Interleukin-26 Has Synergistic Catabolic Effects with Palmitate in Human Articular Chondrocytes via the TLR4-ERK1/2-c-Jun Signaling Pathway

The inflammatory cytokine interleukin-26 (IL-26) is highly expressed in the serum and synovial fluid of patients with inflammatory arthritis. The effect of IL-26 on human articular chondrocytes (HACs) remains unclear. Obesity is associated with disability of patients with rheumatoid arthritis and disease activity in those with ankylosing spondylitis. The saturated free fatty acid palmitate with IL-1β can synergistically induce catabolic effects in HACs. The aim of this study was to evaluate the effects of IL-26 and palmitate in HACs. In this study, palmitate markedly synergizes the IL-26-induced proinflammatory effects and matrix protease, including COX-2, IL-6, and MMP-1, in HACs via the toll-like receptor 4 (TLR4)-ERK1/2-c-Jun signal transduction pathway. The synergistic catabolic effects of palmitate and IL-26 were attenuated by inhibitors of TLR4 (TAK242), ERK1/2 (U0126), or c-Jun (SP600125) in HACs and cartilage matrix. In addition, metformin, a potential inhibitor of TLR4, also decreased expression of COX-2 and IL-6 induced by co-incubation with IL-26 and palmitate. IL-26 and palmitate synergistically induced expression of inflammatory and catabolic mediators, resulting in articular cartilage matrix breakdown. The present study also revealed a possible mechanism and therapeutic targets against articular cartilage degradation by increased saturated fatty acids in patients with inflammatory arthritis.

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The ciliary protein IFT88 controls post-natal cartilage thickness and influences development of osteoarthritis

10.1101/2020.07.29.225599 ◽

2020 ◽

Author(s):

CR Coveney ◽

L Zhu ◽

J Miotla-Zarebska ◽

B Stott ◽

I Parisi ◽

...

Keyword(s):

Articular Cartilage ◽

Cell Biology ◽

Articular Chondrocytes ◽

Skeletal Development ◽

Cartilage Degradation ◽

Cartilage Thickness ◽

Tissue Growth ◽

Calcified Cartilage ◽

Health And Disease

AbstractMechanical forces are known to drive cellular signalling programmes in cartilage development, health, and disease. Proteins of the primary cilium, implicated in mechanoregulation, control cartilage formation during skeletal development, but their role in post-natal cartilage is unknown. Ift88fl/fl and AggrecanCreERT2 mice were crossed to create a cartilage specific inducible knockout mouse AggrecanCreERT2;Ift88fl/fl. Tibial articular cartilage thickness was assessed, through adolescence and adulthood, by histomorphometry and integrity by OARSI score. In situ cell biology was investigated by immunohistochemistry (IHC) and qPCR of micro-dissected cartilage. OA was induced by destabilisation of the medial meniscus (DMM). Some mice were provided with exercise wheels in their cage. Deletion of IFT88 resulted in a reduction in medial articular cartilage thickness (atrophy) during adolescence from 102.57μm, 95% CI [94.30, 119.80] in control (Ift88fl/fl) to 87.36μm 95% CI [81.35, 90.97] in AggrecanCreERT2;Ift88fl/fl by 8-weeks p<0.01, and adulthood (104.00μm, 95% CI [100.30, 110.50] in Ift88fl/fl to 89.42μm 95% CI [84.00, 93.49] in AggrecanCreERT2;Ift88fl/fl, 34-weeks, p<0.0001) through a reduction in calcified cartilage. Thinning in adulthood was associated with spontaneous cartilage degradation. Following DMM, AggrecanCreERT2;Ift88fl/fl mice had increased OA (OARSI scores at 12 weeks Ift88fl/fl = 22.08 +/− 9.30, and AggrecanCreERT2;Ift88fl/fl = 29.83 +/− 7.69). Atrophy was not associated with aggrecanase-mediated destruction or chondrocyte hypertrophy. Ift88 expression positively correlated with Tcf7l2 and connective tissue growth factor. Cartilage thickness was restored in AggrecanCreERT2;Ift88fl/fl by voluntary wheel exercise. Our results demonstrate that ciliary IFT88 regulates cartilage thickness and is chondroprotective, potentially through modulating mechanotransduction pathways in articular chondrocytes.

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Association of articular cartilage degradation and loss of boundary-lubricating ability of synovial fluid following injury and inflammatory arthritis

Arthritis & Rheumatism ◽

10.1002/art.21038 ◽

2005 ◽

Vol 52 (6) ◽

pp. 1746-1755 ◽

Cited By ~ 118

Author(s):

K. A. Elsaid ◽

G. D. Jay ◽

M. L. Warman ◽

D. K. Rhee ◽

C. O. Chichester

Keyword(s):

Articular Cartilage ◽

Synovial Fluid ◽

Inflammatory Arthritis ◽

Cartilage Degradation

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Hypoxia upregulates the expression of angiopoietin-like-4 in human articular chondrocytes: Role of angiopoietin-like-4 in the expression of matrix metalloproteinases and cartilage degradation

Journal of Orthopaedic Research® ◽

10.1002/jor.20703 ◽

2009 ◽

Vol 27 (1) ◽

pp. 50-57 ◽

Cited By ~ 39

Author(s):

Minako Murata ◽

Kazuo Yudo ◽

Hiroshi Nakamura ◽

Junji Chiba ◽

Kazuki Okamoto ◽

...

Keyword(s):

Matrix Metalloproteinases ◽

Articular Chondrocytes ◽

Cartilage Degradation ◽

Human Articular Chondrocytes ◽

And Cartilage

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MicroRNA-27a alleviates IL-1β-induced inflammatory response and articular cartilage degradation via TLR4/NF-κB signaling pathway in articular chondrocytes

International Immunopharmacology ◽

10.1016/j.intimp.2019.105839 ◽

2019 ◽

Vol 76 ◽

pp. 105839 ◽

Cited By ~ 1

Author(s):

Wen-Jun Qiu ◽

Ming-Ze Xu ◽

Xiao-dong Zhu ◽

Yun-Han Ji

Keyword(s):

Articular Cartilage ◽

Inflammatory Response ◽

Signaling Pathway ◽

Articular Chondrocytes ◽

Cartilage Degradation

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The Lysine Specific Demethylase-1 Negatively Regulates the COL9A1 Gene in Human Articular Chondrocytes

International Journal of Molecular Sciences ◽

10.3390/ijms21176322 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6322

Author(s):

Anne-Laure Durand ◽

Alexandre Dufour ◽

Elisabeth Aubert-Foucher ◽

Christine Oger-Desfeux ◽

Marielle Pasdeloup ◽

...

Keyword(s):

Articular Chondrocytes ◽

Cartilage Matrix ◽

Human Articular Chondrocytes ◽

Collagen Molecule ◽

Sequencing Analysis ◽

Loss Of Function ◽

Gene Encoding ◽

Lysine Specific Demethylase ◽

Function Strategy

Osteoarthritis (OA) is a degenerative disease of the joints which is associated with an impaired production of the cartilage matrix by the chondrocytes. Here, we investigated the role of Lysine-Specific Demethylase-1 (LSD1), a chromatin remodeling enzyme whose role in articular chondrocytes was previously associated with a catabolic activity and which is potentially involved during OA. Following a loss of function strategy and RNA sequencing analysis, we detail the genes which are targeted by LSD1 in human articular chondrocytes and identify COL9A1, a gene encoding the α1 chain of the cartilage-specific type IX collagen, as negatively regulated by LSD1. We show that LSD1 interacts with the transcription factor SOX9 and is recruited to the promoter of COL9A1. Interestingly, we observe that OA cartilage displays stronger LSD1 immunostaining compared with normal, and we demonstrate that the depletion of LSD1 in OA chondrocytes prevents the decrease in COL9A1 following Il-1β treatment. These results suggest LSD1 is a new regulator of the anabolic activity of articular chondrocytes potentially destabilizing the cartilage matrix, since it negatively regulates COL9A1, a gene encoding a crucial anchoring collagen molecule. This newly identified role played by LSD1 may thus participate in the alteration of the cartilage matrix during OA.

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