Oxidative Stress Inhibits Insulin-like Growth Factor-I Induction of Chondrocyte Proteoglycan Synthesis through Differential Regulation of Phosphatidylinositol 3-Kinase-Akt and MEK-ERK MAPK Signaling Pathways

Yin, Weihong; Park, Jong In; Loeser, Richard F.

doi:10.1074/jbc.m109.056838

Cited by 159 publications

(177 citation statements)

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“…We also analyzed the extent by which the candidate treatment with the rAAV-human IGF-I (rAAV-hIGF-I) vector was capable of durably restoring the structure of human OA cartilage vis-à-vis normal cartilage. Finally, we investigated the influence of rAAV-mediated IGF-I production upon the expression of key effectors of the IGF-I axis, specifically the IGF-binding proteins 3, 4 and 5 (IGFBP-3 to IGFBP-5) as well as the IGF-I receptor (IGF-IR) and downstream mitogenactivated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK-1/2) and phosphatidylinisitol-3/Akt (PI3K/Akt) signal transduction pathways (33)(34)(35)(36)(37)(38)(39), reported as being inhibitors (IGFBP3 and IGFBP4) (40)(41)(42) or potentiators (IGFBP5 and IGF-IR) (42,43) of the IGF-I actions during OA pathogenesis.…”

Section: Benefits Of Recombinant Adeno-associated Virus (Raav)-mediatmentioning

confidence: 99%

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

Weimer

Madry

Venkatesan

et al. 2011

Mol Med

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Administration of therapeutic genes to human osteoarthritic (OA) cartilage is a potential approach to generate effective, durable treatments against this slow, progressive disorder. Here, we tested the ability of recombinant adeno-associated virus (rAAV)-mediated overexpression of human insulinlike growth factor (hIGF)-I to reproduce an original surface in human OA cartilage in light of the pleiotropic activities of the factor. We examined the proliferative, survival and anabolic effects of the rAAV-hIGF-I treatment in primary human normal and OA chondrocytes in vitro and in explant cultures in situ compared with control (reporter) vector delivery. Efficient, prolonged IGF-I secretion via rAAV stimulated the biological activities of OA chondrocytes in all the systems evaluated over extended periods of time, especially in situ, where it allowed for the long-term reconstruction of OA cartilage (at least for 90 d). Remarkably, production of high, stable amounts of IGF-I in OA cartilage using rAAV advantageously modulated the ex-

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Section: Benefits Of Recombinant Adeno-associated Virus (Raav)-mediatmentioning

confidence: 99%

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

Weimer

Madry

Venkatesan

et al. 2011

Mol Med

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“…Disrupted pro-anabolic IGF-1 signaling has been implicated in the pathogenesis of OA, and age-associated reductions in the chondrocyte response to IGF-1 have been associated with oxidative stress (26,27). The aim of this study was to examine whether menadione-induced oxidative stress could promote chondrocyte PRX hyperoxidation in an age-related manner and determine whether this was associated with disrupted IGF-1 signaling, chondrocyte cell death, and osteoarthritis.…”

mentioning

confidence: 99%

“…We chose to focus on the redox regulation of the chondrocyte insulin-like growth factor-1 (IGF-1) signaling pathway because of previous studies demonstrating that IGF-1 promotes cartilage matrix synthesis and chondrocyte survival while reducing chondrocyte catabolic activity (25,26). Disrupted pro-anabolic IGF-1 signaling has been implicated in the pathogenesis of OA, and age-associated reductions in the chondrocyte response to IGF-1 have been associated with oxidative stress (26,27).…”

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confidence: 99%

Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes

Collins

Wood

Nelson

et al. 2016

Journal of Biological Chemistry

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112

126

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Oxidative stress-mediated post-translational modifications of redox-sensitive proteins are postulated as a key mechanism underlying age-related cellular dysfunction and disease progression. Peroxiredoxins (PRX) are critical intracellular antioxidants that also regulate redox signaling events. Age-related osteoarthritis is a common form of arthritis that has been associated with mitochondrial dysfunction and oxidative stress. The objective of this study was to determine the effect of aging and oxidative stress on chondrocyte intracellular signaling, with a specific focus on oxidation of cytosolic PRX2 and mitochondrial PRX3. Menadione was used as a model to induce cellular oxidative stress. Compared with chondrocytes isolated from young adult humans, chondrocytes from older adults exhibited higher levels of PRX1-3 hyperoxidation basally and under conditions of oxidative stress. Peroxiredoxin hyperoxidation was associated with inhibition of pro-survival Akt signaling and stimulation of pro-death p38 signaling. These changes were prevented in cultured human chondrocytes by adenoviral expression of catalase targeted to the mitochondria (MCAT) and in cartilage explants from MCAT transgenic mice. Peroxiredoxin hyperoxidation was observed in situ in human cartilage sections from older adults and in osteoarthritic cartilage. MCAT transgenic mice exhibited less age-related osteoarthritis. These findings demonstrate that age-related oxidative stress can disrupt normal physiological signaling and contribute to osteoarthritis and suggest peroxiredoxin hyperoxidation as a potential mechanism.Aging is characterized by an inability to maintain homeostasis resulting in a progressive loss of function and is associated with many chronic conditions including cancer, type II diabetes, neurodegenerative disease, cardiovascular disease, and osteoarthritis (1, 2). Although several theories aimed at explaining the aging phenotype have been suggested, an age-related imbalance between the production of reactive oxygen species (ROS) 2 and the antioxidant capacity of the cell has been identified as a contributing factor (3-5). Although the original free radical theory of aging focused on accumulation of cellular damage from excessive ROS as a cause for aging and age-related conditions, more recent studies suggest that disturbances in redox signaling that result from age-related oxidative stress are likely to play a key role (5-7). Increased levels of ROS caused by mitochondrial dysfunction, one of the hallmarks of aging, have been proposed to contribute to age-related oxidative stress, but the underlying mechanisms for how this increase causes a disruption in cell signaling leading to cell and tissue dysfunction is poorly understood (1, 4, 8).Recent advances in redox signaling recognize that reversible post-translational oxidative modifications of reactive protein cysteine thiols mediated by controlled production of H 2 O 2 regulate key signal transduction events (9, 10). The cysteine-dependent peroxiredoxins (PRXs), which display high rea...

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“…ROS could decrease the collagen and protein synthesis through suppressing the mitochondrial oxidative phosphorylation and adenosine triphosphate (ATP) formation (Johnson et al, 2000). It was suggested that insulin-like growth factor-1 (IGF-1) might be the promoter of the matrix formation, but there were evidences indicating that ROS contributed to the chondrocyte IGF-1 resistance and reduced the proteoglycan synthesis by causing an imbalance in the activity between the phosphatidylinositol 3-kinase-Akt pathway and the MEK-ERK MAPK signaling pathway (Yin et al, 2009). The decomposition was more than the synthesis, which speedups the progression of matrix degradation.…”

Section: Oa and Rosmentioning

confidence: 99%

Can hydrogen retard the progression of osteoarthritis?

Li¹

2012

Afr. J. Pharm. Pharmacol.

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There is a direct relationship between reactive oxygen species (ROS) and the progression of osteoarthritis (OA). Hydrogen is considered as a selective antioxidant, which can neutralize the superfluous ROS. This investigation aimed to describe whether hydrogen can be used as a new treatment to retard the progression of OA based on recent studies. The peer-reviewed literature published prior to July, 2011 in the PubMed database was searched using pre-defined search criteria. Articles, published in English, were selected for their relevance to ROS, hydrogen or OA. The pathogenesis of OA is multifactor. Studies have revealed that ROS can contribute to the onset and progression of OA by inducing indispensable chondrocyte death and matrix degradation. Meanwhile, hydrogen is considered to be a selective antioxidant and can be used as a kind of therapeutic medical gas which has recently been explored in animal model and in clinic. We propose a hypothesis that hydrogen may be a new treatment to retard the progression of OA, although further researches need to be carried out in vivo or clinical studies.

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Oxidative Stress Inhibits Insulin-like Growth Factor-I Induction of Chondrocyte Proteoglycan Synthesis through Differential Regulation of Phosphatidylinositol 3-Kinase-Akt and MEK-ERK MAPK Signaling Pathways

Cited by 159 publications

References 63 publications

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes

Can hydrogen retard the progression of osteoarthritis?

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