Differential regulation of matrix metalloproteinase-9 by monocytes adherent to collagen and platelets

Circulating monocytes adhere to platelets and matrix proteins at sites of v ascular injury, where engagement of specific surface tethering molecules me diates outside-in signaling and synthesis of gene products by the leukocyte s. Here we demonstrate that interaction of isolated human monocytes with co llagen induces matrix metalloproteinase-9 (MMP-9; gelatinase B) synthesis b y monocytes, a process that is greatly enhanced in the presence of platelet s. 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 f ollowing adhesion to collagen and platelets. Adhesion to control matrix pro teins alone did not result in MMP-9 protein production and, similarly, adhe sion of monocytes to platelets activated with thrombin in suspension was no t sufficient to induce MMP-9 synthesis in the absence of monocyte adhesion to collagen. Interruption of intercellular contact between platelets and mo nocytes dramatically inhibited MMP-9 synthesis. These observations demonstr ate that discrete adhesion-dependent signaling pathways govern MMP-9 synthe sis by monocytes. The synthesis of MMP-9 by monocytes may be critical in va scular syndromes and other pathological processes that are dependent on dys regulated cell-cell and cell-matrix interactions.