Isolation and characterization of vitreous insulin-like growth factor binding proteins.

摘要: Proliferative diabetic retinopathy (PDR) is a late-stage complication of diabetes in which fibrovascular tissues emerge from the retina and exert tractional forces that can cause retinal detachment.1 Though complex incompletely understood, PDR ultimately cellular disorder involving progression specific activities minimally include cell translocation retina, division, generation forces.2 There considerable interest identifying causal types stimuli leading to their pathogenic because ability arrest or attenuate any these processes would represent significant gain control this complication. Immunohistochemical studies epiretinal have identified number different types, including glia, immune cells, pigment epithelial fibroblastlike cells unknown origin.3–8 Muller principal are consistently scar using traditional immunocytochemical markers glial fibrillary acidic protein glutamine synthetase.3,6,8,9 In addition, more recent laboratory revealed mentioned also derived, at least part, phenotypically altered cells.9 Described was progressive loss glial-specific proteins de novo expression alpha smooth muscle actin ending with myofibroblastlike unrecognizable as glia process closely resembles phenotype changes previously described primary cultures cells.10,11 There abundant circumstantial evidence indicating source detachment PDR. Although freshly isolated, recognizable lack capacity generate forces, not case described.11,12 concert change, particular α-smooth actin, acquire for force culture. Systematic study vitro activity constitutive but instead stimulated by certain exogenous promoters, ligands, insulin-like growth factor platelet-derived systems.11,12 Consistent findings, force–stimulating respond present diabetic, normal, vitreous, factor–neutralizing antibodies attributed most IGF-related ligands.13 As consequence there now gaining an improved understanding vitreous and, particular, those result increased IGF biological activity. Several laboratories examined diabetes-associated IGF-I IGF-II levels, reporting increases varying between 150% 300%.14–20 However, values reported normal correlate poorly observed absence activity, us speculate mechanism attenuates ligands.13,21 The system contains six high-affinity binding (IGFBPs) potentiate inhibit direct factor–independent effects.22–27 used ELISA-type assays examine IGFBP levels detecting IGFBP-2 IGFBP-3.15,18,20 We since effects all IGFBPs on generating response determined IGFBP-3 potent inhibitors activities.28 Together observations led propose function sink, limiting concentration free ligand thus controlling activity.28 several confounding elements hypothesis, report suggesting cleaved inactive form local proteases.29 reportedly increase rather than decrease diabetes, may be protective.15,18,20 goal project determine retain bind ligands modulate