Insulin-like growth factor binding proteins: regulation in chronic active plaques in multiple sclerosis and functional analysis of glial cells

Studies in experimental allergic encephalomyelitis, an animal model of multiple sclerosis (MS), suggest that astrocyte-secreted insulin-like growth factor binding protein-2 (IGFBP-2) helps target IGF-1 to IGF-1 receptor-expressing oligodendrocytes and promote remyelination. We examined the presence of IGFBPs 1-6 in astrocytes in normal post-mortem human brain tissue and lesions of MS by means of immunohistochemistry. Under normal conditions all six IGFBPs were detected. Compared to controls, hypertrophic astrocytes at the borders of chronic active MS lesions displayed increased immunoreactivity for IGFBP-2 and IGFBP-4. In vitro studies were performed to analyse the effects of IGFBPs on cellular proliferation of neonatal rat glial cells. Treatment of astrocytes with IGF-1 and -2 enhanced proliferation whereas IGFBP-2 and -4 inhibited cellular growth. Interestingly, combined treatment with IGFBP-2 and IGF-1 potentiated effects on cellular proliferation whereas combined treatment with IGFBP-2 and IGF-2 inhibited growth. Unlike IGFBP-2, IGFBP-4 inhibited proliferation in combined treatment with IGF-1. In contrast, combined treatment with IGFBP-2 and IGF-1 resulted in decreased cell survival of oligodendrocyte precursor cells. Our results suggest that the up-regulation of IGFBP-2 in reactive astrocytes in MS lesions may primarily serve to enhance the IGF-1-mediated mitogenic stimulus for astrocytes rather than supporting oligodendrocyte survival.