Alterations in insulin-like growth factor binding protein-3 proteolysis and complex formation in the arthritic joint

Increased concentrations of insulin-like growth factor (IGF) system compone nts have previously been observed in rheumatoid arthritis (RA) and osteoart hritis (OA); however, disruption of the IGF axis and the implications for t he disease process remain largely unaddressed. This study was undertaken to characterise the IGF binding protein (IGFBP)-3 proteolysis and complex for mation systems in synovial fluid and to investigate changes in these system s in arthritic disease, and their impact on the availability of IGF. Wester n blotting or autoradiography of SDS gels was used to visualise IGFBP-3 or its proteolysis. IGF-I and IGFBP-3 concentrations were determined by radioi mmunoassays and acid-labile subunit (ALS) was measured by ELISA. A shift in distribution of IGFBP-3 and IGF-I in RA and OA synovial fluids (RASynF, OA SynF) and an associated increase in ALS suggested the presence of 150 kDa t ernary complexes. IGFBP-3 proteolysis was decreased in RASynF and OASynF, b ut was apparent in size-fractionated fluid and resembled serum activity. Th e presence of serum-like inhibitors of IGFBP-3 proteolysis in RASynF was al so demonstrated by the ability of this fluid, and 150 kDa fractions from it s size fractionation, to inhibit IGFBP-3 proteolysis in the other synovial fluid. A marked disruption in the IGF system was observed, as considerably more IGF-I was retained in ternary complexes. We also classified the IGFBP- 3 proteolysis system in synovial fluid and found it to be disturbed in RASy nF and OASynF. These changes may be caused by an increased flux of circulat ory proteins into synovial fluid, resulting from an inflammation-induced in crease in vascular permeability. The net result in RA and OA would be a dec rease in IGF availability in arthritic joints, and therefore loss of a pote ntial anabolic stimulus. This disruption to the IGF axis would influence di sease progression in RA and OA.