Skip to Content
MilliporeSigma
  • Diminished Canonical β-Catenin Signaling During Osteoblast Differentiation Contributes to Osteopenia in Progeria.

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

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (2018-07-13)
Ji Young Choi, Jim K Lai, Zheng-Mei Xiong, Margaret Ren, Megan C Moorer, Joseph P Stains, Kan Cao
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
TOPflash (TCF Reporter Plasmid), Transfection grade T-cell factor reporter plasmid containing 2 sets (with the second set in the reverse orientation) of 3 copies of the TCF binding site (wild type) upstream of the Thymidine Kinase minimal promoter and Luciferase open reading frame.
Sigma-Aldrich
Anti-β-Actin−Peroxidase antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture