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Regulation of Insulin-Like Growth Factor (IGF)-I Action by Matrix Metalloproteinase-3 Involves Selective Disruption of IGF-I/IGF-Binding Protein-3 Complexes

Department of Pediatrics (J.L.F., R.C.B., K.M.T.), University of Arkansas for Medical Sciences and Arkansas Children’s Hospital Research Institute, Little Rock, Arkansas 72202; Department of Pediatrics (D.M.S.), Duke University Medical Center, Durham, North Carolina 27710; Department of Molecular and Structural Biology (J.J.E.), University of Aarhus, DK-8000 Aarhus C, Denmark; and Kennedy Institute of Rheumatology Division (H.N.), Faculty of Medicine, Imperial College London, London W6 8LH, United Kingdom

Address all correspondence and requests for reprints to: John L. Fowlkes, M.D., Professor and Chief, Division of Pediatric Endocrinology and Diabetes, University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Arkansas Children’s Hospital Research Institute, 800 Marshall Street, Slot 512-6, Little Rock, Arkansas 72202. E-mail: fowlkesjohnl{at}uams.

IGF-I and IGF-II play important roles in growth and development via interactions with cell-surface receptors; however, in nature, IGFs are sequestered by at least six soluble, high-affinity IGF-binding proteins (IGFBPs), namely IGFBPs 1–6. Herein, we demonstrate that the stromal cell-derived extracellular matrix-degrading metalloproteinase stromelysin 1 (matrix metalloproteinase 3) disrupts IGF/IGFBP-3 complexes and liberates free, intact IGFs, leading to phosphorylation of cell surface type 1 IGF receptors and cellular proliferation. Tissue inhibitor of metalloproteinases (TIMP-1) or an antibody to the type 1 IGF receptor mitigates IGF-mediated cellular proliferation. Thus, these studies suggest that matrix metalloproteinases, beyond their effects on extracellular matrix turnover, regulate cellular proliferation by modulating the bioavailability of IGFs, an event critical for such diverse phenomena as embryo development, morphogenesis, angiogenesis, and tumorigenesis.

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