Targeting RANKL Prevents Bone Loss, Improves Muscle Function and Extends Lifespan in Progeroid Mice.

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by the early development of pathological features associated with aging, ultimately leading to premature death. HGPS primarily affects tissues of mesenchymal origin, as evidenced by the clinical manifestations characteristic of this premature aging disorder, including, but not limited to, osteoporosis, muscle wasting, lipodystrophy, and cardiovascular disease. In this study, we used preclinical mouse models and both genetic and translational approaches to investigate whether an antiresorptive strategy, based on RANKL targeting, ameliorated the bone loss phenotype of progeroid mice. Here we show that osteocyte-derived RANKL deletion in the Zmpste24^-/- mouse model of HGPS reverted bone loss in both long bones and vertebrae. These mice also exhibited increased grip strength and improved endurance capacity. Furthermore, Zmpste24^-/- mice showed increased survival upon osteocyte-specific RANKL deletion. Notably, the use of a translational approach based on the administration of a neutralizing antibody against RANKL also restored bone mass, reduced muscle fibrosis, and extended the lifespan of Zmpste24^-/- mice. Altogether, these findings support that targeting RANKL exerts a beneficial effect on both osseous and extra-osseous phenotypes of HGPS, suggesting the potential of this therapeutic approach to explore in the treatment of this disease.