IGF-I and IGF-Binding Proteins in Articular Exudates of Children with Post-Traumatic Knee Damage and Juvenile Idiopathic Arthritis

Abstract

Objective: IGF-I stimulates multiple functions of connective tissue cells and its activity is modulated by IGF-binding proteins (BPs). Some metalloproteinases are expected to modify IGF-I activity by digestion of IGF-BPs. It was decided to evaluate the concentration of IGF-I, IGF-BPs and the activity of gelatinases A and B in knee exudates of children with post-traumatic damage (PTD) and children with juvenile idiopathic arthritis (JIA) in comparison with those in the sera of the same patients. Methods: ELISA (for IGF-I assay), polyacrylamine gel electrophoresis following Western immunoblotting (for IGF-I and IGF-BPs expression), and zymography (for gelatinase detection) were used. Results: The knee exudates, especially those taken from patients with JIA, contained large amounts of IGF-I. The exudates of PTD and JIA patients contained some forms of IGF-BP-1 of molecular weight lower than those occurring in serum. Low expression BP-3 and high activity of gelatinase B were detected in the JIA exudates. Conclusions: The high gelatinase activities in exudates imply joint tissue damage. The cellular response to damage of this kind is an increase in IGF-I production, which stimulates repair processes. High proteolytic activities of gelatinase B in JIA patients may lower the amount of BP-3, possibly causing a relative decrease of IGF-I concentration and impairing the reparation processes stimulated by IGF-I.

Changes in Growth Hormone Receptor Gene Expression during Therapy in Children with Juvenile Idiopathic Arthritis

“…While the inflammatory process is enhanced by pro-inflammatory cytokines, the reparation response is influenced by peptide growth factors, which improve both the number of cell divisions and the biosynthesis of extracellular matrix components [11]. …”

“…IGF-I is an important metabolic and mitogenic factor involved in cell growth and differentiation. In plasma and tissues it is complexed to binding proteins (BP) which are important regulators of its biological activity [11]. Under normal conditions, the majority of IGF-I circulates in a form that is bound to a high-molecular-weight complex, containing IGFBP-3 as an active constituent.…”

“…Another factor that may be important in regulating the availability of IGF-I to its receptor is the level of IGFBP1, which inhibits IGF-I correlated functions, and the IGFBP3 cleavage product, as proteolysis of IGFBP-3 produces a fragment that can still bind IGF-I but with reduced affinity. It is also known that the peptide growth factors, especially IGF-I and IGFBPs, play an important role in the regulation of cell division and maintain equilibrium between synthesis and degradation of extracellular matrix components [11]. …”

“…In these studies most patients had received steroid therapy. Glucocorticoids themselves may alter IGF-I values, interfering with the GH-IGF-I axis, by reducing the GH level and affecting growth rates [6,11,20]. For this reason, we decided to study patients never treated with oral steroids, from onset over the entire follow-up period.…”

“…All JIA patients had evidence of synovitis in at least one joint. Patients were consecutively recruited, over 8 months and were evaluated prospectively for 2 years.Exclusion criteria included systemic arthritis, which is usually treated with oral prednisone and may represent a confounding factor in the analysis of hormonal values and growth velocity [6,10] since corticosteroids are known to be inhibitors of IGF-I biosynthesis [11]. Moreover, we excluded systemic JIA which may necessitate anti-IL-6 receptor antibody therapy, a confounding factor in the interpretation of IL-6 results [12].…”