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Assessing the efficacy of protein farnesyltransferase inhibitors in mouse models of progeria.

Yang SH, Chang SY, Andres DA, Spielmann HP, Young SG, Fong LG - J. Lipid Res. (2009)

Bottom Line: However, the interpretation of the FTI treatment studies is open to question in light of recent studies showing that mice expressing a nonfarnesylated version of progerin (Lmna(nHG/+)) develop progeria-like disease phenotypes.To address this issue, we compared the ability of an FTI to improve progeria-like disease phenotypes in both Lmna(HG/+) and Lmna(nHG/+) mice.In Lmna(HG/+) mice, the FTI reduced disease phenotypes in a highly significant manner, but the drug had no effect in Lmna(nHG/+) mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA.

ABSTRACT
Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of a farnesylated form of prelamin A (progerin). Previously, we showed that blocking protein farnesylation with a farnesyltransferase inhibitor (FTI) ameliorates the disease phenotypes in mouse model of HGPS (Lmna(HG/+)). However, the interpretation of the FTI treatment studies is open to question in light of recent studies showing that mice expressing a nonfarnesylated version of progerin (Lmna(nHG/+)) develop progeria-like disease phenotypes. The fact that Lmna(nHG/+) mice manifest disease raised the possibility that the beneficial effects of an FTI in Lmna(HG/+) mice were not due to the effects of the drug on the farnesylation of progerin, but may have been due to unanticipated secondary effects of the drug on other farnesylated proteins. To address this issue, we compared the ability of an FTI to improve progeria-like disease phenotypes in both Lmna(HG/+) and Lmna(nHG/+) mice. In Lmna(HG/+) mice, the FTI reduced disease phenotypes in a highly significant manner, but the drug had no effect in Lmna(nHG/+) mice. The failure of the FTI to ameliorate disease in Lmna(nHG/+) mice supports the idea that the beneficial effects of an FTI in Lmna(HG/+) mice are due to the effect of drug on the farnesylation of progerin.

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An FTI improves bone disease in LmnaHG/+ mice, but not in LmnanHG/+ mice. A: Numbers of rib fractures in FTI-treated (closed circles) and vehicle-treated (open circles) LmnaHG/+ and LmnanHG/+ mice at the time of death. All mice that survived to 38 weeks of age were euthanized at that time point. The FTI-treated male and female LmnaHG/+ mice had fewer rib fractures (P < 0.0001) than vehicle-treated LmnaHG/+ mice. The numbers of rib fractures in FTI- and vehicle-treated mice were similar (n = 24 mice/group). FTI treatment improved the bone density (B) and cortical thickness (C) in the ribs of male and female LmnaHG/+ mice (n = 24 mice/group, P < 0.0001) but not in Lmna+/+ (WT) and LmnanHG/+ mice (n = 24 mice/group). Error bars indicate SEM.
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fig6: An FTI improves bone disease in LmnaHG/+ mice, but not in LmnanHG/+ mice. A: Numbers of rib fractures in FTI-treated (closed circles) and vehicle-treated (open circles) LmnaHG/+ and LmnanHG/+ mice at the time of death. All mice that survived to 38 weeks of age were euthanized at that time point. The FTI-treated male and female LmnaHG/+ mice had fewer rib fractures (P < 0.0001) than vehicle-treated LmnaHG/+ mice. The numbers of rib fractures in FTI- and vehicle-treated mice were similar (n = 24 mice/group). FTI treatment improved the bone density (B) and cortical thickness (C) in the ribs of male and female LmnaHG/+ mice (n = 24 mice/group, P < 0.0001) but not in Lmna+/+ (WT) and LmnanHG/+ mice (n = 24 mice/group). Error bars indicate SEM.

Mentions: We assessed the impact of the FTI treatment on spontaneous rib fractures in both male and female mice. The FTI clearly reduced the number of rib fractures in LmnaHG/+ mice (P < 0.0001) (Fig. 6A). In contrast, the drug had no significant effect on the number of rib fractures in LmnanHG/+ mice (Fig. 6A). The FTI improved mean bone density and bone cortical thickness in LmnaHG/+ mice (P < 0.0001 for both males and females) (Fig. 6B, C). In contrast, the FTI had no effect on these bone phenotypes in LmnanHG/+ mice (Fig. 6B, C).


Assessing the efficacy of protein farnesyltransferase inhibitors in mouse models of progeria.

Yang SH, Chang SY, Andres DA, Spielmann HP, Young SG, Fong LG - J. Lipid Res. (2009)

An FTI improves bone disease in LmnaHG/+ mice, but not in LmnanHG/+ mice. A: Numbers of rib fractures in FTI-treated (closed circles) and vehicle-treated (open circles) LmnaHG/+ and LmnanHG/+ mice at the time of death. All mice that survived to 38 weeks of age were euthanized at that time point. The FTI-treated male and female LmnaHG/+ mice had fewer rib fractures (P < 0.0001) than vehicle-treated LmnaHG/+ mice. The numbers of rib fractures in FTI- and vehicle-treated mice were similar (n = 24 mice/group). FTI treatment improved the bone density (B) and cortical thickness (C) in the ribs of male and female LmnaHG/+ mice (n = 24 mice/group, P < 0.0001) but not in Lmna+/+ (WT) and LmnanHG/+ mice (n = 24 mice/group). Error bars indicate SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2803242&req=5

fig6: An FTI improves bone disease in LmnaHG/+ mice, but not in LmnanHG/+ mice. A: Numbers of rib fractures in FTI-treated (closed circles) and vehicle-treated (open circles) LmnaHG/+ and LmnanHG/+ mice at the time of death. All mice that survived to 38 weeks of age were euthanized at that time point. The FTI-treated male and female LmnaHG/+ mice had fewer rib fractures (P < 0.0001) than vehicle-treated LmnaHG/+ mice. The numbers of rib fractures in FTI- and vehicle-treated mice were similar (n = 24 mice/group). FTI treatment improved the bone density (B) and cortical thickness (C) in the ribs of male and female LmnaHG/+ mice (n = 24 mice/group, P < 0.0001) but not in Lmna+/+ (WT) and LmnanHG/+ mice (n = 24 mice/group). Error bars indicate SEM.
Mentions: We assessed the impact of the FTI treatment on spontaneous rib fractures in both male and female mice. The FTI clearly reduced the number of rib fractures in LmnaHG/+ mice (P < 0.0001) (Fig. 6A). In contrast, the drug had no significant effect on the number of rib fractures in LmnanHG/+ mice (Fig. 6A). The FTI improved mean bone density and bone cortical thickness in LmnaHG/+ mice (P < 0.0001 for both males and females) (Fig. 6B, C). In contrast, the FTI had no effect on these bone phenotypes in LmnanHG/+ mice (Fig. 6B, C).

Bottom Line: However, the interpretation of the FTI treatment studies is open to question in light of recent studies showing that mice expressing a nonfarnesylated version of progerin (Lmna(nHG/+)) develop progeria-like disease phenotypes.To address this issue, we compared the ability of an FTI to improve progeria-like disease phenotypes in both Lmna(HG/+) and Lmna(nHG/+) mice.In Lmna(HG/+) mice, the FTI reduced disease phenotypes in a highly significant manner, but the drug had no effect in Lmna(nHG/+) mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA.

ABSTRACT
Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of a farnesylated form of prelamin A (progerin). Previously, we showed that blocking protein farnesylation with a farnesyltransferase inhibitor (FTI) ameliorates the disease phenotypes in mouse model of HGPS (Lmna(HG/+)). However, the interpretation of the FTI treatment studies is open to question in light of recent studies showing that mice expressing a nonfarnesylated version of progerin (Lmna(nHG/+)) develop progeria-like disease phenotypes. The fact that Lmna(nHG/+) mice manifest disease raised the possibility that the beneficial effects of an FTI in Lmna(HG/+) mice were not due to the effects of the drug on the farnesylation of progerin, but may have been due to unanticipated secondary effects of the drug on other farnesylated proteins. To address this issue, we compared the ability of an FTI to improve progeria-like disease phenotypes in both Lmna(HG/+) and Lmna(nHG/+) mice. In Lmna(HG/+) mice, the FTI reduced disease phenotypes in a highly significant manner, but the drug had no effect in Lmna(nHG/+) mice. The failure of the FTI to ameliorate disease in Lmna(nHG/+) mice supports the idea that the beneficial effects of an FTI in Lmna(HG/+) mice are due to the effect of drug on the farnesylation of progerin.

Show MeSH
Related in: MedlinePlus