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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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GW0742 does not reduce EAE symptoms in PPARδ- miceC57Bl/6 control mice (A) and PPARδ- (B) mice were immunized with MOG35–55 peptide and clinical scores monitored to 50 days. On day 25 the mice were split into two subgroups having comparable disease progression (the two subgroups are indicated by the open and closed circles) and were provided free access to chow containing 0, control (○) or 100 p.p.m. GW0742 (•). Values are means±S.E.M. of clinical scores. The incidence of disease reached 100% in all groups by day 14; there was no difference in the average day of onset (9.3±0.4 compared with 10.8±0.9,  compared with WT; means±S.E.M.). In the WT mice, there was a statistically significant effect of GW0742 on clinical scores over time (two-way repeated measures ANOVA of day 25–49 scores, F[14,1] =  2.75, P = 0.0012). Cont, control.
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Figure 1: GW0742 does not reduce EAE symptoms in PPARδ- miceC57Bl/6 control mice (A) and PPARδ- (B) mice were immunized with MOG35–55 peptide and clinical scores monitored to 50 days. On day 25 the mice were split into two subgroups having comparable disease progression (the two subgroups are indicated by the open and closed circles) and were provided free access to chow containing 0, control (○) or 100 p.p.m. GW0742 (•). Values are means±S.E.M. of clinical scores. The incidence of disease reached 100% in all groups by day 14; there was no difference in the average day of onset (9.3±0.4 compared with 10.8±0.9, compared with WT; means±S.E.M.). In the WT mice, there was a statistically significant effect of GW0742 on clinical scores over time (two-way repeated measures ANOVA of day 25–49 scores, F[14,1] =  2.75, P = 0.0012). Cont, control.

Mentions: We have previously shown that treatment of C57BL/6 mice with the PPARδ agonist GW0742 ameliorated clinical and histological signs of EAE when administered to mice with moderate disease severity (Polak et al., 2005). To confirm that these effects were mediated via activation of PPARδ, and not by off-target actions of the agonist, we tested whether GW0742 influenced the course of disease in PPARδ- mice in which endogenous PPARδ is inactivated in all cells and tissues by insertion of the neomycin gene into the DNA-binding domain. As previously observed, providing GW0742 to WT mice at 25 days after immunization (at which time they show moderate clinical signs) significantly reduced clinical signs beginning approx. 15 days later (Figure 1A). Immunization of PPARδ- mice with MOG peptide resulted in a similar disease incidence and severity as WT mice, suggesting that PPARδ does not play a significant role in the early stages of EAE. However, in contrast with the WT mice, treatment with GW0742 did not effect disease progression for up to 25 days of treatment (Figure 1B). This provides strong evidence that the effects of GW0742 are mediated through this receptor and are not due to off-target actions. Since the receptor is inactivated in all cells throughout the body, these results do not allow us to conclude whether the loss of GW0742 benefit is due to lack of PPARδ from brain, or from some other tissue; however, our previous studies did not reveal any effect of GW0742 on splenic T-cells, suggesting that lack of PPARδ from brain may account for the current findings.


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)

GW0742 does not reduce EAE symptoms in PPARδ- miceC57Bl/6 control mice (A) and PPARδ- (B) mice were immunized with MOG35–55 peptide and clinical scores monitored to 50 days. On day 25 the mice were split into two subgroups having comparable disease progression (the two subgroups are indicated by the open and closed circles) and were provided free access to chow containing 0, control (○) or 100 p.p.m. GW0742 (•). Values are means±S.E.M. of clinical scores. The incidence of disease reached 100% in all groups by day 14; there was no difference in the average day of onset (9.3±0.4 compared with 10.8±0.9,  compared with WT; means±S.E.M.). In the WT mice, there was a statistically significant effect of GW0742 on clinical scores over time (two-way repeated measures ANOVA of day 25–49 scores, F[14,1] =  2.75, P = 0.0012). Cont, control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: GW0742 does not reduce EAE symptoms in PPARδ- miceC57Bl/6 control mice (A) and PPARδ- (B) mice were immunized with MOG35–55 peptide and clinical scores monitored to 50 days. On day 25 the mice were split into two subgroups having comparable disease progression (the two subgroups are indicated by the open and closed circles) and were provided free access to chow containing 0, control (○) or 100 p.p.m. GW0742 (•). Values are means±S.E.M. of clinical scores. The incidence of disease reached 100% in all groups by day 14; there was no difference in the average day of onset (9.3±0.4 compared with 10.8±0.9, compared with WT; means±S.E.M.). In the WT mice, there was a statistically significant effect of GW0742 on clinical scores over time (two-way repeated measures ANOVA of day 25–49 scores, F[14,1] =  2.75, P = 0.0012). Cont, control.
Mentions: We have previously shown that treatment of C57BL/6 mice with the PPARδ agonist GW0742 ameliorated clinical and histological signs of EAE when administered to mice with moderate disease severity (Polak et al., 2005). To confirm that these effects were mediated via activation of PPARδ, and not by off-target actions of the agonist, we tested whether GW0742 influenced the course of disease in PPARδ- mice in which endogenous PPARδ is inactivated in all cells and tissues by insertion of the neomycin gene into the DNA-binding domain. As previously observed, providing GW0742 to WT mice at 25 days after immunization (at which time they show moderate clinical signs) significantly reduced clinical signs beginning approx. 15 days later (Figure 1A). Immunization of PPARδ- mice with MOG peptide resulted in a similar disease incidence and severity as WT mice, suggesting that PPARδ does not play a significant role in the early stages of EAE. However, in contrast with the WT mice, treatment with GW0742 did not effect disease progression for up to 25 days of treatment (Figure 1B). This provides strong evidence that the effects of GW0742 are mediated through this receptor and are not due to off-target actions. Since the receptor is inactivated in all cells throughout the body, these results do not allow us to conclude whether the loss of GW0742 benefit is due to lack of PPARδ from brain, or from some other tissue; however, our previous studies did not reveal any effect of GW0742 on splenic T-cells, suggesting that lack of PPARδ from brain may account for the current findings.

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