Regulation of oligodendrocyte progenitor cell maturation by PPARδ: effects on bone morphogenetic proteins.
In EAE (experimental autoimmune encephalomyelitis), agonists of PPARs (peroxisome proliferator-activated receptors) provide clinical benefit and reduce damage. In contrast with PPARγ, agonists of PPARδ are more effective when given at later stages of EAE and increase myelin gene expression, suggesting effects on OL (oligodendrocyte) maturation. In the present study we examined effects of the PPARδ agonist GW0742 on OPCs (OL progenitor cells), and tested whether the effects involve modulation of BMPs (bone morphogenetic proteins). We show that effects of GW0742 are mediated through PPARδ since no amelioration of EAE clinical scores was observed in PPARδ-null mice. In OPCs derived from E13 mice (where E is embryonic day), GW0742, but not the PPARγ agonist pioglitazone, increased the number of myelin-producing OLs. This was due to activation of PPARδ since process formation was reduced in PPARδ-null compared with wild-type OPCs. In both OPCs and enriched astrocyte cultures, GW0742 increased noggin protein expression; however, noggin mRNA was only increased in astrocytes. In contrast, GW0742 reduced BMP2 and BMP4 mRNA levels in OPCs, with lesser effects in astrocytes. These findings demonstrate that PPARδ plays a role in OPC maturation, mediated, in part, by regulation of BMP and BMP antagonists.
Vittoria Simonini
Maria
M
Department of Anesthesiology, University of Illinois, Chicago, IL 60612, U.S.A.
Polak
Paul E
PE
Boullerne
Anne I
AI
Peters
Jeffrey M
JM
Richardson
Jill C
JC
Feinstein
Douglas L
DL
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D047494:PPAR delta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000077205:Pioglitazone; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D000099176:Noggin Protein; D010636:Phenols; D013438:Sulfhydryl Compounds
D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D047494:PPAR delta; D000077205:Pioglitazone; D013844:Thiazoles; D045162:Thiazolidinediones; D000099176:Noggin Protein; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds