Mechanisms of RANKL delivery to the osteoclast precursor cell surface.

RANKL is biosynthesized as a single-pass transmembrane protein, and soluble molecular species are produced by enzymatic cleavage at the cell surface. Recent studies have revealed that the transmembrane form of RANKL is a major contributor to the induction of mature osteoclasts under physiological conditions in vivo. In osteoblasts and osteocytes, most newly synthesized RANKL forms a protein complex with OPG and is selectively sorted to lysosomes. Only the small proportion of newly synthesized RANKL that does not form a complex with OPG is transported to the cell surface. Then, the transmembrane RANKL is delivered to the surface of osteoclast precursors to stimulate RANK, and induces the activation of a downstream signaling pathway. The ability of osteocytes to support the formation of mature osteoclasts appears to depend upon the amount of RANKL molecules present on their cell surfaces. However, the way in which osteocytes, which are embedded in the bone matrix, deliver transmembrane RANKL to the cell surfaces of osteoclast precursors, which are localized in the bone marrow cavity, remains to be elucidated. Further studies are needed to clarify the mechanisms underlying this process.