Insulin-like growth factor 1-induced interleukin-1 receptor II overrides the activity of interleukin-1 and controls the homeostasis of the extracellular matrix of cartilage.

OBJECTIVE We examined the effect of the insulin-like growth factor 1 (IGF-1)/IGF receptor I (IGFRI) autocrine/paracrine anabolic pathway on the extracellular matrix (ECM) of human chondrocytes and the mechanism by which IGF-1 reverses the catabolic effects of interleukin-1 (IL-1). METHODS Phenotypically stable human articular cartilage cells were obtained from normal cartilage and maintained in culture in alginate beads for 1 week to reach equilibrium of accumulated cell-associated matrix (CAM) compounds. Levels of CAM components aggrecan and type II collagen (CII) and levels of intracellular IGF-1, IL-1alpha, and IL-1beta and their respective plasma membrane-bound receptors IGFRI, IL-1 receptor I (IL-1RI), and the decoy receptor IL-1RII were assayed using flow cytometry to investigate the relationship between the autocrine/paracrine pathways and the homeostasis of ECM molecules in the CAM. The effects of IGF-1 on the expression of IGF-1, IL-1alpha, and IL-1beta and their respective receptor systems, the aggrecan core protein, and CII were determined by flow cytometry. RESULTS Cause-effect relationship experiments showed that IGF-1 up-regulates the levels of IGF-1, IGFRI, aggrecan, and CII in the CAM. No effects on the expression of IL-1alpha and IL-1beta and their signaling receptor IL-1RI were observed. However, IGF-1 was able to reverse IL-1beta-mediated degradation of aggrecan and the repression of the aggrecan synthesis rate. Interestingly, levels of aggrecan and CII in the CAM strongly correlated not only with IGF-1, but also with IL-1RII, which acts as a decoy receptor for IL-1alpha and IL-1beta. This suggests that IGF-1 and IL-1RII may cooperate in regulating ECM homeostasis. Additional experiments demonstrated that IGF-1 up-regulated IL-1RII, thereby overriding the catabolic effects of IL-1. CONCLUSION These findings reveal a new paradigm by which IGF-1 influences chondrocyte metabolism, by reversing the IL-1-mediated catabolic pathway through up-regulation of its decoy receptor.

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