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FASEB J. 2015 Aug;29(8):3193-205. doi: 10.1096/fj.14-269217. Epub 2015 Apr 15.

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

Author information

1
*Department of Biosciences and Nutrition, Center for Innovative Medicine, and Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland; Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; and Department of Experimental Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
2
*Department of Biosciences and Nutrition, Center for Innovative Medicine, and Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland; Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; and Department of Experimental Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark maria.eriksson.2@ki.se.

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.

KEYWORDS:

lamin A/C; nuclear lamina; osteoblasts; osteocytes; premature aging

PMID:
25877214
DOI:
10.1096/fj.14-269217
[Indexed for MEDLINE]

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