Differential regulation of matrix metalloproteinase-9 by monocytes adherent to collagen and platelets
S W Galt1, S Lindemann, D Medd
1Division of Vascular Surgery, Department of Internal Medicine, Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah, USA. sgalt@hsc.utah.edu
Abstract:
Circulating monocytes adhere to platelets and matrix proteins at sites of vascular injury, where engagement of specific surface tethering molecules mediates outside-in signaling and synthesis of gene products by the leukocytes. Here we demonstrate that interaction of isolated human monocytes with collagen induces matrix metalloproteinase-9 (MMP-9; gelatinase B) synthesis by monocytes, a process that is greatly enhanced in the presence of platelets. MMP-9 is a potent matrix degrading enzyme implicated in atherosclerotic plaque rupture, aneurysm formation, and other vascular syndromes. Synthesis of MMP-9 by monocytes is tightly regulated and synergistically increased following adhesion to collagen and platelets. Adhesion to control matrix proteins alone did not result in MMP-9 protein production and, similarly, adhesion of monocytes to platelets activated with thrombin in suspension was not sufficient to induce MMP-9 synthesis in the absence of monocyte adhesion to collagen. Interruption of intercellular contact between platelets and monocytes dramatically inhibited MMP-9 synthesis. These observations demonstrate that discrete adhesion-dependent signaling pathways govern MMP-9 synthesis by monocytes. The synthesis of MMP-9 by monocytes may be critical in vascular syndromes and other pathological processes that are dependent on dysregulated cell-cell and cell-matrix interactions.
Insights
Monocyte interaction with collagen and platelets significantly enhances matrix metalloproteinase-9 (MMP-9) synthesis. This adhesion-dependent process is crucial for understanding vascular syndromes involving cell-matrix interactions.
Area of Science:
- Immunology
- Vascular Biology
- Biochemistry
Background:
- Circulating monocytes play a key role in vascular injury response.
- Monocyte adhesion to extracellular matrix and platelets triggers signaling pathways.
- Matrix metalloproteinase-9 (MMP-9) is implicated in vascular pathologies like atherosclerosis.
Purpose of the Study:
- To investigate the regulation of MMP-9 synthesis by human monocytes.
- To determine the role of monocyte adhesion to collagen and platelets in MMP-9 production.
- To elucidate the signaling pathways involved in MMP-9 synthesis.
Main Methods:
- Isolated human monocytes were cultured with collagen and/or activated platelets.
- MMP-9 synthesis was measured following monocyte adhesion.
- Intercellular contact between monocytes and platelets was disrupted to assess its effect.
Main Results:
- Monocyte adhesion to collagen induced MMP-9 synthesis.
- The presence of platelets synergistically enhanced collagen-induced MMP-9 synthesis.
- Adhesion to matrix proteins alone or to suspended activated platelets did not induce MMP-9 synthesis.
- Disruption of monocyte-platelet contact significantly inhibited MMP-9 synthesis.
Conclusions:
- Monocyte MMP-9 synthesis is critically dependent on adhesion to collagen and platelets.
- Discrete adhesion-dependent signaling pathways regulate MMP-9 production.
- Monocyte-derived MMP-9 may be a key mediator in vascular syndromes characterized by dysregulated cell-cell and cell-matrix interactions.
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