Ut. Shankavaram et al., Monocyte membrane type 1-matrix metalloproteinase - Prostaglandin-dependent regulation and role in metalloproteinase-2 activation, J BIOL CHEM, 276(22), 2001, pp. 19027-19032
Membrane type 1-matrix metalloproteinase (MT1-MMP)-mediated activation of M
MP-2 is thought to be important in the proteolysis of extracellular matrix
in pathological events in which monocytes/macrophages are found. Here we re
port on the induction and regulation of human monocyte MT1-MMP and its role
in MMP-2 activation. Activation of monocytes by lipopolysaccharide resulte
d in the induction of MT1-MMP mRNA and protein that was suppressed by inhib
itors of prostaglandin synthesis (indomethacin), adenylyl cyclase (SQ 22536
), and protein kinase A (Rp-cAMPs). Suppression of MT1-MMP by indomethacin
and SQ 22536 was reversed by prostaglandin E, and dibutyryl cyclic AMP, res
pectively, demonstrating that induction of monocyte MT1-MMP is regulated th
rough a prostaglandin-cAMP pathway. Functional analysis revealed that pro-M
MP-2 in the supernatants from human bone marrow stromal fibroblasts, normal
male-derived fibroblasts and melanoma cells (A2058) was converted to activ
e MMP-2 when cultured with activated but not control monocytes, Antibodies
against MT1-MMP blocked the activation of MMP-2. Tissue inhibitor of metall
oproteinase-2 regulation of MMP-2 activation was shown through the addition
of varying amounts of recombinant tissue inhibitor of metalloproteinase-2
with pro-MMP-2 to MT1-MMP-expressing monocytes, These findings demonstrate
that activated monocytes express functionally active MT1-MMP that may play
a significant role in the activation of MMP-2 produced by other cells and a
s such influence developmental and pathological conditions.