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

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-β family members and through this mechanism regulates osteogenesis (Binkert et al., 1999, J Biol Chem 274:28514–28520.). We studied the effects of TGF-β1 and fetuin on proMMP-9 release by the human monocyte line THP-1. Exogenous TGF-β1 stimulated proMMP-9 release by THP-1 cells, with half-maximal stimulation at ≈ 0.01 ng/ml TGF-β1. Human fetuin (0.5–2 μM) partially inhibited this stimulation. Human fetuin alone stimulated THP-1 monocyte proMMP-9 release, with half maximal stimulation at ≈ 0.25 μM fetuin. Neutralizing antibody specific for TGF-β1 also stimulated proMMP-9 release, suggesting that endogenously-derived TGF-β1 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-β1 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-β1. Such modulation could prove important under pathological conditions where TGF-β1 derived from paracrine sources is abundant, such as in epithelial malignancies. J. Cell. Physiol. 185:174–183, 2000. © 2000 Wiley-Liss, Inc.