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218)
Orthopaedic Research Laboratory, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212; and the Departments of Medicine, Veterans Affairs Medical Center and University of Washington, Seattle, Washington 98108
Using the major
bone insulin-like growth factor-binding protein (IGFBP) IGFBP-5, we
took a mechanistic approach in evaluating the role of the
heparin-binding domain of IGFBP-5 in regulating plasmin (Pm)
proteolysis of IGFBP-5. Using synthetic IGFBP-5 peptide fragments, we
determined that the heparin-binding domain, IGFBP-5-(208
218), inhibits Pm proteolysis of intact IGFBP-5. The mechanism of action of
IGFBP-5-(201218) was by inhibiting Pm binding to substrate IGFBP-5.
IGFBP-5-(201218) action was independent of site of proteolysis, fluid, or solid phase interaction. In addition, IGFBP-5-(201218) was
found to inhibit plasminogen (Pg) activation to Pm. IGFBP-5-(201218) did not directly inhibit the activity of Pm, urokinase Pg activator (PA), or tissue-type PA but acted as a competitive inhibitor of Pg
activation by PA, which is in contrast to the stimulating effect of
heparin on Pg activation. These data indicate that the heparin-binding domain contains the serine protease (Pg-to-Pm) binding site region of
IGFBP-5, and that this region, which is presumed to represent a
Pm-induced proteolytic product of IGFBP-5, is capable of regulating Pm
action.
osteoblast physiology; hydroxyapatite; insulin-like growth factor bioavailability
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