Matrix metalloproteinases as insulin-like growth factor binding protein-degrading proteinases

John L. Fowlkes, Kathryn M. Thrailkill, Delila M. Serra, Ko Suzuki, Hideaki Nagase

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)255-263
Number of pages9
JournalProgress in Growth Factor Research
Volume6
Issue number2-4
DOIs
StatePublished - 1995

Bibliographical note

Funding Information:
Acknowledgements--We wish to thank Dr Christophere Maack (Celtrix Pharmaceuticals, Santa Clara, CA, U.S.A.) for providing rhlGFBP-3 and IGFBP-3 antisera and Dr Michael Kiefer (Chiron, Corp., Emeryville, CA, U.S.A.) for providing rhlGFBP-5. This work was supported by National Institutes of Health Grants AR39189 (to H.N.) and DK02276 (to J.L.F.), and a March of Dimes Basil O'Connor Starter Scholar Research Award (#5-FY93-0953) to J.L.F. and a Duke Children's Telethon Grant (to K.M.T.).

Keywords

  • Insulin-like growth factor (IGF)
  • gelatinase
  • insulin-like growth factor binding protein (IGFBP)
  • interstitial collagnease
  • matrix metalloproteinase (MMP)
  • stromelysin

ASJC Scopus subject areas

  • General Agricultural and Biological Sciences

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