Expression of the Hutchinson-Gilford Progeria Mutation during Osteoblast Development Results in Loss of Osteocytes, Irregular Mineralization, and Poor Biomechanical Properties

Schmidt, Éva; Nilsson, Ola; Koskela, Antti; Tuukkanen, Juha; Ohlsson, Claes; Rozell, Björn; Eriksson, Maria

doi:10.1074/jbc.m112.366450

Cited by 44 publications

(71 citation statements)

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“…Bitransgenic mice were generated as previously described (22). Genotyping was performed according to published protocols (23, 24).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

“…In this study, we used a mouse model with the osteoblast‐and osteocyte‐specific inducible transgenic expression of the most common HGPS mutation (22). These mice develop a bone phenotype that closely resembles the bone abnormalities of individuals who are affected by HGPS and that is reminiscent to aging bone changes (22). To investigate the possibility of reversing an existing HGPS bone phenotype, we suppressed the transgenic expression and investigated whether the complete silencing of the HGPS mutation for up to 48 weeks would inhibit disease progression and lead to normal bone remodeling.…”

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confidence: 99%

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

Strandgren¹,

Nasser²,

McKenna³

et al. 2015

The FASEB Journal

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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.

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“…Bitransgenic mice were generated as previously described (22). Genotyping was performed according to published protocols (23, 24).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Strandgren¹,

Nasser²,

McKenna³

et al. 2015

The FASEB Journal

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“…Similarly, lymphocytes from patients with type 2 diabetes (T2D) have reduced capacity to repair ROS-induced DNA damage, and NHEJ deficiency impairs pancreatic β-cells 55,56 . Furthermore, differentiation of bone-forming osteoblasts is inhibited by DNA damage and contributes to weakened bone structure in a progeria mouse model 57 . In line with this evidence, defective NHEJ can result in osteopenia, a less severe ageing-related form of osteoporosis 58 .…”

Section: Genomic Instability In Ageing and Aadsmentioning

confidence: 99%

Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases

Kubben

Misteli

2017

Nat Rev Mol Cell Biol

235

203

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Ageing is the predominant risk factor for many common diseases. Human premature ageing diseases are powerful model systems to identify and characterize cellular mechanisms that underpin physiological ageing. Their study also leads to a better understanding of the causes, drivers and potential therapeutic strategies of common diseases associated with ageing, including neurological disorders, diabetes, cardiovascular diseases and cancer. Using the rare premature ageing disorder Hutchinson–Gilford progeria syndrome as a paradigm, we discuss here the shared mechanisms between premature ageing and ageing-associated diseases, including defects in genetic, epigenetic and metabolic pathways; mitochondrial and protein homeostasis; cell cycle; and stem cell-regenerative capacity.

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“…A few pieces of evidence have suggested that HGPS might be associated with defective WNT/β‐catenin signaling cascades . Stem cells isolated from Zmpste24‐/‐ mice exhibit alterations in the WNT signaling pathway .…”

Section: Introductionmentioning

confidence: 99%

Diminished Canonical β-Catenin Signaling During Osteoblast Differentiation Contributes to Osteopenia in Progeria

Choi¹,

Lai

Xiong³

et al. 2018

Journal of Bone and Mineral Research

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Patients with Hutchinson-Gilford progeria syndrome (HGPS) have low bone mass and an atypical skeletal geometry that manifests in a high risk of fractures. Using both in vitro and in vivo models of HGPS, we demonstrate that defects in the canonical WNT/β-catenin pathway, seemingly at the level of the efficiency of nuclear import of β-catenin, impair osteoblast differentiation and that restoring β-catenin activity rescues osteoblast differentiation and significantly improves bone mass. Specifically, we show that HGPS patient-derived iPSCs display defects in osteoblast differentiation, characterized by a decreased alkaline phosphatase activity and mineralizing capacity. We demonstrate that the canonical WNT/β-catenin pathway, a major signaling cascade involved in skeletal homeostasis, is impaired by progerin, causing a reduction in the active β-catenin in the nucleus and thus decreased transcriptional activity, and its reciprocal cytoplasmic accumulation. Blocking farnesylation of progerin restores active β-catenin accumulation in the nucleus, increasing signaling, and ameliorates the defective osteogenesis. Moreover, in vivo analysis of the Zmpste24-/- HGPS mouse model demonstrates that treatment with a sclerostin-neutralizing antibody (SclAb), which targets an antagonist of canonical WNT/β-catenin signaling pathway, fully rescues the low bone mass phenotype to wild-type levels. Together, this study reveals that the β-catenin signaling cascade is a therapeutic target for restoring defective skeletal microarchitecture in HGPS. © 2018 American Society for Bone and Mineral Research.

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Expression of the Hutchinson-Gilford Progeria Mutation during Osteoblast Development Results in Loss of Osteocytes, Irregular Mineralization, and Poor Biomechanical Properties

Cited by 44 publications

References 50 publications

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

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

Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases

Diminished Canonical β-Catenin Signaling During Osteoblast Differentiation Contributes to Osteopenia in Progeria

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