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Regulation of human monocyte proMMP-9 production by fetuin, an endogenous TGF-beta antagonist
T Tajirian1, J W Dennis, C J Swallow
1Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
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.
Insights
Fetuin promotes matrix degradation by stimulating monocyte matrix metalloproteinase-9 (MMP-9) release and activation. It also counteracts the inhibitory effects of transforming growth factor-beta1 (TGF-beta1) on MMP-9 release.
Area of Science:
- Biochemistry
- Cell Biology
- Immunology
Background:
- Matrix metalloproteinases (MMPs), particularly MMP-9, are crucial for extracellular matrix degradation and are implicated in inflammatory and neoplastic conditions.
- Monocytes are a primary source of MMP-9 in destructive diseases.
- Fetuin, a serum glycoprotein, regulates osteogenesis by binding and inactivating TGF-beta family members.
Purpose of the Study:
- To investigate the effects of TGF-beta1 and fetuin on proMMP-9 release from human monocytes.
- To elucidate the role of fetuin in modulating MMP-9 activity in the context of TGF-beta1 signaling.
Main Methods:
- Utilized the human monocyte cell line THP-1 and freshly isolated human peripheral blood monocytes.
- Assessed proMMP-9 release in response to varying concentrations of TGF-beta1 and fetuin.
- Employed neutralizing antibodies against TGF-beta1 to study endogenous TGF-beta1 effects.
- Investigated fetuin's capacity to activate proMMP-9 in conditioned medium.
Main Results:
- Exogenous TGF-beta1 dose-dependently stimulated proMMP-9 release from THP-1 cells.
- Human fetuin partially inhibited TGF-beta1-induced proMMP-9 release but stimulated release independently.
- Neutralizing TGF-beta1 antibodies increased proMMP-9 release, indicating an endogenous inhibitory role for TGF-beta1.
- Fetuin stimulated proMMP-9 release in primary human monocytes and activated latent proMMP-9.
Conclusions:
- Fetuin promotes matrix degradation by monocyte-derived MMP-9 under physiological conditions.
- Fetuin facilitates MMP-9 release by opposing endogenous TGF-beta1's inhibitory effects and activates proMMP-9.
- Fetuin may limit excessive monocyte proMMP-9 release stimulated by high exogenous TGF-beta1 levels, relevant in pathological settings.