Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


The Enhanced Expression of Suppressor of Cytokine Signaling (SOCS)-3 in Human Pathological Chondrocytes Impairs the TLR4 and IGF-1 Signaling in These Cells.

A. J. van de Loo,  Fons, B. Bennink,  Miranda, J. Arntz,  Onno, M. van Beuningen,  Henk, M. van der Kraan,  Peter, S. Veenbergen,  Sharon, B. van den Berg,  Wim

Introduction:

Osteoarthritis (OA), a degenerative joint disease, and Rheumatoid arthritis (RA), an inflammatory joint disease, are both characterized by progressive loss of the articular cartilage matrix due to an imbalance between matrix synthesis and degradation. Loss in the chondrocytes ability to respond to growth factor stimulation may be a key factor contributing to the development of OA and RA. We recently found that enforced expression of SOCS3 caused IGF-1 resistance in chondrocytes, thereby preventing upregulation of matrix proteoglycan synthesis. This study is designed to determine the expression of SOCS3 in human pathological chondrocytes and unravel the biological/functional consequences.

Methods:

Chondrocytes were isolated from cartilage of patients undergoing surgical joint replacement. The mRNA and protein levels of SOCS1 and SOCS3 were measured by qPCR and westernblotting. Levels of SOCS3 were compared to a human immortalized chondrocyte cell-line (G6), mesenchymal-stem cells differentiated chondrocytes, and primary chondrocytes isolated from healthy bovine cartilage or from a SLE patient. The regulation of SOCS1 and 3 expression was studied in OA chondrocytes by incubation with different cytokines and TLR agonists. To determine the functional consequences the cytokine and TLR ligand induced nitric-oxide production and IGF-1-stimulated proteoglycan (PG) synthesis was studied.

Results:

The SOCS3 mRNA expression in articular chondrocytes and cartilage was markedly upregulated (32-fold) in 21/24 OA, 5/5 RA patients, 3/3 trauma patients tested, as compared to the G6 cell-line, stem cell-differentiated chondrocytes, and chondrocytes derived from a SLE-patient. Exposure of the mesenchymal stem cell-derived chondrocytes with conditioned media of OA synovial explants upregulated SOCS3 to the same extent as seen in the OA chondrocytes. Exposure of OA chondrocytes to different cytokines (IL-1b, IL-17, IL-18) and TLR ligands (LPS, Pam2Cys, Poly(I:C), FK156, MDP could not further upregulate SOCS3 expression. In contrast, SOCS1 expression was markedly lower (20-fold) in comparison to SOCS3 in OA chondrocytes and could be upregulated to the level of SOCS3 using IL-1b, IFNg, IL-17, Pam2Cys, Poly(I:C), and especially with the combination of IFNg and Poly(I:C). SOCS3 expression in OA chondrocytes was confirmed at the protein level. This means that the SOCS3 and SOCS1 genes are independently regulated and that SOCS3 has reached the maximal expression level. In the OA chondrocytes, the TLR4 ligand LPS was unable to induce NO production and IGF-1 failed to stimulate PG synthesis. Forced expression of SOCS3 in bovine cartilage-derived chondrocytes blocked the LPS (NO) and IGF-1 (PG-synthesis) response in these cells.

Conclusion:

We found increased SOCS3 but not SOCS1 expression in human pathological chondrocytes. SOCS3 could block TLR4 and IGF-1 activation in chondrocytes. This suggests that SOCS3 modifies normal chondrocyte function and this could play a major role in the development of cartilage pathology seen in osteoarthritis and rheumatoid arthritis patients.

To cite this abstract, please use the following information:
A. J. van de Loo, Fons, B. Bennink, Miranda, J. Arntz, Onno, M. van Beuningen, Henk, M. van der Kraan, Peter, S. Veenbergen, Sharon, et al; The Enhanced Expression of Suppressor of Cytokine Signaling (SOCS)-3 in Human Pathological Chondrocytes Impairs the TLR4 and IGF-1 Signaling in These Cells. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1501
DOI: 10.1002/art.29267

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