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Regulation of human monocyte proMMP‐9 production by fetuin, an endogenous TGF‐β antagonist
Author(s) -
Tajirian Tania,
Dennis James W.,
Swallow Carol J.
Publication year - 2000
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/1097-4652(200011)185:2<174::aid-jcp2>3.0.co;2-x
Subject(s) - fetuin , monocyte , chemistry , collagenase , medicine , endogeny , endocrinology , stimulation , autocrine signalling , transforming growth factor , cell culture , microbiology and biotechnology , biology , biochemistry , glycoprotein , enzyme , receptor , genetics
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.