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Active and Inhibitory Components of the Insulin-Like Growth Factor Binding Protein-3 Protease System in Adult Serum, Interstitial, and Synovial Fluid

University of Bristol Division of Surgery (L.A.M., S.X., S.C.-H., J.K.F., J.M.P.H.), Department of Hospital Medicine, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom; and Department of Cellular Physiology (J.M.P.), Babraham Institute, Babraham, Cambridge CB2 4AT, United Kingdom

Address all correspondence and requests for reprints to: Professor J. M. P. Holly, University of Bristol Division of Surgery, Department of Hospital Medicine, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom. E-mail: jeff.holly{at}bris.ac.uk

Circulating insulin-like growth factor binding protein-3 (IGFBP-3) proteolytic activity is normally low but increases in serum from pregnant women and from patients with various pathologies. In contrast, we have recently reported that outside the circulation, such activity is normally high but decreases in various pathologies. We have now compared components of the IGFBP-3 proteolytic system revealed after size fractionation of serum and extravascular fluids with different intrinsic levels of such activity. Normal serum, serum from pregnant women, and synovial fluid from patients with rheumatoid arthritis revealed high and low molecular weight (MW) areas of activity. However, only the low MW activity was apparent in interstitial fluid from normal skin (N Inst F) or psoriatic lesions (P Inst F) and in synovial fluid from normal volunteers (N Syn F) or patients with osteoarthritis (OA Syn F). Addition of inhibitors revealed both areas to comprise more than one enzyme, including serine proteases and metalloproteinases; both could also be inhibited by P Inst F, NS, RA Syn F, and inhibitory fractions from the separation of the latter two. These findings demonstrate low and high MW regions of proteolytic activity, which may contribute to the IGFBP-3 protease system, the former always present, whereas the latter seems to be retained within the circulation apart from inflammatory conditions. The variations apparent in IGFBP-3 protease activity in the intact samples related to the presence of an inhibitor, which may protect IGFBP-3 from proteolysis, rather than to changes in the component proteases.

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