RANKL is best studied in the context of bone remodeling. Its activity, binding to the cell surface receptor RANK, is necessary for the function of the osteoclast cells that break down bone extracellular matrix. Bone tissue is in a constant state of remodeling, built up by osteoblast cells and broken down by osteoclast cells. The loss of bone mineral density that leads to osteoporosis arises from a growing age-related imbalance between osteoblast and osteoclast activity, favoring the osteoclasts. The various established therapies used to slow the progression of osteoporosis attempt to tilt that balance away from loss of bone mineral density, such as via monoclonal antibodies targeting RANKL to suppress osteoclast activity.
In today's open access paper, researchers note that RANKL inhibition extends life in progeroid mice. The details are interesting, adding to other data suggesting that RANKL has roles in aging that go beyond issues with bone tissue, such as influence on muscle aging. One would want to see a study in normally aged mice to confirm that this is the case, of course. In the broader context, it might be worth noting that another class of drug that inhibits osteoclast activity in a different way, bisphosphonates, may also act to slow aging. There is evidence for bisphosphonates to be senolytic, for example, and human data showing a survival advantage of five years in people using bisphosphonates versus the general population.
Targeting RANKL Prevents Bone Loss, Improves Muscle Function and Extends Lifespan in Progeroid Mice
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.
View the full article at FightAging
