| First Author | Choi JY | Year | 2018 |
| Journal | J Bone Miner Res | Volume | 33 |
| Issue | 11 | Pages | 2059-2070 |
| PubMed ID | 30001457 | Mgi Jnum | J:278902 |
| Mgi Id | MGI:6359242 | Doi | 10.1002/jbmr.3549 |
| Citation | Choi JY, et al. (2018) Diminished Canonical beta-Catenin Signaling During Osteoblast Differentiation Contributes to Osteopenia in Progeria. J Bone Miner Res 33(11):2059-2070 |
| abstractText | 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/beta-catenin pathway, seemingly at the level of the efficiency of nuclear import of beta-catenin, impair osteoblast differentiation and that restoring beta-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/beta-catenin pathway, a major signaling cascade involved in skeletal homeostasis, is impaired by progerin, causing a reduction in the active beta-catenin in the nucleus and thus decreased transcriptional activity, and its reciprocal cytoplasmic accumulation. Blocking farnesylation of progerin restores active beta-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/beta-catenin signaling pathway, fully rescues the low bone mass phenotype to wild-type levels. Together, this study reveals that the beta-catenin signaling cascade is a therapeutic target for restoring defective skeletal microarchitecture in HGPS. (c) 2018 American Society for Bone and Mineral Research. |
