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Regulation of oligodendrocyte progenitor cell maturation by PPARδ: effects on bone morphogenetic proteins.

Vittoria Simonini M, Polak PE, Boullerne AI, Peters JM, Richardson JC, Feinstein DL - ASN Neuro (2010)

Bottom Line: 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).This was due to activation of PPARδ since process formation was reduced in PPARδ- compared with wild-type OPCs.In contrast, GW0742 reduced BMP2 and BMP4 mRNA levels in OPCs, with lesser effects in astrocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, University of Illinois, Chicago, IL 60612, U.S.A.

ABSTRACT
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- 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- 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.

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Regulation of PPARδ target gene expression in astrocytesPrimary rat astrocytes were treated with 3 μM GW0742 or vehicle (VEH) for 24 h then RNA isolated and qPCR used to measure relative mRNA levels of (A) PPARδ and its target genes, (B) UCP3 and (C) ANGPTL-4. Values are means±S.E.M. of the relative mRNA level normalized to values for GDH measured in the same samples, n = 3. The mRNA values for the vehicle groups were set to 1.0; *P<0.05, compared with the corresponding vehicle-treated sample (as measured using an unpaired Student's t test).
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Figure 9: Regulation of PPARδ target gene expression in astrocytesPrimary rat astrocytes were treated with 3 μM GW0742 or vehicle (VEH) for 24 h then RNA isolated and qPCR used to measure relative mRNA levels of (A) PPARδ and its target genes, (B) UCP3 and (C) ANGPTL-4. Values are means±S.E.M. of the relative mRNA level normalized to values for GDH measured in the same samples, n = 3. The mRNA values for the vehicle groups were set to 1.0; *P<0.05, compared with the corresponding vehicle-treated sample (as measured using an unpaired Student's t test).

Mentions: Since there are some astrocytes present in the OPC cultures, we tested whether GW0742 influenced BMP or BMP antagonist expression in enriched astrocyte cultures. After 24 h we observed a significant increase of noggin mRNA levels in astrocytes (Figure 8B); interestingly, this increase appeared to be selective for noggin since mRNA levels of other BMP antagonists (gremlin, follistatin and bambi) were not increased (in fact gremlin mRNA levels were significantly reduced). In contrast with OPCs, GW0742 did not increase PPARδ mRNA levels (Figure 9A). Interestingly, GW0742 caused a significant increase in the PPARδ target gene UCP3, but not in ANGPTL-4. Consistent with the increase in noggin mRNA, we observed a large increase in noggin staining, present in vesicular structures around the nucleus of primary astrocytes treated with 3 μM GW0742 for 24 h (Figure 10).


Regulation of oligodendrocyte progenitor cell maturation by PPARδ: effects on bone morphogenetic proteins.

Vittoria Simonini M, Polak PE, Boullerne AI, Peters JM, Richardson JC, Feinstein DL - ASN Neuro (2010)

Regulation of PPARδ target gene expression in astrocytesPrimary rat astrocytes were treated with 3 μM GW0742 or vehicle (VEH) for 24 h then RNA isolated and qPCR used to measure relative mRNA levels of (A) PPARδ and its target genes, (B) UCP3 and (C) ANGPTL-4. Values are means±S.E.M. of the relative mRNA level normalized to values for GDH measured in the same samples, n = 3. The mRNA values for the vehicle groups were set to 1.0; *P<0.05, compared with the corresponding vehicle-treated sample (as measured using an unpaired Student's t test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2807733&req=5

Figure 9: Regulation of PPARδ target gene expression in astrocytesPrimary rat astrocytes were treated with 3 μM GW0742 or vehicle (VEH) for 24 h then RNA isolated and qPCR used to measure relative mRNA levels of (A) PPARδ and its target genes, (B) UCP3 and (C) ANGPTL-4. Values are means±S.E.M. of the relative mRNA level normalized to values for GDH measured in the same samples, n = 3. The mRNA values for the vehicle groups were set to 1.0; *P<0.05, compared with the corresponding vehicle-treated sample (as measured using an unpaired Student's t test).
Mentions: Since there are some astrocytes present in the OPC cultures, we tested whether GW0742 influenced BMP or BMP antagonist expression in enriched astrocyte cultures. After 24 h we observed a significant increase of noggin mRNA levels in astrocytes (Figure 8B); interestingly, this increase appeared to be selective for noggin since mRNA levels of other BMP antagonists (gremlin, follistatin and bambi) were not increased (in fact gremlin mRNA levels were significantly reduced). In contrast with OPCs, GW0742 did not increase PPARδ mRNA levels (Figure 9A). Interestingly, GW0742 caused a significant increase in the PPARδ target gene UCP3, but not in ANGPTL-4. Consistent with the increase in noggin mRNA, we observed a large increase in noggin staining, present in vesicular structures around the nucleus of primary astrocytes treated with 3 μM GW0742 for 24 h (Figure 10).

Bottom Line: 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).This was due to activation of PPARδ since process formation was reduced in PPARδ- compared with wild-type OPCs.In contrast, GW0742 reduced BMP2 and BMP4 mRNA levels in OPCs, with lesser effects in astrocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, University of Illinois, Chicago, IL 60612, U.S.A.

ABSTRACT
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- 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- 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.

Show MeSH
Related in: MedlinePlus