Diminished Canonical β‐Catenin Signaling During Osteoblast Differentiation Contributes to Osteopenia in Progeria. (1st August 2018)

• Record Type: Journal Article
• Authors: Choi, Ji Young; Lai, Jim K; Xiong, Zheng‐Mei; Ren, Margaret; Moorer, Megan C; Stains, Joseph P; Cao, Kan
• Is Part Of: Journal of bone and mineral research. Volume 33:Number 11(2018)
• Page Start: 2059
• Page End: 2070
• Publication Date: 2018-08-01
• Subjects: PROGERIA -- HGPS -- MESENCHYMAL STEM CELL -- WNT/β‐CATENIN SIGNALING -- OSTEOGENIC DIFFERENTIATION AND AGING; Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.3549
• Languages: English
• ISSNs: 0884-0431

Abstract

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.