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. 2007 Sep;171(3):938-46.
doi: 10.2353/ajpath.2007.061083. Epub 2007 Jul 19.

Activation of interleukin-1 signaling cascades in normal and osteoarthritic articular cartilage

Zhiyong Fan  1 , Stephan Söder, Stephan Oehler, Katrin Fundel, Thomas Aigner
Affiliations

Activation of interleukin-1 signaling cascades in normal and osteoarthritic articular cartilage

Zhiyong Fan et al. Am J Pathol. 2007 Sep.

Abstract

Interleukin (IL)-1 is one of the most important catabolic cytokines in rheumatoid arthritis. In this study, we were interested in whether we could identify IL-1 expression and activity within normal and osteoarthritic cartilage. mRNA expression of IL-1beta and of one of its major target genes, IL-6, was observed at very low levels in normal cartilage, whereas only a minor up-regulation of these cytokines was noted in osteoarthritic cartilage, suggesting that IL-1 signaling is not a major event in osteoarthritis. However, immunolocalization of central mediators involved in IL-1 signaling pathways [38-kd protein kinases, phospho (P)-38-kd protein kinases, extracellular signal-regulated kinase 1/2, P-extracellular signal-regulated kinase 1/2, c-Jun NH(2)-terminal kinase 1/2, P-c-Jun NH(2)-terminal kinase 1/2, and nuclear factor kappaB] showed that the four IL-1 signaling cascades are functional in normal and osteoarthritic articular chondrocytes. In vivo, we found that IL-1 expression and signaling mechanisms were detectible in the upper zones of normal cartilage, whereas these observations were more pronounced in the upper portions of osteoarthritic cartilage. Given these expression and distribution patterns, our data support two roles for IL-1 in the pathophysiology of articular cartilage. First, chondrocytes in the upper zone of osteoarthritic articular cartilage seem to activate catabolic signaling pathways that may be in response to diffusion of external IL-1 from the synovial fluid. Second, IL-1 seems to be involved in normal cartilage tissue homeostasis as shown by identification of baseline expression patterns and signaling cascade activation.

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Figures

Figure 1
Figure 1
A: Real-time PCR analysis for expression of mRNA levels of IL-1β and IL-6 in normal, early degenerative (early deg.), and late-stage osteoarthritic (late OA) cartilage. Bars show the means and standard deviations (expression levels standardized to glyceraldehyde-3-phosphate dehydrogenase; GAPDH). B: Correlation blot analysis in between IL-1 and IL-6 expression in cartilage samples investigated (normal, early degenerated, and late-stage osteoarthritic).
Figure 2
Figure 2
Quantitative TaqMan analysis for mRNA expression levels of IL-1β (A) and IL-6 (B) in normal articular chondrocytes with and without stimulation with IL-1β (in Dulbecco’s modified Eagle’s medium/Ham’s F-12 media supplemented with 10% fetal calf serum) for 96 hours (given are the log ratios of stimulation/control of six independent experiments each). *P < 0.05 versus control; **P < 0.01 versus control; ***P < 0.001 versus control. C: Table showing the absolute values (per glyceraldehyde-3-phosphate dehydrogenase; GAPDH) with standard deviations.
Figure 3
Figure 3
A–L: Immunostaining of total ERK (A and C), JNK (E and G), and p38 (I and K) as well as activated P-ERK (B and D), P-JNK (F and H), and P-p38 (J and L) in normal (A, B, E, F, I, and J) and osteoarthritic (C, D, G, H, K, and L) cartilage. M–P: Immunostaining of NF-κB in normal (M and N) and osteoarthritic (O and P) cartilage (N and P; confocal imaging micrographs: red, antigen staining; green, nuclear DNA counterstain). Scale bars: 50 μm (A–M, O); 10 μm (N and P).
Figure 4
Figure 4
A–C: Schematic representation of semiquantitative evaluation of the activated/phosphorylated MAPKs in normal and osteoarthritic articular cartilage sections depending on the location of the chondrocytes within the different cartilage zones. Note that the superficial zone is missing in osteoarthritic cartilage. sup, superficial zone; inter, intermediate cartilage zone; up-d, upper deep cartilage zone; lw-d, lower deep cartilage zone.
Figure 5
Figure 5
Immunostaining of phosphorylated ERK1/2 (A and B), p38 (C and D), JNK1/2 (E and F), and NF-κB (G and H; confocal analysis: red, antigen staining; green, nuclear DNA counterstain) in normal cartilage unstimulated (A, C, E, and G) and after treatment with 10 ng/ml IL-1β for 60 minutes (B, D, F, and H).
Figure 6
Figure 6
A: Western blot analysis of cell lysates of chondrocytes isolated enzymatically from normal (N; n = 2) and osteoarthritic (OA; n = 2) cartilage showing the presence of all JNK, p38, and ERK1/2 MAPKs as well as NF-κB. B: Chondrocytes were stimulated in vitro with 10 ng/ml IL-1β for 10 and 20 minutes (lanes 2 and 3; lane 1, control) and probed for the three activated MAPKs. For control, PC-12 cells were treated with (lane 4) and without (lane 5) IL-1β as positive and negative controls.
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