Synergistic effects of glycoprotein 130 binding cytokines in combination with interleukin-1 on cartilage collagen breakdown.

Abstract

OBJECTIVE:

To determine whether other glycoprotein 130 (gp130) binding cytokines can mimic the effects of oncostatin M (OSM) in acting synergistically with interleukin-1alpha (IL-1alpha) to induce cartilage collagen breakdown and collagenase expression, and to determine which receptors mediate these effects.

METHODS:

The release of collagen and proteoglycan was assessed in bovine and human cartilage explant cultures. Messenger RNA (mRNA) and protein production from immortalized human chondrocytes (T/C28a4) was analyzed by Northern blotting and specific enzyme-linked immunosorbent assays. Collagenase activity was measured by bioassay. Cell surface receptors were detected by flow cytometry.

RESULTS:

OSM in combination with IL-1alpha caused a rapid synergistic induction of matrix metalloproteinase 1 mRNA, which was sustained over a 72-hour period. Flow cytometric analyses detected both the OSM-specific receptor and the gp130 receptor at the chondrocyte cell surface, but failed to detect the leukemia inhibitory factor receptor (LIFR). Cartilage degradation assays revealed that, of the gp130 binding cytokines, only OSM and IL-6, in the presence of its soluble receptor (sIL-6R), were able to act synergistically with IL-1alpha to promote collagen release.

CONCLUSION:

This study demonstrates that IL-6 can mimic OSM in synergizing with IL-1alpha to induce chondrocyte-mediated cartilage collagen breakdown and collagenase production. In order to have this effect, IL-6 requires the presence of its soluble receptor. The apparent absence of LIFR explains why other gp130 binding cytokines do not act in synergy with IL-1alpha. Since OSM, IL-6, and sIL-6R levels have all been shown to be elevated in the rheumatoid joint, our findings suggest that these cytokines may be key mediators of cartilage collagen catabolism in the inflammatory arthritides.

• Authors: A D Rowan, P J Koshy, W D Shingleton, B A Degnan, J K Heath, A B Vernallis, J R Spaull, P F Life, K Hudson, T E Cawston
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 44 Issue 7 Pg. 1620-32 (Jul 2001) ISSN: 0004-3591 [Print] United States
• PMID: 11465713 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Ciliary Neurotrophic Factor
• Cytokines
• Growth Inhibitors
• IL6ST protein, human
• Interleukin-1
• Interleukin-11
• Interleukin-6
• LIF protein, human
• Leukemia Inhibitory Factor
• Lymphokines
• Membrane Glycoproteins
• OSM protein, human
• Peptides
• RNA, Messenger
• Receptors, Interleukin-6
• Tissue Inhibitor of Metalloproteinase-1
• Oncostatin M
• Tissue Inhibitor of Metalloproteinase-2
• Cytokine Receptor gp130
• Collagen
• cardiotrophin 1
• Matrix Metalloproteinase 1

Topics

• Animals
• Antigens, CD (metabolism)
• Cartilage, Articular (cytology)
• Cattle
• Cell Line, Transformed
• Chondrocytes (cytology, drug effects, enzymology)
• Ciliary Neurotrophic Factor (metabolism, pharmacology)
• Collagen (metabolism)
• Cytokine Receptor gp130
• Cytokines (metabolism, pharmacology)
• Drug Synergism
• Gene Expression Regulation, Enzymologic (drug effects)
• Growth Inhibitors (metabolism, pharmacology)
• Humans
• Interleukin-1 (metabolism, pharmacology)
• Interleukin-11 (metabolism, pharmacology)
• Interleukin-6 (metabolism, pharmacology)
• Leukemia Inhibitory Factor
• Lymphokines (metabolism, pharmacology)
• Matrix Metalloproteinase 1 (genetics, metabolism)
• Membrane Glycoproteins (metabolism)
• Oncostatin M
• Peptides (metabolism, pharmacology)
• RNA, Messenger (analysis)
• Receptors, Interleukin-6 (metabolism)
• Tissue Inhibitor of Metalloproteinase-1 (genetics, metabolism)
• Tissue Inhibitor of Metalloproteinase-2 (genetics, metabolism)