TY - JOUR
T1 - Transgene silencing of the Hutchinson-Gilford progeria syndrome mutation results in a reversible bone phenotype, whereas resveratrol treatment does not show overall beneficial effects
AU - Strandgren, Charlotte
AU - Nasser, Hasina Abdul
AU - McKenna, Tomás
AU - Koskela, Antti
AU - Tuukkanen, Juha
AU - Ohlsson, Claes
AU - Rozell, Björn
AU - Eriksson, Maria
N1 - © FASEB.
PY - 2015/8/1
Y1 - 2015/8/1
N2 - Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder that is most commonly causedby a de novopointmutation inexon11of 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 andmineralization 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.-Strandgren, C., Nasser, H. A., McKenna, T., Koskela, A., Tuukkanen, J., Ohlsson, C., Rozell, B., Eriksson, M. Transgene silencing of the Hutchinson- Gilford progeria syndrome mutation results in a reversible bone phenotype, whereas resveratrol treatment does not show overall beneficial effects.
AB - Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder that is most commonly causedby a de novopointmutation inexon11of 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 andmineralization 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.-Strandgren, C., Nasser, H. A., McKenna, T., Koskela, A., Tuukkanen, J., Ohlsson, C., Rozell, B., Eriksson, M. Transgene silencing of the Hutchinson- Gilford progeria syndrome mutation results in a reversible bone phenotype, whereas resveratrol treatment does not show overall beneficial effects.
U2 - 10.1096/fj.14-269217
DO - 10.1096/fj.14-269217
M3 - Journal article
C2 - 25877214
SN - 0892-6638
VL - 29
SP - 3193
EP - 3205
JO - F A S E B Journal
JF - F A S E B Journal
IS - 8
ER -