Ja. Ardans et al., Raloxifene-mediated increase in matrix metalloproteinase-1 production by activated monocytes, ART THROM V, 21(8), 2001, pp. 1265-1268
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.