Raloxifene-mediated increase in matrix metalloproteinase-1 production by activated monocytes

Matrix metalloproteinases (MMPs), proteolytic enzymes produced by monocytes , may contribute to atherosclerotic arterial wall remodeling and to plaque rupture. Because estrogen influences the synthesis of MMPs, we examined the effect of raloxifene, a selective estrogen receptor modulator, on monocyte MMP production. Human primary blood monocytes treated with raloxifene (10 mu mol/L) in the presence of lipopolysaccharide (LPS) or tumor necrosis fac tor-alpha and granulocyte-macrophage colony-stimulating factor induced a 2- to 3-fold increase in MMP-1 production by monocytes. The enhancement of MM P-1 production by raloxifene in LPS-activated monocytes occurred through a cyclooxygenase-2- and prostaglandin E-2-independent mechanism. Additionally , compared with monocytes acquired during the placebo phase, peripheral blo od monocytes from 5 of 6 healthy postmenopausal women treated with raloxife ne (60 mg daily for 1 month) in a clinical trial produced significantly hig her levels of MMP-1 when the monocytes were activated with LPS. Furthermore , serum obtained during the raloxifene phase from 4 of these subjects, when added to control monocytes, significantly enhanced LPS-induced MMP-1 produ ction compared with that from serum obtained during the placebo phase. In s ummary, raloxifene increases the production of MMP-1 in activated monocytes ; this effect may be favorable in atherosclerotic arterial wall remodeling but unfavorable for plaque stability.