FGF-2 and Anosmin-1 are selectively expressed in different types of multiple sclerosis lesions.
Multiple sclerosis is a demyelinating disease that affects ≈ 2,000,000 people worldwide. In the advanced stages of the disease, endogenous oligodendrocyte precursors cannot colonize the lesions or differentiate into myelinating oligodendrocytes. During development, both FGF-2 and Anosmin-1 participate in oligodendrocyte precursor cell migration, acting via the FGF receptor 1 (FGFR1). Hence, we performed a histopathological and molecular analysis of these developmental modulators in postmortem tissue blocks from multiple sclerosis patients. Accordingly, we demonstrate that the distribution of FGF-2 and Anosmin-1 varies between the different types of multiple sclerosis lesions: FGF-2 is expressed only within active lesions and in the periplaque of chronic lesions, whereas Anosmin-1 is upregulated within chronic lesions and is totally absent in active lesions. We show that the endogenous oligodendrocyte precursor cells recruited toward chronic-active lesions express FGFR1, possibly in response to the FGF-2 produced by microglial cells in the periplaque. Also in human tissue, FGF-2 is upregulated in perivascular astrocytes in regions of the normal-appearing gray matter, where the integrity of the blood-brain barrier is compromised. In culture, FGF-2 and Anosmin-1 influence adult mouse oligodendrocyte precursor cell migration in the same manner as at embryonic stages, providing an explanation for the histopathological observations: FGF-2 attracts/enhances its migration, which is hindered by Anosmin-1. We propose that FGF-2 and Anosmin-1 are markers for the histopathological type and the level of inflammation of multiple sclerosis lesions, and that they may serve as novel pharmacogenetic targets to design future therapies that favor effective remyelination and protect the blood-brain barrier.
Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos-Servicio de Salud de Castilla-La Mancha, Finca La Peraleda s/n, E-45071 Toledo, Spain.
Diego
D
Clemente
María Cristina
MC
Ortega
Francisco Javier
FJ
Arenzana
Fernando
F
de Castro
D000328:Adult; D053687:Adult Stem Cells / Q000187:drug effects / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000941:Antigens / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005732:Gangliosides / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000145:classification* / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D011180:Postmortem Changes; D011509:Proteoglycans / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D014162:Transfection / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D062826:Zonula Occludens-1 Protein; D000099216:Chondroitin Sulfate Proteoglycan 4; D000097382:CD68 Molecule
D000941:Antigens; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D051792:Basic Helix-Loop-Helix Proteins; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D016222:Fibroblast Growth Factor 2; D005732:Gangliosides; D005904:Glial Fibrillary Acidic Protein; D006684:HLA-DR Antigens; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011509:Proteoglycans; D011758:Pyrroles; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020796:Receptor, Platelet-Derived Growth Factor alpha; D062826:Zonula Occludens-1 Protein; D000099216:Chondroitin Sulfate Proteoglycan 4; C076266:ANOS1 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C494786:Olig1 protein, mouse; C105686:SU 5402; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; C062875:ganglioside A2B5; C496348:FGFR1 protein, human