TNFα suppresses link protein and type II collagen expression in chondrocytes: Role of MEK1/2 and NF‐κB signaling pathways

Séguin, Cheryle A.; Bernier, Suzanne M.

doi:10.1002/jcp.10371

Cited by 130 publications

(133 citation statements)

References 55 publications

(60 reference statements)

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“…21 Cells were plated at a density of 4.5 Â 10 4 cells per cm 2 on tissue culture-coated multi-well plates (BD Falcon, Mississauga, ON, Canada) in 2:3 DMEM:F12 culture medium with 10% fetal bovine serum, supplemented with 50 mg/ml ascorbic acid, 0.25% L-glutamine and 0.25% penicillin/ streptomycin for 48 h. Media was replaced with serum-free media 24 h before the treatment. Treatment was carried out for 48 h in the serum-free media plus 0.1% DMSO vehicle (control) or 10 ng/ml recombinant human TGFa (Biosource-Medicorp, Montréal, QC, Canada) in the presence or absence of 10 mM pharmacological inhibitor of ROCK (Y27632), MEK1/2 (U0126), PI3K (LY294002), or p38 MAPK (SB202190) or 1 mg/ml cell-permeable toxin C3 Rho inhibitor (Cytoskeleton, Denver, CO, USA).…”

Section: Materials and Methods Reagentsmentioning

confidence: 99%

Rho/ROCK and MEK/ERK activation by transforming growth factor-α induces articular cartilage degradation

Appleton

Usmani

Mort

et al. 2010

Laboratory Investigation

103

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Identification and characterization of therapeutic targets for joint conditions, such as osteoarthritis (OA), is exceedingly important for addressing the increasing burden of disease. Transforming growth factor-a (TGFa) is upregulated by articular chondrocytes in experimentally induced and human OA. To test the potential involvement of TGFa, which is an activator of epidermal growth factor receptor (EGFR) signaling, in joint degeneration and to identify signaling mechanisms mediating articular chondrocyte responses to TGFa, rat chondrocytes and osteochondral explants were treated with TGFa and various inhibitors of intracellular signaling pathways. Stimulation of EGFR signaling in articular chondrocytes by TGFa resulted in the activation of RhoA/ROCK (Rho kinase), MEK (MAPK/ERK kinase)/ERK (extracellularsignal-regulated kinase), PI3K (phosphoinositide 3-kinase) and p38 MAPK (mitogen-activated protein kinase) pathways. Modification of the chondrocyte actin cytoskeleton was stimulated by TGFa, but inhibition of only Rho or ROCK activation prevented morphological changes. TGFa suppressed expression of anabolic genes including Sox9, type II collagen and aggrecan, which were rescued only by inhibiting MEK/ERK activation. Furthermore, catabolic factor upregulation by TGFa was prevented by ROCK and p38 MAPK inhibition, including matrix metalloproteinase-13 and tumor necrosis factor-a, which are well known to contribute to cartilage digestion in OA. To assess the ability of TGFa to stimulate degradation of mature articular cartilage, type II collagen and aggrecan cleavage fragments were analyzed in rat osteochondral explants exposed to exogenous TGFa. Normal articular cartilage contained low levels of both cleavage fragments, but high levels were observed in the cartilage treated with TGFa. Selective inhibition of MEK/ERK and Rho/ROCK activation greatly reduced or completely prevented excess type II collagen and aggrecan degradation in response to TGFa. These data suggest that TGFa is a strong stimulator of cartilage degradation and that Rho/ROCK and MEK/ERK signaling have critical roles in mediating these effects. KEYWORDS: articular cartilage; chondrocyte; epidermal growth factor receptor; osteoarthritis; transforming growth factor alpha Osteoarthritis (OA) is a chronic, degenerative, synovial joint condition, which affects the knees, hips and other smaller joints of B10% of the North American population. The societal burden of OA is increasing and OA already accounts for 25% of visits to primary care physicians and for 50% of nonsteroidal anti-inflammatory drug prescriptions.1,2 Approximately 80% of individuals have radiographic evidence of OA by age 65 years, of which 60% are symptomatic.1 Furthermore, progressive joint degeneration combined with an inherently low capacity for articular cartilage regeneration makes treatment very difficult. As current therapies are strictly palliative, identification and characterization of therapeutic targets is exceedingly important to meet the increasing burden of disease. Althou...

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Section: Materials and Methods Reagentsmentioning

confidence: 99%

Rho/ROCK and MEK/ERK activation by transforming growth factor-α induces articular cartilage degradation

Appleton

Usmani

Mort

et al. 2010

Laboratory Investigation

103

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“…Chondrocytes were harvested by the method described by Séguin and Bernier (26). Briefly, under sterile conditions, cartilage derived from the limb joints of 2-week-old SD rats was harvested and chopped into fragments of approximately 1 mm 3 .…”

Section: Methodsmentioning

confidence: 99%

Periodic mechanical stress activates MEK1/2-ERK1/2 mitogenic signals in rat chondrocytes through Src and PLCγ1

Huang

Liang

Liu

et al. 2011

Braz J Med Biol Res

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“…In considering the clinical application, questions such as how long the inhibitory effects of decoy ODN continue and whether decoy ODN would regress the size of established AAA should be addressed. Because NFB negatively regulates the production of collagen and elastin, 48,49 it might be possible that decoy ODN could regress the size of AAA.…”

Section: Perspectivesmentioning

confidence: 99%

Hypertension Accelerated Experimental Abdominal Aortic Aneurysm Through Upregulation of Nuclear Factor κB and Ets

et al. 2006

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Abstract-In this study, we focused on the effect of hypertension on the transcription factors nuclear factor B (NFB) and ets in the mechanisms of abdominal aortic aneurysm (AAA), and we investigated how hypertension affects the progression of AAA. AAA was produced by elastase perfusion in hypertensive rats and normotensive rats. The size of AAA rapidly increased in hypertensive rats as compared with normotensive rats. Western blot analysis demonstrated that the expression of matrix metalloproteinase (MMP)-2, -3 , -9, and -12, as well as intercellular adhesion molecule, was increased in hypertensive AAA rats, accompanied by upregulation of NFB and ets. Moreover, in situ zymography showed that the activity of MMPs was increased in the aorta of a hypertensive AAA model as compared with that in a normotensive AAA model. Interestingly, transfection of chimeric decoy oligodeoxynucleotide (ODN) resulted in significant inhibition of aortic dilatation both in normotensive and hypertensive rats at 4 weeks after transfection. Destruction of elastic fibers was also significantly inhibited by transfection of chimeric decoy ODN in both hypertensive rats and normotensive rats. The expression of MMP-2, -3, -9, and -12, as well as intercellular adhesion molecule, was significantly attenuated by the chimeric decoy ODN, accompanied by inhibition of the migration of macrophages. Also, the effect of chimeric decoy ODN was confirmed in an organ culture. The present study demonstrated that hypertension accelerated the progression of experimental AAA through upregulation of NFB and ets. Inhibition of NFB and ets could be a novel therapeutic strategy to treat AAA in hypertensive patients. bdominal aortic aneurysm (AAA) is a common degenerative condition associated with aging and atherosclerosis. 1 Because the main pathogenesis of AAA is considered to be based on atherosclerosis, patients with aneurysms and atherosclerotic disease share similar risk factors, including male sex, 2 older age, 3 and a lipid profile that includes lower high-density lipoprotein and higher triglyceride and lowdensity lipoprotein concentrations. 4 However, the risk factors for atherosclerosis and AAA are not completely the same, because there are certain pathogenetic, epidemiological, and genetic differences between these 2 diseases. 5,6 Indeed, although hypertension induces sheer stress, oxidative stress, and vascular inflammation followed by atherosclerosis, a consistent relation between blood pressure and the prevalence of AAA has not been demonstrated. 7,8 Hypertension has been reported to be both independently associated with AAA and not associated with AAA. 8,9 Basic phenomena in the pathogenesis of AAA are degradation of extracellular matrix components and loss of structural integrity of the aortic wall. 10 AAA disease typically involves tissue inflammation as seen by the presence of inflammatory cells, which are considered to participate in the immunopathogenesis of AAA leading to destruction of the aortic matrix. 11,12 Recent investigations have emph...

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TNFα suppresses link protein and type II collagen expression in chondrocytes: Role of MEK1/2 and NF‐κB signaling pathways

Cited by 130 publications

References 55 publications

Rho/ROCK and MEK/ERK activation by transforming growth factor-α induces articular cartilage degradation

Rho/ROCK and MEK/ERK activation by transforming growth factor-α induces articular cartilage degradation

Periodic mechanical stress activates MEK1/2-ERK1/2 mitogenic signals in rat chondrocytes through Src and PLCγ1

Hypertension Accelerated Experimental Abdominal Aortic Aneurysm Through Upregulation of Nuclear Factor κB and Ets

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