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

Abstract

Increased concentrations of insulin-like growth factor (IGF) system components have previously been observed in rheumatoid arthritis (RA) and osteoarthritis (OA); however, disruption of the IGF axis and the implications for the disease process remain largely unaddressed. This study was undertaken to characterise the IGF binding protein (IGFBP)-3 proteolysis and complex formation systems in synovial fluid and to investigate changes in these systems in arthritic disease, and their impact on the availability of IGF. Western blotting or autoradiography of SDS gels was used to visualise IGFBP-3 or its proteolysis. IGF-I and IGFBP-3 concentrations were determined by radioimmunoassays 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, OASynF) and an associated increase in ALS suggested the presence of 150 kDa ternary complexes. IGFBP-3 proteolysis was decreased in RASynF and OASynF, but was apparent in size-fractionated fluid and resembled serum activity. The presence of serum-like inhibitors of IGFBP-3 proteolysis in RASynF was also demonstrated by the ability of this fluid, and 150 kDa fractions from its 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 RASynF and OASynF. These changes may be caused by an increased flux of circulatory proteins into synovial fluid, resulting from an inflammation-induced increase in vascular permeability. The net result in RA and OA would be a decrease in IGF availability in arthritic joints, and therefore loss of a potential anabolic stimulus. This disruption to the IGF axis would influence disease progression in RA and OA.

Arthritis-induced increase in serum levels of IGF-binding protein-3 in rats is secondary to the decrease in its proteolytic activity

“…3 of this study and which has also been observed by other authors (Whellams et al 2000). In addition, in RA patients, the synovial fluid concentrations of IGFBP-3 were positively correlated with synovial fluid levels of interleukin-1 and tumour necrosis factor- (Neidel et al 1997).…”

“…Similarly, in the synovial fluid of patients with RA, the proteolysis of IGFBP-3 was decreased (Fernihough et al 1996, Whellams et al 2000 and the levels of IGFBP-3 were increased (Fernihough et al 1996, Tavera et al 1996, Whellams et al 2000. Inverse correlation between plasma IGFBP-3 levels and proteolysis of IGFBP-3 has also been found in patients after surgery, but show a reduction in circulating IGFBP-3 as a result of IGFBP-3-specific proteases (Davenport et al 1992).…”

Immunopathological mechanisms in dogs with rupture of the cranial cruciate ligament

“…Thus, IGFBP can regulate the precise mechanism of action of IGF-I and -II (Kelley et al, 1996;Baxter, 2000;Jones and Clemmons, 1995). In human patients with RA and OA, a considerable increase in levels of IGF-I and -II are found in the SF compared with normal patients (Fernihough et al, 1996;Whellams et al, 2000). Levels of IGFBP-3 are also greatly enhanced together with a decrease in protease activity against this binding protein.…”

“…Levels of IGFBP-3 are also greatly enhanced together with a decrease in protease activity against this binding protein. Thus, a molar excess of IGFBP-3 to IGF exists whereas the opposite is found in normal SF (Whellams et al, 2000). This implies that, despite having an increased level of IGF-I and -II, the growth factors are predominantly bound to high-affinity binding proteins and are unable to bind to their receptors.…”

Growth factor regulation of intracellular pH homeostasis under hypoxic conditions in isolated equine articular chondrocytes

“…19 There are little quantified data on exact levels of these growth factors in disease but it is thought that increased exposure to serum and growth factors may occur due to a breach in vascular permeability and studies have shown increase in mRNA levels of growth factors with the assumption is that local pericellular concentrations are elevated. 20 Although not performed, measurements of synovial levels of IGF-1 and TGF-b 1 during isolation procedures may have assisted in determining baseline growth factor levels. In this study we confirmed serum and IGF-1 increased acid efflux in equine chondrocytes, albeit the concentration of IGF-1 required to produce this was higher than reported for other species (for example bovine, 10 ).…”