Interleukin-1 Acts via the JNK-2 Signaling Pathway to Induce Aggrecan Degradation by Human Chondrocytes

Arthritis & Rheumatology
Heba M IsmailJeremy Saklatvala

Abstract

Aggrecan enables articular cartilage to bear load and resist compression. Aggrecan loss occurs early in osteoarthritis and rheumatoid arthritis and can be induced by inflammatory cytokines such as interleukin-1 (IL-1). IL-1 induces cleavage of specific aggrecans characteristic of the ADAMTS proteinases. The aim of this study was to identify the intracellular signaling pathways by which IL-1 causes aggrecan degradation by human chondrocytes and to investigate how aggrecanase activity is controlled by chondrocytes. We developed a cell-based assay combining small interfering RNA (siRNA)-induced knockdown with aggrecan degradation assays. Human articular chondrocytes were overlaid with bovine aggrecan after transfection with siRNAs against molecules of the IL-1 signaling pathway. After IL-1 stimulation, released aggrecan fragments were detected with AGEG and ARGS neoepitope antibodies. Aggrecanase activity and tissue inhibitor of metalloproteinases 3 levels were measured by enzyme-linked immunosorbent assay. Low-density lipoprotein receptor-related protein 1 (LRP-1) shedding was analyzed by Western blotting. ADAMTS-5 is a major aggrecanase in human chondrocytes, regulating aggrecan degradation in response to IL-1. The tumor necrosi...Continue Reading

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Citations

Jan 29, 2016·Journal of Cellular and Molecular Medicine·Selene Pérez-GarcíaYasmina Juarranz
Jun 18, 2016·Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society·Carina L BlakerChristopher B Little
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Sep 30, 2020·The Lancet Rheumatology·Tonia L Vincent
Aug 10, 2021·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Zi-Ling ZouLing-Yi Kong

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