to be arise from aberrations in signal transduction involving the mitogen-activated protein kinase (MAPK) and Janus Kinase/Signal Transduction and Activators of Transcription (JAK/STAT) pathways, negative regulators of JAK/STAT [ 23 – 26 ], and by those cytokines that activate the nuclear factor-κB (NF-κB) pathway [ 27 – 29 ].…”

Section: Introductionmentioning

confidence: 99%

A Role for Soluble IL-6 Receptor in Osteoarthritis

Akeson

Malemud

2017

JFMK

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Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines present at elevated levels in the synovial fluid of individuals with confirmed clinical diagnosis of rheumatoid arthritis (RA) and osteoarthritis (OA). The mechanism of action of IL-6 was shown to involve its capacity to interact with a membrane-bound IL-6 receptor (mIL-6Rα), also known as the “classical” IL-6 pathway, or through its interaction with a soluble IL-6 receptor (sIL-6R) termed the “trans-signaling” pathway. Activation of downstream signaling is transduced via these IL-6 receptors and principally involves the Janus Kinase/Signal Transduction and Activators of Transcription (JAK/STAT) signaling pathway that is further regulated by glycoprotein-130 (gp130) interacting with the IL-6/mIL-6R complex. Phosphorylation of STAT proteins via JAK activation facilitates STAT proteins to act as transcription factors in inflammation. However, the biological function(s) of the sIL-6R in human chondrocytes requires further elucidation, although we previously showed that exogenous sIL-6R significantly suppressed the synthesis of neutrophil gelatinase-associated lipocalin (NGAL) in the immortalized line of human chondrocytes, C28/I2. NGAL was shown to regulate the activity of matrix metalloproteinase-9 (MMP-9), whose activity is crucial in OA for the destruction of articular cartilage. The “shedding” of sIL-6R from the plasma membrane is carried out by a family of enzymes known as A Distintegrin and Metalloproteinase (ADAM), which are also elevated in OA. In this paper, we have systematically reviewed the role played by IL-6 in OA. We have proposed that sIL-6R may be an important target for future drug development in OA by ameliorating cartilage extracellular protein degradation.

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Metalloproteinases and Metalloproteinase Inhibitors in Age-Related Diseases

Cited by 23 publications

References 497 publications

Balneotherapy, Immune System, and Stress Response: A Hormetic Strategy?

Balneotherapy, Immune System, and Stress Response: A Hormetic Strategy?

MicroRNAs and Osteoarthritis

A Role for Soluble IL-6 Receptor in Osteoarthritis

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