Key role of suppressor of cytokine signaling 3 in regulating gp130 cytokine-induced signaling and limiting chondrocyte responses during murine inflammatory arthritis.
OBJECTIVE
To examine the impact of the gp130 cytokine family on murine articular cartilage and to explore a potential regulatory role of suppressor of cytokine signaling 3 (SOCS-3) in murine chondrocytes.


METHODS
In wild-type (WT) mouse chondrocytes, baseline receptor expression levels and gp130 cytokine-induced JAK/STAT signaling were determined by flow cytometry, and expression of SOCS-3 was assessed by quantitative polymerase chain reaction. The role of endogenous SOCS-3 was examined in cartilage explants and chondrocytes from mice with conditional deletion of Socs3 driven by the Col2a1 promoter in vitro (Socs3(Δ/Δcol2) ) and from mice during CD4+ T cell-dependent inflammatory monarthritis. Bone erosions in the murine joints were analyzed by micro-computed tomography.


RESULTS
On chondrocytes from WT mice, gp130 and the oncostatin M (OSM) receptor were strongly expressed, whereas the transmembrane interleukin-6 (IL-6) receptor was expressed at much lower levels. Compared to other gp130 cytokines, OSM was the most potent activator of the JAK/STAT pathway and of SOCS-3 induction. Treatment of Socs3(Δ/Δcol2) mouse cartilage explants and chondrocytes with gp130 cytokines prolonged JAK/STAT signaling, enhanced cartilage degradation, increased the expression of Adamts4, Adamts5, and RANKL, and elevated the production of IL-6, granulocyte colony-stimulating factor, CXCL1, and CCL2. Socs3(Δ/Δcol2) mice developed exacerbated inflammation and joint damage in response to gp130 cytokine injections, and these histopathologic features were also observed in mice with inflammatory monarthritis.


CONCLUSIONS
The results of this study highlight a key role for SOCS-3 in regulating chondrocyte responses during inflammatory arthritis. Within the gp130 cytokine family, OSM is a potent stimulus of chondrocyte responses, while IL-6 probably signals via trans-signaling. The gp130 cytokine-driven production of RANKL in chondrocytes may link chondrocyte activation and bone remodeling during inflammatory arthritis. Thus, these findings suggest that the inhibition of OSM might reduce the development and severity of structural joint damage during inflammatory arthritis.
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia and University of Melbourne, Parkville, Victoria, Australia.
Xiao
X
Liu
Ben A
BA
Croker
Ian K
IK
Campbell
Stephanie J
SJ
Gauci
Warren S
WS
Alexander
Brett A
BA
Tonkin
Nicole C
NC
Walsh
Edmond M
EM
Linossi
Sandra E
SE
Nicholson
Kate E
KE
Lawlor
Ian P
IP
Wicks
D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism*; D002358:Cartilage, Articular / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism*; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism*; D007719:Knee Joint / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053683:Oncostatin M / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D053677:Receptors, Oncostatin M / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*
D019947:Receptors, Interleukin-6; D053677:Receptors, Oncostatin M; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053683:Oncostatin M; D050822:Cytokine Receptor gp130