Aim:
Articular chondrocytes contribute to inflammatory and degenerative arthritis through the production of enzymes that degrade the cartilage extracellular matrix, but little is known about the regulation of chondrocyte function. Suppressor of Cytokine Signalling 3 (SOCS-3) is the primary regulator of signalling through cytokines of the gp130 family. Here we investigate the impact of conditional deficiency of SOCS-3 in chondrocytes, in vitro and in vivo.
Methods:
Conditional gene targeting was used to generate mice lacking SOCS-3 selectively in chondrocytes under the Col2a1-Cre promoter (SOCS3Δ/Δcol2 mice). Primary chondrocytes and femoral head cartilage explants were obtained from control and SOCS3Δ/Δcol2 mice. Cartilage explant cultures were stimulated with gp130 cytokines and aggrecanase activity measured, using both the 1,9-DMMB dye-binding assay and quantitative PCR. STAT3 phosphorylation (pSTAT3) and cytokine/chemokine levels in response to gp130 cytokines were measured by flow cytometry and multiplex bead array, respectively. The responses of control and SOCS3Δ/Δcol2 mice to intraarticular cytokine injection and methylated Bovine Serum Albumin (mBSA)/IL-1-induced arthritis were assessed clinically and histologically.
Results:
SOCS-3 was expressed in wild type (WT) articular chondrocytes. All gp130 cytokines induced pSTAT3 and the production of IL-6, KC, MCP-1, RANTES, and G-CSF from WT chondrocytes. SOCS3Δ/Δcol2 chondrocytes exhibited sustained pSTAT3 induction and increased cytokine production in response to gp130 cytokines. Stimulation of WT femoral head cartilage with gp130 cytokines induced ADAMTS4 and ADAMTS5 expression and this was exacerbated in SOCS-3-deficient cartilage explants. SOCS3Δ/Δcol2 mice had markedly increased responses to intra-articular cytokine administration and to mBSA/IL-1-induced arthritis
Conclusions:
These results demonstrate that SOCS-3 is a critical regulator of gp130 cytokine signalling and a range of cellular responses in articular chondrocytes.