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Arthritis Rheum. 2011 Jul;63(7):1928-37. doi: 10.1002/art.30333.

Chondrocyte AMP-activated protein kinase activity suppresses matrix degradation responses to proinflammatory cytokines interleukin-1β and tumor necrosis factor α.

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  • 1VA San Diego Medical Center and University of California, San Diego, CA, USA.

Abstract

OBJECTIVE:

Interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) stimulate chondrocyte matrix catabolic responses, thereby compromising cartilage homeostasis in osteoarthritis (OA). AMP-activated protein kinase (AMPK), which regulates energy homeostasis and cellular metabolism, also exerts antiinflammatory effects in multiple tissues. This study was undertaken to test the hypothesis that AMPK activity limits chondrocyte matrix catabolic responses to IL-1β and TNFα.

METHODS:

Expression of AMPK subunits was examined, and AMPKα activity was ascertained by the phosphorylation status of AMPKα Thr(172) in human knee articular chondrocytes and cartilage by Western blotting and immunohistochemistry, respectively. Procatabolic responses to IL-1β and TNFα, such as release of glycosaminoglycan, nitric oxide, and matrix metalloproteinases 3 and 13 were determined by dimethylmethylene blue assay, Griess reaction, and Western blotting, respectively, in cartilage explants and chondrocytes with and without knockdown of AMPKα by small interfering RNA.

RESULTS:

Normal human knee articular chondrocytes expressed AMPKα1, α2, β1, β2, and γ1 subunits. AMPK activity was constitutively present in normal articular chondrocytes and cartilage, but decreased in OA articular chondrocytes and cartilage and in normal chondrocytes treated with IL-1β and TNFα. Knockdown of AMPKα resulted in enhanced catabolic responses to IL-1β and TNFα in chondrocytes. Moreover, AMPK activators suppressed cartilage/chondrocyte procatabolic responses to IL-1β and TNFα and the capacity of TNFα and CXCL8 (IL-8) to induce type X collagen expression.

CONCLUSION:

Our findings indicate that AMPK activity is reduced in OA cartilage and in chondrocytes following treatment with IL-1β or TNFα. AMPK activators attenuate dephosphorylation of AMPKα and procatabolic responses in chondrocytes induced by these cytokines. These observations suggest that maintenance of AMPK activity supports cartilage homeostasis by protecting cartilage matrix from inflammation-induced degradation.

Copyright © 2011 by the American College of Rheumatology.

PMID:
21400477
[PubMed - indexed for MEDLINE]
PMCID:
PMC3128233
Free PMC Article

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