Figure 1.

Schematic representation of cellular and molecular players involved in RANKL-RANK signaling axis in the bone and thymus in physiological and in pathological conditions. (A) Membrane-bound and soluble RANKL produced by cells of the osteoblast lineage and by immune cells induce osteoclastogenesis upon its binding to RANK on osteoclast precursors. OPG is the soluble decoy receptor for RANKL. Moreover, RANKL binding to LGR4 on osteoclasts hinders their maturation. RANK expression by MSC and osteoblasts points to a potential RANKL autoregulatory mechanism affecting bone formation. In addition, osteoclast-derived RANK-expressing extracellular vesicles (EV) trigger a reverse signaling on osteoblast. (B) The inflammatory bone environment in pathological condition, such as osteoporosis and rheumatoid arthritis, results in increased production of RANKL by immune cells, osteoblastic cells and synovial fibroblasts. This exacerbates osteoclast generation and bone loss, which are target of denosumab treatment. (C) In the thymus, RANKL produced by resident and recirculating T cells, invariant NKT and LTi cells fosters mTEC AIRE expression and maturation via RANK receptor, allowing correct establishment of central tolerance. (D) In the presence of thymic dysfunction, pharmacological sRANKL administration boosts thymic regeneration, and T cell reconstitution. Similarly, in the early phases of thymic regeneration after body irradiation, CD4⁺ and LTi cells upregulate RANKL. This results in increased expression of LTα in LTi cells. OBs, osteoblasts; OCs, osteoclasts; OCYs, osteocytes.