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

Abstract

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.

Impairment of nuclear F-actin formation and its relevance to cellular phenotypes in Hutchinson-Gilford progeria syndrome

“…Quantitative RT-PCR revealed that the expression level of TCF-1 was significantly reduced by the expression of progerin but not lamin A ( Figure 1(d )). Interestingly, the expression of Wnt/β-catenin-inducible genes is reported to be decreased in cells of HGPS patients [ 13 , 14 ]. We suggest that the decrease of nuclear F-actin by progerin expression contributes to the misregulation of genes in HGPS cells.…”

“…Gene expression is also affected in HGPS cells. Notably, Wnt/β-catenin signaling, known to be a fundamental pathway, is diminished in HGPS cells [ 13 , 14 ]. It has been suggested that the suppression of Wnt/β-catenin signal activity and decreased levels of Wnt/β-catenin-responsive gene expression is the cause of bone defects in HGPS [ 15 , 16 ].…”

L-Plastin deficiency produces increased trabecular bone due to attenuation of sealing ring formation and osteoclast dysfunction

“…47 Microcomputed tomography Femurs were dissected from 8-to 12-week-old female WT and LPL −/− mice and processed as described. 71 Three-dimensional Micro-CT was performed on femurs (n = 5-6) using a SkyScan 1172 (Bruker, Kontich, Belgium) at 60 kV (167 µA) and a 9.91 µm voxel size, as described. 72,73 The skeletal parameters assessed by micro-CT followed published nomenclature guidelines.…”

High Fidelity of Mouse Models Mimicking Human Genetic Skeletal Disorders

“…Teriparatide treatment increases bone mass in Lrp5 KO mice mimicking humans with osteoporosis pseudoglioma syndrome from loss of function LRP5 mutations (88,89). Similarly, anti-sclerostin antibody treatment increases bone mass in mutant mouse models with low bone mass from gene disruptions (90) of Col1a1 (91, 92), Col1a2 (93, 94), Crtap (95), Dmp1 (96), Lrp5 (97), and Zmpste24 (98). Mechanistic hypotheses can be tested, such as periostin treatment retarding skull suture fusion in heterozygous Twist1 mice with craniosynostosis (99).…”