The
PPAR gamma agonists,
thiazolidinediones (TZDs), have anti-inflammatory properties as well as increasing
insulin sensitivity. This has widened their therapeutic scope to treat inflammatory diseases such as
atherosclerosis in addition to
Type 2 Diabetes. TZDs are known to reduce monocyte/macrophage expression of
Matrix metalloproteinase (MMP)-9, which is implicated in
atherosclerotic plaque destabilization. This study aims to identify other
metalloproteinase genes of the ADAM (A Disintegin And
Metalloproteinase) and ADAMTS families that are regulated by
PPAR gamma or RXR agonists, which are potentially important in
type 2 diabetes and/or related
atherosclerosis. The synthetic
PPAR gamma agonist,
GW7845, and the natural agonist
15d-PGJ2, suppressed PMA stimulated MMP-9 in human monocyte-like cells (THP-1) only in the presence of
9-cis-retinoic acid. Quantitative Real-Time PCR showed that this reduction was regulated at the
mRNA level. Expression of ADAMs 8, 9, and 17 were increased, and ADAM15 was decreased by stimulation of THP-1 with PMA, although these ADAMs were not regulated by
PPAR gamma or RXR agonists. PMA-induced ADAM28 expression was further enhanced by the addition of
9-cis-retinoic acid. ADAMTS4, implicated in
rheumatoid arthritis, was expressed in THP-1 cells, and significantly increased after 24 h of PMA stimulation. ADAMTS4 expression was suppressed by both
PPAR gamma and RXR agonists and was undetectable when the agonists were combined. Pretreatment of THP-1 cells with the
PPAR gamma antagonist,
GW9662, suggests that
PPAR gamma plays subtly different roles in the regulation of MMP-9, ADAMTS4 and ADAM28 gene expression. These results indicate that
PPAR gamma and RXR agonists have complex effects on monocyte
metalloproteinase expression, which may have implications for therapeutic strategies.