Tissue inhibitor of metalloproteinases-3 facilitates Fas-mediated neuronal cell death following mild ischemia

Wetzel, Monica; Li, L; Harms, Kristian; Roitbak, Tamara; Ventura, Patrick; Rosenberg, Gary A.; Khokha, Rama; Cunningham, Lee Anna

doi:10.1038/sj.cdd.4402246

Cited by 67 publications

(61 citation statements)

References 39 publications

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“…cellular matrix providing strength to the articular is the type II collagen (26). The degradation of type II collagen is caused by MMP-13, however, its activity is suppressed by TIMP-1 (27,28). Our current study revealed that ginsenoside-Rg5 treatment for one month significantly increased the expression of TIMP-1.…”

Section: Discussionsupporting

confidence: 49%

Ginsenoside-Rg5 treatment inhibits apoptosis of chondrocytes and degradation of cartilage matrix in a rat model of osteoarthritis

Zhang

2017

Oncology Reports

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Abstract. This study investigated the effect of ginsenoside-Rg5 on the degradation of articular cartilage in osteoarthritis rat model and on induction of chondrocyte apoptosis. Osteoarthritis rat model was prepared by ligament transection and medial meniscus resection. The rats were then treated with different doses (1, 2, 5, 10 and 15 µM) of ginsenoside-Rg5 for 48 h. The results from histopathological analysis revealed a significant (P=0.005) prevention of cartilage degradation in OA rat model by ginsenoside-Rg5 treatment at 15 µM. Ginsenoside-Rg5 treatment prevented the disintegration of synovial membrane to a significant (P=0.005) extent. The proportion of apoptotic cells in the knee joints was reduced to 7% by ginsenoside-Rg5 treatment after one month compared to the control. Treatment of the rats with ginsenoside-Rg5 caused increase in the levels of proteoglycan, collagen and type II collagen by 5-, 3-and 4-fold compared to the control group. Immunohistochemistry revealed that the level of MMP-13 was reduced to 45% and that of TIMP-1 was increased by 67% on treatment with ginsenoside-Rg5. The levels of interleukin-1β, tumor necrosis factor-α, nitric oxide and inducible nitric oxide synthetase were reduced by 67, 54, 32 ad 49%, respectively after one month of treatment with 15 mg/kg dose of ginsenoside-Rg5. The expression was increased to 67 and 52% for BMP-2 and TGF-β1, respectively on treatment with ginsenoside-Rg5. Thus ginsenoside-Rg5 prevents cartilage degradation in the OA rats and inhibits cartilage apoptosis, therefore it can be used for osteoarthritis treatment. IntroductionOsteoarthritis (OA) is one of the commonly observed diseases of joints caused by the disintegration of cartilage matrix and death of chondrocytes (1). There is always an equilibrium maintained by extracellular cartilage matrix between the formation and loss of chondrocytes (2,3). Loss of chondrocytes is a limiting factor for the formation of extracellular cartilage matrix which subsequently leads to the development of osteoarthritis (4). Many factors such as proteoglycan and collagen (type II) are involved in the regulation of normal functioning of chondrocytes (5). Studies have revealed that chondrocyte loss and extracellular matrix degradation involve several factors including, generation of peroxide radicals, TNF-α and interleukins (6,7). All these factors initiate inflammatory reactions leading to chondrocyte apoptosis (8). Expression of interleukin-1β is responsible for the production of inhibitors of metalloproteinase (TIMPs) leading to the inhibition of matrix metalloproteinase (MMP) generation and subsequent chondrocyte death and OA (9-11).Traditional Chinese medicine (TCM) involves the use of various herbs as well as dietary ingredients for several disorders depending upon the type of the syndrome (12). Numerous studies have been performed to demonstrate the chemotherapeutic potential of TCM against various types of cancers (13). Ginseng has a long traditional medicinal importance for the treatment of cancers, stress and...

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Section: Discussionsupporting

confidence: 49%

Ginsenoside-Rg5 treatment inhibits apoptosis of chondrocytes and degradation of cartilage matrix in a rat model of osteoarthritis

Zhang

2017

Oncology Reports

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“…Our results provide insight into EGFR activation and ERK1/2 signal transduction in a TIMP3-deficient state, which commits hepatocytes to survival following Fas-mediated toxicity. In support of this interpretation, the protective role of the EGFR pathway is demonstrated in models of stress induced by UV and ROS (10,63), and a proapoptotic role of TIMP3 in Fas-mediated apoptosis has been suggested in neuronal and synovial fibroblast models in vitro (64,65). Our finding that dampened TNFR1 activation coupled with enhanced EGFR signaling is protective against acute hepatic failure is consistent with observations that individually, ablating JNK signaling or elevating EGFR activation can protect, at least in part, against receptor-mediated apoptosis (7,9).…”

Section: Discussionmentioning

confidence: 80%

Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice

et al. 2010

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The cell death receptor Fas plays a role in the establishment of fulminant hepatitis, a major cause of druginduced liver failure. Fas activation elicits extrinsic apoptotic and hepatoprotective signals; however, the mechanisms by which these signals are integrated during disease are unknown. Tissue inhibitor of metalloproteinases 3 (TIMP3) controls the critical sheddase a disintegrin and metalloproteinase 17 (ADAM17) and may dictate stress signaling. Using mice and cells lacking TIMP3, ADAM17, and ADAM17-regulated cell surface molecules, we have found that ADAM17-mediated ectodomain shedding of TNF receptors and EGF family ligands controls activation of multiple signaling cascades in Fas-induced hepatitis. We demonstrated that TNF signaling promoted hepatotoxicity, while excessive TNF receptor 1 (TNFR1) shedding in Timp3 -/-mice was protective. Compound Timp3 -/-Tnf -/-and Timp3 -/-Tnfr1 -/-knockout conferred complete resistance to Fas-induced toxicity. Loss of Timp3 enhanced metalloproteinase-dependent EGFR signaling due to increased release of the EGFR ligands TGF-α, amphiregulin, and HB-EGF, while depletion of shed amphiregulin resensitized Timp3 -/-hepatocytes to apoptosis. Finally, adenoviral delivery of Adam17 prevented acetaminophen-induced liver failure in a clinically relevant model of Fas-dependent fulminant hepatitis. These findings demonstrate that TIMP3 and ADAM17 cooperatively dictate cytokine signaling during death receptor activation and indicate that regulated metalloproteinase activity integrates survival and death signals during acute hepatotoxic stress.

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“…Tissue inhibitor of metalloproteinase-3 also has been associated with neuronal apoptosis after ischemia (Wallace et al, 2002). Recently, TIMP-3 gene deletion was shown to prevent Fas-mediated cell death in focal ischemia (Wetzel et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Matrix metalloproteinases and TIMP-3 have been associated with neuronal apoptosis in cerebral ischemia (Wallace et al, 2002;Copin et al, 2005;Wetzel et al, 2007). We evaluated DNA fragmentation by TUNEL staining and cleaved caspase-3 expression in the caudate putamen and the cortex at 24 h after ischemia.…”

Section: Neuronal Apoptosis and Cleaved Caspase-3mentioning

confidence: 99%

Tissue Inhibitor of Metalloproteinases Protect Blood—Brain Barrier Disruption in Focal Cerebral Ischemia

Fujimoto

Takagi

Aoki

et al. 2008

J Cereb Blood Flow Metab

138

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Enhanced matrix metalloproteinases (MMPs) can cause vasogenic edema and hemorrhagic transformation after cerebral ischemia, and affect the extent of ischemic injury. We hypothesized that the endogenous MMP inhibitors, tissue inhibitor of MMPs (TIMPs), were essential to protect against blood-brain barrier (BBB) disruption after ischemia by regulating the activities of MMPs. We confirmed the transition of MMP-2 and MMP-9, and the TIMPs family after 30 mins of middle cerebral artery occlusion, and elucidated the function of TIMP-1 and TIMP-2 in focal ischemia, using TIMP-1 À/À and TIMP-2 À/À mice. TIMP-1 mRNA expression was gradually increased until 24 h after reperfusion. In TIMP-1 À/À mice, MMP-9 protein expression and gelatinolytic activity were significantly more augmented after cerebral ischemia than those in WT mice, and were accompanied by exacerbated BBB disruption, neuronal apoptosis, and ischemic injury. In contrast, TIMP-2 gene deletion mice exhibited no significant difference in MMP expressions and the degree of ischemic injury despite an increased Evans blue leakage. These results suggest that TIMP-1 inhibits MMP-9 activity and can play a neuroprotective role in cerebral ischemia.

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Tissue inhibitor of metalloproteinases-3 facilitates Fas-mediated neuronal cell death following mild ischemia

Cited by 67 publications

References 39 publications

Ginsenoside-Rg5 treatment inhibits apoptosis of chondrocytes and degradation of cartilage matrix in a rat model of osteoarthritis

Ginsenoside-Rg5 treatment inhibits apoptosis of chondrocytes and degradation of cartilage matrix in a rat model of osteoarthritis

Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice

Tissue Inhibitor of Metalloproteinases Protect Blood—Brain Barrier Disruption in Focal Cerebral Ischemia

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