Clinical Relevance of Modifying RANKL Signaling During Folliculogenesis

Female infertility presents a significant societal challenge that will be aggravated in the future due to delayed parenthood. Our translational research suggests that receptor activator of NF-κB ligand (RANKL) is a novel treatment target, during assisted reproductive techniques and that inhibition of this pathway may reduce the impact of aging on the ovary. RANKL is a regulator of bone health, and an antibody (denosumab) blocking RANKL activity is used clinically to treat osteoporosis. Previously, we have shown that inhibition of RANKL increases sperm production in rodents, in human tissue models, and in a subpopulation of infertile men. Now, we show that all factors of the RANKL signalling system are expressed in human and mouse ovaries. Granulosa cell-specific Rankl knockdown lowers the number of primordial follicles, which suggests that RANKL has an important role during early stages of folliculogenesis. Additionally, our data from women undergoing in vitro fertilisation show that follicular fluid concentrations of RANKL and OPG are associated with age and the number of matured follicles, and RANKL inhibition promoted maturation of human oocytes in vitro, which suggests an effect also late in folliculogenesis. Thus, the proposed project aims to: 1) Clarify the role of RANKL in ovaries of mice and humans 2) Determine the reproductive effect of modulating RANKL activity systemically or locally in mice and monkeys 3) Investigate whether manipulation of RANKL can optimise in vitro maturation and rescue of immature human oocytes and 4) Determine whether follicular fluid concentrations of soluble RANKL and OPG may serve as markers of ovarian pathophysiology. The overall aim of this project is to uncover how RANKL regulates follicle reserve and oocyte maturation during the final stages of follicle development. Thereby, determining whether this pathway may be a target for optimisation of IVF treatment and a future treatment option for female infertility.