title: 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.
authors: *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.
authors: Charlotte
authors: C
authors: Strandgren
authors: *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.
authors: Hasina Abdul
authors: HA
authors: Nasser
authors: *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.
authors: Tomás
authors: T
authors: McKenna
authors: *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.
authors: Antti
authors: A
authors: Koskela
authors: *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.
authors: Juha
authors: J
authors: Tuukkanen
authors: *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.
authors: Claes
authors: C
authors: Ohlsson
authors: *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.
authors: Björn
authors: B
authors: Rozell
authors: *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.
authors: Maria
authors: M
authors: Eriksson
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D020868:Gene Silencing / Q000502:physiology*; D034904:Lamin Type A / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D011371:Progeria / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D019076:Transgenes / Q000235:genetics*
chemical_list: D034904:Lamin Type A; D013267:Stilbenes; D000077185:Resveratrol
keywords: lamin A/C; nuclear lamina; osteoblasts; osteocytes; premature aging