Cysteine‐Mediated Redox Regulation of Cell Signaling in Chondrocytes Stimulated With Fibronectin Fragments

Wood, Scott T.; Long, David; Reisz, Julie A.; Yammani, Raghunatha R.; Burke, Elizabeth; Klomsiri, Chananat; Poole, Leslie B.; Furdui, Cristina M.; Loeser, Richard F.

doi:10.1002/art.39326

Cited by 39 publications

(40 citation statements)

References 51 publications

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“…AF645) for immunohistochemistry (IHC), recombinant Wnt5a protein and recombinant Wnt3a protein were from R&D Systems. Purified endotoxin-free recombinant 42kDa FN-f, containing the cell binding RGD domain, was produced as previously described 17 . RT 2 qPCR primers were from Qiagen except that aggrecan (ACAN) primer was as previously described 18 .…”

Section: Methodsmentioning

confidence: 99%

Wnt5a induces catabolic signaling and matrix metalloproteinase production in human articular chondrocytes

Huang

Chubinskaya

Liao

et al. 2017

Osteoarthritis and Cartilage

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Objective Aberrant Wnt signaling may contribute to osteoarthritis (OA) but the Wnt family members involved have not been fully identified. The purpose of this study was to investigate the role of Wnt5a as a potential mediator of cartilage destruction in OA. Design Immunohistochemistry to detect Wnt5a was performed using normal and OA human articular cartilage. Cultured normal human chondrocytes were treated with fibronectin fragments (FN-f) as a catabolic stimulus or recombinant Wnt5a protein with or without pretreatment using a panel of signaling inhibitors. Expression of Wnt5a, anabolic genes and catabolic genes were determined by quantitative real-time PCR. Production of Wnt5a protein and matrix metalloproteinases (MMPs) as well as activation of signaling proteins were analyzed by immunoblotting. Results Wnt5a was present in human articular cartilage with OA changes and its expression and secretion were increased in FN-f stimulated chondrocytes. FN-f stimulated Wnt5a production through the JNK and ERK pathways. Wnt5a reduced aggrecan gene expression after 48 hours of treatment. Wnt5a seemed to promote MMP1, -3, and -13 expression as well as MMP1 and MMP13 protein production in normal human chondrocytes. Wnt5a inhibitor peptides did not affect FN-f induced MMP production. Wnt5a activated β-catenin independent signaling including calmodulin-dependent protein kinase II (CaMKII), JNK, p38, ERK1/2, p65 and Akt. Inhibition of JNK, p38, ERK, PI-3 kinase and CaMKII by specific signaling inhibitors suppressed Wnt5a mediated MMP1 and MMP13 production. Conclusions Wnt5a is present in human OA cartilage and can promote chondrocyte catabolic activity through non-canonical Wnt signaling, which suggests a potential role in OA.

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Section: Methodsmentioning

confidence: 99%

Wnt5a induces catabolic signaling and matrix metalloproteinase production in human articular chondrocytes

Huang

Chubinskaya

Liao

et al. 2017

Osteoarthritis and Cartilage

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“…Cysteine oxidation initially results in the formation of a cysteine sulfenic acid (Cys-SOH) in a process known as S -sulfenylation. In a 2016 study, chondrocytes from patients with OA had an increased basal level of S -sulfenylation compared with those from healthy controls 80 . ROS induced sulfenylation of multiple chondrocyte proteins including the tyrosine kinase SRC, the activity of which promoted an increase in the production of matrix metalloproteinase 13 (MMP-13) 80 .…”

Section: Oxidative Stress and The Mitochondriamentioning

confidence: 98%

“…In a 2016 study, chondrocytes from patients with OA had an increased basal level of S -sulfenylation compared with those from healthy controls 80 . ROS induced sulfenylation of multiple chondrocyte proteins including the tyrosine kinase SRC, the activity of which promoted an increase in the production of matrix metalloproteinase 13 (MMP-13) 80 . These data suggest that ROS-induced sulfenylation of chondrocyte proteins can alter signalling pathways that can promote cartilage degradation.…”

Section: Oxidative Stress and The Mitochondriamentioning

confidence: 98%

Ageing and the pathogenesis of osteoarthritis

Loeser¹,

Collins²,

2016

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Ageing-associated changes that affect articular tissues promote the development of osteoarthritis (OA). Although ageing and OA are closely linked, they are independent processes. Several potential mechanisms by which ageing contributes to OA have been elucidated. This Review focuses on the contributions of the following factors: age-related inflammation (also referred to as ‘inflammaging’); cellular senescence (including the senescence-associated secretory phenotype (SASP)); mitochondrial dysfunction and oxidative stress; dysfunction in energy metabolism due to reduced activity of 5′-AMP-activated protein kinase (AMPK), which is associated with reduced autophagy; and alterations in cell signalling due to age-related changes in the extracellular matrix. These various processes contribute to the development of OA by promoting a proinflammatory, catabolic state accompanied by increased susceptibility to cell death that together lead to increased joint tissue destruction and defective repair of damaged matrix. The majority of studies to date have focused on articular cartilage, and it will be important to determine whether similar mechanisms occur in other joint tissues. Improved understanding of ageing-related mechanisms that promote OA could lead to the discovery of new targets for therapies that aim to slow or stop the progression of this chronic and disabling condition.

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“…Other studies have proposed activation of Src through intramolecular disulfide bond formation between Cys245 and Cys487 induced by H 2 O 2 [106], and possibly by nitric oxide [107] and peroxynitrite [108], though the NO and ONOO − mechanisms of Src activation have not been fully elucidated. In a recent study, increased Src sulfenylation and activity were detected and proposed to contribute to cartilage degradation in osteoarthritis [109]. Thus, it is likely that both mechanisms exist and come into play depending on stimuli, timing, and presence of other co-regulatory events.…”

Section: Redox Regulation Of Signalingmentioning

confidence: 99%

Biological chemistry and functionality of protein sulfenic acids and related thiol modifications

Devarie‐Baez

Lopez

Furdui

2015

Free Radical Research

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Selective modification of proteins at cysteine residues by reactive oxygen, nitrogen or sulfur species formed under physiological and pathological states is emerging as a critical regulator of protein activity impacting cellular function. This review focuses primarily on protein sulfenylation (-SOH), a metastable reversible modification connecting reduced cysteine thiols to many products of cysteine oxidation. An overview is first provided on the chemistry principles underlining synthesis, stability and reactivity of sulfenic acids in model compounds and proteins, followed by a brief description of analytical methods currently employed to characterize these oxidative species. The following chapters present a selection of redox-regulated proteins for which the -SOH formation was experimentally confirmed and linked to protein function. These chapters are organized based on the participation of these proteins in the regulation of signaling, metabolism and epigenetics. The last chapter discusses the therapeutic implications of altered redox microenvironment and protein oxidation in disease.

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Cysteine‐Mediated Redox Regulation of Cell Signaling in Chondrocytes Stimulated With Fibronectin Fragments

Cited by 39 publications

References 51 publications

Wnt5a induces catabolic signaling and matrix metalloproteinase production in human articular chondrocytes

Wnt5a induces catabolic signaling and matrix metalloproteinase production in human articular chondrocytes

Ageing and the pathogenesis of osteoarthritis

Biological chemistry and functionality of protein sulfenic acids and related thiol modifications

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