Key role of suppressor of cytokine signaling 3 in regulating gp130 cytokine-induced signaling and limiting chondrocyte responses during murine inflammatory arthritis
Details
Publication Year 2014-05-16, Volume 66, Issue #9, Page 2391-2402
Journal Title
Arthritis Rheumatol
Publication Type
Journal Article
Abstract
Objective. This study examines the impact of the gp130 cytokine family on cartilage and a potential regulatory role for Suppressor of Cytokine Signaling-3 (SOCS3) in chondrocytes. Methods. Baseline receptor expression levels and gp130 cytokine-induced JAK-STAT signaling were determined by flow cytometry in wild-type (WT) chondrocytes and SOCS3 expression in chondrocytes was assessed by quantitative polymerase chain reaction (qPCR). The role of endogenous SOCS3 in chondrocytes was examined in mice with conditional deletion of SOCS3 driven by the Col2a1 promoter (Socs3Delta/Deltacol2 mice) in vitro and during CD4+ dependent inflammatory monoarthritis. Bone erosion was analyzed by micro-computed tomography (microCT). Results. gp130 and the oncostatin M (OSM) receptor were strongly expressed on WT chondrocytes, whereas the transmembrane IL-6 receptor was not. Compared to other gp130 cytokines, OSM was the most potent activator of the JAK-STAT pathway and of SOCS3 induction. Treatment of Socs3Delta/Deltacol2 cartilage explants and chondrocytes with gp130 cytokines prolonged JAK-STAT signaling, enhanced cartilage degradation, increased Adamts4, Adamts5 and RANKL expression, and elevated production of IL-6, G-CSF, CXCL1 and CCL2. Socs3Delta/Deltacol2 mice developed exacerbated inflammation and joint damage in response to gp130 cytokine injections and during inflammatory monoarthritis. Conclusion. These data highlight a key role for SOCS3 in regulating chondrocyte responses during inflammatory arthritis. Within the gp130-cytokine family OSM is a potent stimulus for chondrocytes, while IL-6 probably signals via trans-signaling. gp130 cytokine driven RANKL production in chondrocytes may link chondrocyte activation and bone remodeling during inflammatory arthritis. These findings suggest OSM inhibition might reduce structural joint damage during inflammatory arthritis. (c) 2014 American College of Rheumatology.
Publisher
Wiley
WEHI Research Division(s)
Cancer And Haematology; Inflammation
Publisher's Version
https://doi.org/10.1002/art.38701
NHMRC Grants
NHMRC/1023407 NHMRC/1016647
Rights Notice
Copyright © 2014 American College of Rheumatology


Creation Date: 2014-05-22 07:46:40
Last Modified: 2015-09-07 12:26:20
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