Mechanisms of RANKL delivery to the osteoclast precursor cell surface
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INVITED REVIEW
Mechanisms of RANKL delivery to the osteoclast precursor cell surface Masashi Honma1 · Yuki Ikebuchi1 · Hiroshi Suzuki1 Received: 30 June 2020 / Accepted: 14 September 2020 © The Japanese Society Bone and Mineral Research and Springer Japan KK, part of Springer Nature 2020
Abstract 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. Keywords RANKL · OPG · RANKL reverse signaling · Osteocyte · Osteoclast
RANKL in a transmembrane form which efficiently activates a signaling pathway downstream of RANK Receptor activator of nuclear factor-kappa B ligand (RANKL) is a single-pass type II membrane protein that non-covalently forms a homo trimer [1]. The cytoplasmic tail, which consists of fewer than 50 amino acid residues, is located at the N-terminus; while, the receptor-binding tumor necrosis factor (TNF) domain is located at the C-terminus [1, 2]. Some membrane-anchored metalloproteinases, including matrix metallopeptidase 14 (MMP14), ADAM metallopeptidase domain 10 (ADAM10), and ADAM17, are known to cleave between the TNF domain and the transmembrane domain of RANKL, to release a soluble form of RANKL (sRANKL) from the cell surface [3]. Stimulation of osteoclast precursor cells with sRANKL recombinant protein in vitro leads to the formation of mature osteoclasts [4]. Administration of sRANKL * Masashi Honma mhonma‑[email protected] 1
Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Hongo 7‑3‑1, Bunkyo‑ku, Tokyo 113‑8655, Japan
recombinant protein to mice results in the enhancement of bone resorption, associated with an increase in the number of mature osteoclasts in vivo [5]. It has long been a matter of controversy whether the transmembrane form or the soluble form is the major contributor to the induction of osteoclast maturation under physiological conditions. The ability of osteoblasts to support in vitro ost
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