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An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model.

Gong JH, Ratkay LG, Waterfield JD, Clark-Lewis I - J. Exp. Med. (1997)

Bottom Line: In contrast, controls treated with native MCP-1 had enhanced arthritis symptoms, indicating that the inhibitory effect is specific to the antagonist.In experiments where the antagonist was given only after the disease had already developed, there was a marked reduction in symptoms and histopathology, although individuals varied in the magnitude of the response.The mechanism of inhibition of disease is not known, although the results suggest that it could be more complex than the competitive inhibition of ligand binding that is observed in vitro.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Research Centre and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.

ABSTRACT
An antagonist of human monocyte chemoattractant protein (MCP)-1, which consists of MCP-1(9-76), had previously been characterized and shown to inhibit MCP-1 activity in vitro. To test the hypothesis that, by inhibiting endogenous MCP-1, the antagonist has antiinflammatory activity in vivo, we examined its effect in the MRL-lpr mouse model of arthritis. This strain spontaneously develops a chronic inflammatory arthritis that is similar to human rheumatoid arthritis. Daily injection of the antagonist, MCP-1(9-76), prevented the onset of arthritis as monitored by measuring joint swelling and by histopathological evaluation of the joints. In contrast, controls treated with native MCP-1 had enhanced arthritis symptoms, indicating that the inhibitory effect is specific to the antagonist. In experiments where the antagonist was given only after the disease had already developed, there was a marked reduction in symptoms and histopathology, although individuals varied in the magnitude of the response. The mechanism of inhibition of disease is not known, although the results suggest that it could be more complex than the competitive inhibition of ligand binding that is observed in vitro. The demonstration of the beneficial effects of an MCP-1 antagonist in arthritis suggests that chemokine receptor antagonists could have therapeutic application in inflammatory diseases.

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The effects of MCP-1 antagonist on the joint histopathology. Representative photomicrographs of histology from the experiment in Fig. 1  a are shown. For the control group: (a) marked subsynovial infiltration by mononuclear cells resembling rheumatoid nodule formation (×20 objective);  (b) pannus formation and synovial hyperplasia (×40) objective; (c) bone erosion (arrow; ×20 objective). For the antagonist (2.0 mg/kg) -treated group: (d)  indicates some stromal thickening of the subsynovium, but absence of infiltrating cells or joint destruction (×20 objective). as, articular surface; b, bone;  bm, bone marrow; bv, blood vessel; jc, joint cavity; mc, mononuclear cell infiltrate; p, pannus; sh, synovial hyperplasia; si, subsynovial inflammation; ss,  subsynovium.
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Figure 2: The effects of MCP-1 antagonist on the joint histopathology. Representative photomicrographs of histology from the experiment in Fig. 1 a are shown. For the control group: (a) marked subsynovial infiltration by mononuclear cells resembling rheumatoid nodule formation (×20 objective); (b) pannus formation and synovial hyperplasia (×40) objective; (c) bone erosion (arrow; ×20 objective). For the antagonist (2.0 mg/kg) -treated group: (d) indicates some stromal thickening of the subsynovium, but absence of infiltrating cells or joint destruction (×20 objective). as, articular surface; b, bone; bm, bone marrow; bv, blood vessel; jc, joint cavity; mc, mononuclear cell infiltrate; p, pannus; sh, synovial hyperplasia; si, subsynovial inflammation; ss, subsynovium.

Mentions: Histological analysis of the ankle joints was performed at day 30 for all the experiments described. Shown in Fig. 2 are photomicrographs taken from representative antagonist-treated and control animals, from the experiment described in Fig. 1 a. The effects observed in control mice that were not given MCP-1 antagonist included infiltration of mononuclear cells into the subsynovial tissue (Fig. 2 a), synovial hyperplasia, pannus formation (Fig. 2 b), and bone erosion (Fig. 2 c). In contrast, mononuclear cell infiltration and bone and cartilage pathology was absent in the MCP-1 antagonist–treated example. Only minor thickening of the subsynovium can be seen (Fig. 2 d). Analysis of the histological results (Fig. 3) for the experiment described in Figure 1 a, indicates that the group that received 2.0 mg/kg antagonist had significant lower subsynovial inflammation, synovial hyperplasia, pannus formation and cartilage erosion, bone destruction, and overall histopathology. The histopathology results for the antagonist-treated group compared favorably to age-matched animals that have not been primed with CFA and have no disease symptoms (not shown). Interestingly, compared to the controls, the group (Fig. 1 a) that received 0.5 mg/kg had significantly lower overall histopathology (Fig. 3), even though joint swelling was not significantly reduced. This suggests that the antagonist is affecting cellular infiltration and pathology even in the absence of an apparent effect on externally measurable symptoms.


An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model.

Gong JH, Ratkay LG, Waterfield JD, Clark-Lewis I - J. Exp. Med. (1997)

The effects of MCP-1 antagonist on the joint histopathology. Representative photomicrographs of histology from the experiment in Fig. 1  a are shown. For the control group: (a) marked subsynovial infiltration by mononuclear cells resembling rheumatoid nodule formation (×20 objective);  (b) pannus formation and synovial hyperplasia (×40) objective; (c) bone erosion (arrow; ×20 objective). For the antagonist (2.0 mg/kg) -treated group: (d)  indicates some stromal thickening of the subsynovium, but absence of infiltrating cells or joint destruction (×20 objective). as, articular surface; b, bone;  bm, bone marrow; bv, blood vessel; jc, joint cavity; mc, mononuclear cell infiltrate; p, pannus; sh, synovial hyperplasia; si, subsynovial inflammation; ss,  subsynovium.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198969&req=5

Figure 2: The effects of MCP-1 antagonist on the joint histopathology. Representative photomicrographs of histology from the experiment in Fig. 1 a are shown. For the control group: (a) marked subsynovial infiltration by mononuclear cells resembling rheumatoid nodule formation (×20 objective); (b) pannus formation and synovial hyperplasia (×40) objective; (c) bone erosion (arrow; ×20 objective). For the antagonist (2.0 mg/kg) -treated group: (d) indicates some stromal thickening of the subsynovium, but absence of infiltrating cells or joint destruction (×20 objective). as, articular surface; b, bone; bm, bone marrow; bv, blood vessel; jc, joint cavity; mc, mononuclear cell infiltrate; p, pannus; sh, synovial hyperplasia; si, subsynovial inflammation; ss, subsynovium.
Mentions: Histological analysis of the ankle joints was performed at day 30 for all the experiments described. Shown in Fig. 2 are photomicrographs taken from representative antagonist-treated and control animals, from the experiment described in Fig. 1 a. The effects observed in control mice that were not given MCP-1 antagonist included infiltration of mononuclear cells into the subsynovial tissue (Fig. 2 a), synovial hyperplasia, pannus formation (Fig. 2 b), and bone erosion (Fig. 2 c). In contrast, mononuclear cell infiltration and bone and cartilage pathology was absent in the MCP-1 antagonist–treated example. Only minor thickening of the subsynovium can be seen (Fig. 2 d). Analysis of the histological results (Fig. 3) for the experiment described in Figure 1 a, indicates that the group that received 2.0 mg/kg antagonist had significant lower subsynovial inflammation, synovial hyperplasia, pannus formation and cartilage erosion, bone destruction, and overall histopathology. The histopathology results for the antagonist-treated group compared favorably to age-matched animals that have not been primed with CFA and have no disease symptoms (not shown). Interestingly, compared to the controls, the group (Fig. 1 a) that received 0.5 mg/kg had significantly lower overall histopathology (Fig. 3), even though joint swelling was not significantly reduced. This suggests that the antagonist is affecting cellular infiltration and pathology even in the absence of an apparent effect on externally measurable symptoms.

Bottom Line: In contrast, controls treated with native MCP-1 had enhanced arthritis symptoms, indicating that the inhibitory effect is specific to the antagonist.In experiments where the antagonist was given only after the disease had already developed, there was a marked reduction in symptoms and histopathology, although individuals varied in the magnitude of the response.The mechanism of inhibition of disease is not known, although the results suggest that it could be more complex than the competitive inhibition of ligand binding that is observed in vitro.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Research Centre and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.

ABSTRACT
An antagonist of human monocyte chemoattractant protein (MCP)-1, which consists of MCP-1(9-76), had previously been characterized and shown to inhibit MCP-1 activity in vitro. To test the hypothesis that, by inhibiting endogenous MCP-1, the antagonist has antiinflammatory activity in vivo, we examined its effect in the MRL-lpr mouse model of arthritis. This strain spontaneously develops a chronic inflammatory arthritis that is similar to human rheumatoid arthritis. Daily injection of the antagonist, MCP-1(9-76), prevented the onset of arthritis as monitored by measuring joint swelling and by histopathological evaluation of the joints. In contrast, controls treated with native MCP-1 had enhanced arthritis symptoms, indicating that the inhibitory effect is specific to the antagonist. In experiments where the antagonist was given only after the disease had already developed, there was a marked reduction in symptoms and histopathology, although individuals varied in the magnitude of the response. The mechanism of inhibition of disease is not known, although the results suggest that it could be more complex than the competitive inhibition of ligand binding that is observed in vitro. The demonstration of the beneficial effects of an MCP-1 antagonist in arthritis suggests that chemokine receptor antagonists could have therapeutic application in inflammatory diseases.

Show MeSH
Related in: MedlinePlus