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
Ji Young ChoiKan 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 an...Continue Reading

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Citations

Feb 20, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yixuan ChenYoushui Gao
Mar 3, 2020·Frontiers in Endocrinology·Robert Brommage, Claes Ohlsson
Nov 19, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Marika SjöqvistCecilia Sahlgren
May 1, 2021·International Journal of Molecular Sciences·Samantha DonsanteMara Riminucci
Aug 20, 2020·Current Gene Therapy·Paolo CapparèPaola Panina-Bordignon
May 30, 2021·Bone·Scott Birks, Gunes Uzer

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