Regulation of human monocyte proMMP-9 production by fetuin, an endogenous TGF-? antagonist

Abstract

Members of the matrix metalloproteinase family of enzymes degrade specific components of the extracellular matrix. MMP-9 is a type IV/V collagenase necessary for normal osteogenesis and is increased in inflammatory and neoplastic conditions. In such destructive diseases as emphysema and arthritis, and in epithelial cancers, MMP-9 is produced by cells of the monocyte lineage. Fetuin, a prominent serum glycoprotein, binds to and inactivates TGF-beta family members and through this mechanism regulates osteogenesis (Binkert et al., 1999, J Biol Chem 274:28514-28520.). We studied the effects of TGF-beta1 and fetuin on proMMP-9 release by the human monocyte line THP-1. Exogenous TGF-beta1 stimulated proMMP-9 release by THP-1 cells, with half-maximal stimulation at approximately 0.01 ng/ml TGF-beta1. Human fetuin (0.5-2 microM) partially inhibited this stimulation. Human fetuin alone stimulated THP-1 monocyte proMMP-9 release, with half maximal stimulation at approximately 0.25 microM fetuin. Neutralizing antibody specific for TGF-beta1 also stimulated proMMP-9 release, suggesting that endogenously-derived TGF-beta1 has an inhibitory effect. In freshly isolated human peripheral blood monocytes, fetuin stimulated proMMP-9 release with a dose-response curve similar to that observed in THP-1 cells. Human fetuin also activated proMMP-9 present in THP-1 conditioned medium. Taken together, these data suggest that under physiological conditions, fetuin facilitates matrix degradation by monocyte-derived MMP-9, both by opposing the autocrine inhibitory effect of endogenous TGF-beta1 on proMMP-9 release, and by activating proMMP-9 in the pericellular milieu. Conversely, fetuin may limit the stimulation of monocyte proMMP-9 release by high levels of exogenous TGF-beta1. Such modulation could prove important under pathological conditions where TGF-beta1 derived from paracrine sources is abundant, such as in epithelial malignancies.

Cardiovascular Drugs Inhibit MMP-9 Activity from Human THP-1 Macrophages

“…Furthermore knockout mouse models directly demonstrate that deficiency of MMP-9 is related to reduced aneurysm formation (Pyo et al, 2000) and impaired monocyte migration (Ducharme et al, 2000). As previously described, cytokines, LPS, or phorbol esters can induce the secretion of MMP-9 using different cells such as murine (Yoo et al, 2002) and human monocytes (Shu et al, 2000;Tajirian et al, 2000), renal cells (Eberhardt et al, 2002), intestinal epithelial cells (Gan et al, 2001), and smooth muscle cells (Marx et al, 1998a). Although MMP secretion has been widely studied in several cell types, they are less well understood in macrophages.…”

“…MMPs are regulated at several levels: transcription, activation of the inactive zymogens (pro-MMPs), and inhibition of proteolytic activity by tissue inhibitors (TIMPs). In vitro experiments have shown that phorbol esters, lipopolysaccharides or cytokines can stimulate MMP secretion (Shu et al, 2000;Tajirian et al, 2000;Yoo et al, 2002). In vivo, plasmin is a potent proenzyme activator, but alternative pathways can exist such as autocatalyzation of the cleavage of the propeptide.…”

Renal tubular fluid shear stress facilitates monocyte activation toward inflammatory macrophages

“…Yet, although considered as a powerful inflammation suppressor, TGF-␤ is equally recognized for its proinflammatory properties in certain conditions (46). In particular, in vitro treatment of monocytes with TGF-␤ stimulated TNF-␣, IL-1␤, and MMP9 release and decreased MSR-1 expression (14,41,55,61,66), thus promoting their maturation into M1 macrophages (3). Taken together, a decreased release of CCL2, IL-6, and CCL17 associated with an increased secretion of TGF-␤ may explain the preferential differentiation of THP-1 cells into inflammatory macrophages in response to FSS stimulated-HK-2 cells.…”

α2HS-glycoprotein, an Antagonist of Transforming Growth Factor β In vivo , Inhibits Intestinal Tumor Progression

“…␣2-HS-glycoprotein (Ahsg)/ fetuin is a glycoprotein present in serum and extracellular matrix that binds to TGF-␤ cytokines (bone morphogenetic proteins 2, 4, and 6 and TGF-␤1 and TGF-␤2) via a 19 amino acid cytokine-binding domain homologous to an extracellular sequence in the T␤RII (26). Ahsg antagonized binding of TGF-␤1 to T␤RII in surface plasmon resonance assays and inhibited the effect of TGF-␤1 on mink lung epithelial cell proliferation, rat bone marrow cell osteogenic differentiation (27), and human monocyte matrix metalloproteinase 9 release (28). Ahsg and TGF-␤1 are also concentrated in mineralized bone, and Ahsg Ϫ/Ϫ mice display a bone phenotype characterized by increased trabecular bone remodeling, osteoblast density, femur thickness, and bone mineral density (29).…”