Mitochondrial dysfunction triggers a catabolic response in chondrocytes via ROS-mediated activation of the JNK/AP1 pathway

ABSTRACTMitochondrial function is impaired in osteoarthritis (OA) but its impact on cartilage catabolism is not fully understood. Here, we investigated the molecular mechanism of mitochondrial dysfunction-induced activation of the catabolic response in chondrocytes. Using cartilage slices from normal and OA cartilage, we showed that mitochondrial membrane potential was lower in OA cartilage, and that this was associated with increased production of mitochondrial superoxide and catabolic genes [interleukin 6 (IL-6), COX-2 (also known as PTGS2), MMP-3, -9, -13 and ADAMTS5]. Pharmacological induction of mitochondrial dysfunction in chondrocytes and cartilage explants using carbonyl cyanide 3-chlorophenylhydrazone increased mitochondrial superoxide production and the expression of IL-6, COX-2, MMP-3, -9, -13 and ADAMTS5, and cartilage matrix degradation. Mitochondrial dysfunction-induced expression of catabolic genes was dependent on the JNK (herein referring to the JNK family)/activator protein 1 (AP1) pathway but not the NFκB pathway. Scavenging of mitochondrial superoxide with MitoTEMPO, or pharmacological inhibition of JNK or cFos and cJun, blocked the mitochondrial dysfunction-induced expression of the catabolic genes in chondrocytes. We demonstrate here that mitochondrial dysfunction contributes to OA pathogenesis via JNK/AP1-mediated expression of catabolic genes. Our data shows that AP1 could be used as a therapeutic target for OA management.This article has an associated First Person interview with the first author of the paper.

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Effect of Rubus idaeus Extracts in Murine Chondrocytes and Explants

Biomolecules ◽

10.3390/biom11020245 ◽

2021 ◽

Vol 11 (2) ◽

pp. 245

Author(s):

Morgane Bourmaud ◽

Mylene Zarka ◽

Romain Le Cozannet ◽

Pascale Fança-Berthon ◽

Eric Hay ◽

...

Keyword(s):

Rubus Idaeus ◽

Cartilage Explants ◽

Cartilage Loss ◽

Primary Chondrocytes ◽

Inflammatory Conditions ◽

Catabolic Genes ◽

Gene And Protein Expression ◽

Chondrocyte Metabolism ◽

Cox2 Expression ◽

And Cartilage

Osteoarthritis is characterized by cartilage loss resulting from the activation of chondrocytes associated with a synovial inflammation. Activated chondrocytes promote an increased secretion of matrix proteases and proinflammatory cytokines leading to cartilage breakdown. Since natural products possess anti-inflammatory properties, we investigated the direct effect of Rubus idaeus extracts (RIE) in chondrocyte metabolism and cartilage loss. The effect of RIE in chondrocyte metabolism was analyzed in murine primary chondrocytes and cartilage explants. We also assessed the contribution of RIE in an inflammation environment by culturing mice primary chondrocytes with the supernatant of Raw 264.7 macrophage-like cells primed with RIE. In primary chondrocytes, RIE diminished chondrocyte hypertrophy (Col10), while increasing the expression of catabolic genes (Mmp-3, Mmp-13) and reducing anabolic genes (Col2a1, Acan). In cartilage explants, Rubus idaeus prevented the loss of proteoglycan (14.84 ± 3.07% loss of proteoglycans with IL1 alone vs. 3.03 ± 1.86% with IL1 and 100 µg/mL of RIE), as well as the NITEGE neoepitope expression. RIE alone reduced the expression of Il1 and Il6 in macrophages, without changes in Tnf and Cox2 expression. The secretome of macrophages pre-treated with RIE and transferred to chondrocytes decreases the gene and protein expression of Mmp-3 and Cox2. In conclusion, these data suggest that RIE may protect from chondrocyte catabolism and cartilage loss in inflammatory conditions. Further evaluations are need before considering RIE as a candidate for the treatment for osteoarthritis.

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Cytokine synergy, collagenases and cartilage collagen breakdown

Biochemical Society Symposium ◽

10.1042/bss0700125 ◽

2003 ◽

Vol 70 ◽

pp. 125-133 ◽

Cited By ~ 7

Author(s):

Tim E. Cawston ◽

Jenny M. Milner ◽

Jon B. Catterall ◽

Andrew D. Rowan

Keyword(s):

Matrix Metalloproteinases ◽

Inflammatory Cytokines ◽

Activator Protein 1 ◽

Activator Protein ◽

And Cartilage ◽

Pro Inflammatory Cytokines

We have investigated proteinases that degrade cartilage collagen. We show that pro-inflammatory cytokines act synergistically with oncastatin M to promote cartilage collagen resorption by the up-regulation and activation of matrix metalloproteinases (MMPs). The precise mechanisms are not known, but involve the up-regulation of c-fos, which binds to MMP promoters at a proximal activator protein-1 (AP-1) site. This markedly up-regulates transcription and leads to higher levels of active MMP proteins.

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Deoxycholic (DOC) acid-induced expression of cyclooxygenase-2 (COX-2) in human colonic fibroblasts

Gastroenterology ◽

10.1016/s0016-5085(01)80840-4 ◽

2001 ◽

Vol 120 (5) ◽

pp. A170-A170

Author(s):

S RAFIQ ◽

Y ZHU ◽

P LANCE

Keyword(s):

Cyclooxygenase 2 ◽

Induced Expression ◽

Cox 2

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POS0393 FIBRIN DEPOSITION IS AN ACTIVE TRIGGER OF CARTILAGE DEGENERATION IN RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2521 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 426.1-426

Author(s):

T. Hügle ◽

S. Nasi ◽

D. Ehirchiou ◽

P. Omoumi ◽

A. So ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cartilage Damage ◽

Cartilage Degeneration ◽

Cartilage Explants ◽

Fibrin Deposition ◽

Qrt Pcr ◽

Catabolic Genes ◽

Key Factor ◽

Calcific Deposits

Background:Fibrin(ogen) maintains inflammation in various disorders but has never been linked to cartilage damage in rheumatoid arthritis (RA) or other forms of inflammatory arthritis.Objectives:To investigate the role of fibrin deposition on cartilage integrity in arthritis.Methods:Fibrin deposition on knee cartilage was analyzed by immunohistochemistry in RA patients and in murine adjuvant-induced arthritis (AIA). In chondrocytes, fibrinogen expression (Fgα, Fgβ, Fgγ) and procoagulant activity were evaluated by qRT-PCR and turbidimetry respectively. Fibrin-induced catabolic genes were assessed by qRT-PCR in chondrocytes. Fibrin-mediated chondro-synovial adhesion (CSA) with subsequent cartilage tears was studied in co-cultures of human RA cartilage with autologous synoviocytes, in the AIA model, and by MRI. The link between fibrin and calcification was examined in human RA cartilage stained for calcific deposits and in vitro in fibrinogen-stimulated chondrocytes.Results:Fibrin deposition on cartilage correlated with the severity of cartilage damage in human RA explants and in AIA wildtype (WT) mice, while fibrinogen deficient (Fg-/-) mice were protected. Accordingly, fibrin upregulated catabolic enzymes (Adamts5 and Mmp13) in chondrocytes. Secondly, CSA was present in fibrin-rich and damaged cartilage in AIA WT but not in Fg-/- mice. In line, autologous human synoviocytes, cultured on RA cartilage explants, adhered exclusively to fibrin-positive degraded areas. Gadolinium-enhanced MRI of human joints showed contrast-enhancement along cartilage surface in RA patients but not in controls. Finally, fibrin co-localized with calcification in human RA cartilage and triggered chondrocyte mineralization inducing pro-calcification genes (Anx5, Pit1, Pc1) and cytokine (IL-6). Although at a much lesser extent, we observed similar fibrin-mediated mechanisms in osteoarthritis (OA).Conclusion:Fibrin deposition directly impacts on cartilage integrity via induction of catabolism, mechanical stress, and calcification. Potentially, fibrin is a key factor of cartilage damage occurring in RA as a secondary consequence of inflammation.Disclosure of Interests:None declared

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COX-2, NO, and cartilage damage and repair

Current Rheumatology Reports ◽

10.1007/s11926-000-0019-5 ◽

2000 ◽

Vol 2 (6) ◽

pp. 447-453 ◽

Cited By ~ 96

Author(s):

Ashok R. Amin ◽

Mandar Dave ◽

Mukundan Attur ◽

Steven B. Abramson

Keyword(s):

Cartilage Damage ◽

Cox 2 ◽

And Cartilage

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Xanthotoxin suppresses LPS-induced expression of iNOS, COX-2, TNF-α, and IL-6 via AP-1, NF-κB, and JAK-STAT inactivation in RAW 264.7 macrophages

International Immunopharmacology ◽

10.1016/j.intimp.2017.05.021 ◽

2017 ◽

Vol 49 ◽

pp. 21-29 ◽

Cited By ~ 31

Author(s):

Seung-Bin Lee ◽

Woo Seok Lee ◽

Ji-Sun Shin ◽

Dae Sik Jang ◽

Kyung Tae Lee

Keyword(s):

Raw 264.7 ◽

Induced Expression ◽

Raw 264.7 Macrophages ◽

Tnf Α ◽

Cox 2

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Oleic acid reduces lipopolysaccharide-induced expression of iNOS and COX-2 in BV2 murine microglial cells: Possible involvement of reactive oxygen species, p38 MAPK, and IKK/NF-κB signaling pathways

Neuroscience Letters ◽

10.1016/j.neulet.2009.08.040 ◽

2009 ◽

Vol 464 (2) ◽

pp. 93-97 ◽

Cited By ~ 67

Author(s):

Young Taek Oh ◽

Jung Yeon Lee ◽

Jinhwa Lee ◽

Hocheol Kim ◽

Kyung-Sik Yoon ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Oleic Acid ◽

Signaling Pathways ◽

P38 Mapk ◽

Reactive Oxygen ◽

Microglial Cells ◽

Oxygen Species ◽

Induced Expression ◽

Cox 2

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Functional Organization of the Endoplasmic Reticulum Dictates the Susceptibility of Target Cells to Arsenite-Induced Mitochondrial Superoxide Formation, Mitochondrial Dysfunction and Apoptosis

10.21203/rs.3.rs-479781/v1 ◽

2021 ◽

Author(s):

Andrea Guidarelli ◽

Alessia Catalani ◽

Ersilia Varone ◽

Stefano Fumagalli ◽

Ester Zito ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Mitochondrial Dysfunction ◽

Functional Organization ◽

Close Contact ◽

Cell Types ◽

Target Cells ◽

Close Apposition ◽

Mitochondrial Superoxide ◽

Low Concentrations ◽

Absolute Requirement

Abstract Arsenite induces many critical effects associated with the formation of reactive oxygen species (ROS) through different mechanisms. We focused on the Ca2+-dependent mitochondrial superoxide (mitoO2-.) formation and addressed questions on the effects of low concentrations of arsenite on the mobilization of the cation from the endoplasmic reticulum and the resulting mitochondrial accumulation. Using various differentiated and undifferentiated cell types uniquely expressing the inositol-1, 4, 5-triphosphate receptor (IP3R), or both the IP3R and the ryanodine receptor (RyR), we determined that expression of this second Ca2+ channel is an absolute requirement for mitoO2-. formation and for the ensuing mitochondrial dysfunction and downstream apoptosis. In arsenite-treated cells, RyR was recruited after IP3R stimulation and agonist studies indicated that in these cells RyR is in close apposition with mitochondria. It was also interesting to observe that arsenite fails to promote mitochondrial Ca2+ accumulation, mitoO2-. formation, mitochondrial toxicity in RyR-devoid cells, in which the IP3R is in close contact with the mitochondria. We therefore conclude that low dose arsenite-induced mitoO2- formation and the resulting mitochondrial dysfunction and toxicity, are prerequisite of cell types expressing the RyR in close apposition with mitochondria.

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