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.
Chesik
Daniel
D
Department of Neurology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. d.chesik@med.umcg.nl
De Keyser
Jacques
J
Glazenburg
Lisa
L
Wilczak
Nadine
N
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000494:pharmacology; D018969:Insulin-Like Growth Factor Binding Proteins / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology*; D009457:Neuroglia / Q000378:metabolism*; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D011180:Postmortem Changes; D051381:Rats; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D013778:Tetrazolium Salts; D013844:Thiazoles
D005904:Glial Fibrillary Acidic Protein; D018971:Insulin-Like Growth Factor Binding Protein 2; D018969:Insulin-Like Growth Factor Binding Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue