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.

• Authors: Ji Young Choi, Jim K Lai, Zheng-Mei Xiong, Margaret Ren, Megan C Moorer, Joseph P Stains, Kan Cao
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 33 Issue 11 Pg. 2059-2070 (11 2018) ISSN: 1523-4681 [Electronic] United States
• PMID: 30001457 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 American Society for Bone and Mineral Research.

Chemical References

• Adaptor Proteins, Signal Transducing
• Antibodies, Neutralizing
• Glycoproteins
• Intercellular Signaling Peptides and Proteins
• Lamin Type A
• Sost protein, mouse
• beta Catenin
• prelamin A

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Antibodies, Neutralizing (pharmacology)
• Bone Diseases, Metabolic (complications, metabolism, pathology)
• Cell Differentiation (drug effects)
• Cell Line
• Disease Models, Animal
• Glycoproteins (immunology)
• Humans
• Induced Pluripotent Stem Cells (metabolism)
• Intercellular Signaling Peptides and Proteins
• Lamin Type A (metabolism)
• Mesenchymal Stem Cells (drug effects, metabolism)
• Mice
• Models, Biological
• Mutation (genetics)
• Osteoblasts (drug effects, metabolism)
• Osteogenesis (drug effects)
• Phenotype
• Progeria (complications, genetics, metabolism, pathology)
• Protein Prenylation (drug effects)
• Signal Transduction
• Wnt Signaling Pathway (drug effects)
• beta Catenin (metabolism)