Transgene silencing of the Hutchinson-Gilford progeria syndrome mutation results in a reversible bone phenotype, whereas resveratrol treatment does not show overall beneficial effects

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder that is most commonly caused by a de novo point mutation in exon 11 of the LMNA gene, c.1824C>T, which results in an increased production of a truncated form of lamin A known as progerin. In this study, we used a mouse model to study the possibility of recovering from HGPS bone disease upon silencing of the HGPS mutation, and the potential benefits from treatment with resveratrol. We show that complete silencing of the transgenic expression of progerin normalized bone morphology and mineralization already after 7 weeks. The improvements included lower frequencies of rib fractures and callus formation, an increased number of osteocytes in remodeled bone, and normalized dentinogenesis. The beneficial effects from resveratrol treatment were less significant and to a large extent similar to mice treated with sucrose alone. However, the reversal of the dental phenotype of overgrown and laterally displaced lower incisors in HGPS mice could be attributed to resveratrol. Our results indicate that the HGPS bone defects were reversible upon suppressed transgenic expression and suggest that treatments targeting aberrant progerin splicing give hope to patients who are affected by HGPS.

Cytoskeleton and nuclear lamina affection in recessive osteogenesis imperfecta: A functional proteomics perspective

“…Also Zmpste24 −/− mice, which lack zmpste24 enzyme for lamin A/C processing, show an osteopenic phenotype with brittle bones and spontaneous bone fractures [92] . In transgenic mice, which resemble the Hutchinson-Gilford progeria syndrome (HGPS), the bone phenotype is reverted by completely silencing endogenous mutated Lmna gene and inducing transgenic expression of human lamin A/C [93] .…”

Rare progerin-expressing preadipocytes and adipocytes contribute to tissue depletion over time

“…Relative qPCR analysis was performed in accordance with previously described procedures 57, 58 . ddPCR was carried out as previously described 59 .…”

Potential therapeutic effects of the MTOR inhibitors for preventing ageing and progeria‐related disorders

“…In spite of the initial encouraging results on the anti‐ageing therapeutic potential of resveratrol in mice and primates , recent studies have shown that this drug does not affect lifespan or longevity in male or female mice , or in a cohort of more than 800 people over the age of 65 years . Moreover, the use of resveratrol in progeric mice carrying an LMNA mutation did not improve the senescent phenotype .…”