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Osteoarthritis Cartilage. 2015 Oct;23(10):1743-54. doi: 10.1016/j.joca.2015.05.011. Epub 2015 Jun 2.

Distinctive pro-inflammatory gene signatures induced in articular chondrocytes by oncostatin M and IL-6 are regulated by Suppressor of Cytokine Signaling-3.

Author information

1
Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, 3010, Australia.
2
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.
3
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA.
4
Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia; Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, 3010, Australia.
5
Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, 3010, Australia; Rheumatology Unit, Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia. Electronic address: wicks@wehi.edu.au.

Abstract

OBJECTIVE:

To describe gene expression in murine chondrocytes stimulated with IL-6 family cytokines and the impact of deleting Suppressor of Cytokine Signaling-3 (SOCS-3) in this cell type.

METHOD:

Primary chondrocytes were isolated from wild type and SOCS-3-deficient (Socs3(Δ/Δcol2)) mice and stimulated with oncostatin M (OSM), IL-6 plus the soluble IL-6 receptor (IL-6/sIL-6R), IL-11 or leukemia inhibitory factor (LIF) for 4 h. Total RNA was extracted and gene expression was evaluated by microarray analysis. Validation of the microarray results was performed using Taqman probes on RNA derived from chondrocytes stimulated for 1, 2, 4 or 8 h. Gene ontology was characterized using DAVID (database for annotation, visualization and integrated discovery).

RESULTS:

Multiple genes, including Bcl3, Junb, Tgm1, Angptl4 and Lrg1, were upregulated in chondrocytes stimulated with each gp130 cytokine. The gene transcription profile in response to OSM stimulation was pro-inflammatory and was highly correlated to IL-6/sIL-6R, rather than IL-11 or LIF. In the absence of SOCS-3, OSM and IL-6/sIL-6R stimulation induced an interferon (IFN)-like gene signature, including expression of IL-31ra and S100a9.

CONCLUSION:

While each gp130 cytokine induced a transcriptional response in chondrocytes, OSM- and IL-6/sIL-6R were the most potent members of this cytokine family. SOCS-3 plays an important regulatory role in this cell type, as it does in hematopoietic cells. Our results provide new insights into a hierarchy of gp130-induced transcriptional responses in chondrocytes that is normally restrained by SOCS-3 and suggest therapeutic inhibition of OSM may have benefit over and above antagonism of IL-6 during inflammatory arthritis.

KEYWORDS:

Arthritis; Cartilage and chondrocytes; Cytokines; Inflammation

PMID:
26045176
DOI:
10.1016/j.joca.2015.05.011
[Indexed for MEDLINE]
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