Matrix metalloproteinases as insulin-like growth factor binding protein-degrading proteinases.
Insulin-like growth factor (IGF) bioavailability is modulated by specific IGFBPs, six of which are known (IGFBPs 1-6). Since IGFBPs have equal or higher affinity for IGFs than do IGF receptors, it is believed that degradation of IGFBPs by IGFBP-degrading proteinases is an important step in regulating IGF bioactivity. Recent studies from our laboratory have demonstrated that at least two IGFBPs, i.e. IGFBP-3 and -5, are degraded under physiologic conditions by matrix metalloproteinases (MMPs). In vitro, we have demonstrated that IGFBP-3 is degraded in human dermal fibroblast cultures by MMPs using a variety of techniques, including proteinase inhibition with a specific inhibitor of MMPs, i.e. tissue inhibitor of metalloproteinases (TIMP-1), immunoabsorption with specific antisera to human MMPs and a unique method developed in our laboratory, IGFBP-3 substrate zymography. Using similar methods, we have also demonstrated that MMPs, along with an unidentified 97-kDa proteinase, degrade IGFBP-5 in murine osteoblast cultures. In rat pregnancy serum, we have shown that degradation of IGFBP-3 is associated with MMP activity present in the serum, which likely arises from the placental compartment. Analysis of the cleavage products of IGFBP-3 produced by MMPs 1, 2 and 3 reveals that MMPs cleave exclusively within the non-homologous, mid-region of the molecule. Together, these studies suggest that MMPs, beyond their previously described roles as extracellular matrix degrading enzymes, may also exert effects on cellular growth and differentiation via degradation of IGFBPs.
Fowlkes
J L
JL
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Thrailkill
K M
KM
Serra
D M
DM
Suzuki
K
K
Nagase
H
H
D000818:Animals; D010450:Endopeptidases / Q000378:metabolism*; D005260:Female; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism; D011247:Pregnancy / Q000378:metabolism; D051381:Rats
D018975:Insulin-Like Growth Factor Binding Protein 5; D007334:Insulin-Like Growth Factor I; D010450:Endopeptidases; D008666:Metalloendopeptidases; C080473:insulin-like growth factor binding protein-3 protease