The molecular mechanism of osteoclastogenesis: ODF/RANKL-dependent and independent pathways

Abstract

It is well established that osteoblasts and bone marrow stromal cells express osteoclast differentiation factor (ODF, also called RANKL) in response to several bone-resorbing factors to support osteoclast differentiation from their precursors. Osteoclast precursors which express RANK, a TNF receptor family member, recognize ODF/ RANKL through cell-to-cell interaction with osteoblasts/stromal cells, and differentiate into osteoclasts in the presence of M-CSF. Osteoclastogenesis inhibitory factor (OCIF, also called OPG) acts as a decoy receptor for ODF/RANKL. ODF/RANKL is responsible for inducing not only differentiation, but also survival and activation of osteoclasts. IL-1 and TNFα also play a major role in the pathogenesis of bone resorption induced by inflammation. IL-1 induced osteoclast differentiation by a classical ODF/RANKL-dependent mechanism, indicating that osteoblasts are essential for IL-1-induced osteoclast formation. In contrast, mouse TNFα strongly stimulated differentiation of M-CSF-dependent bone marrow macrophages (M-BMMφ) into osteoclasts without any help of osteoblasts/stromal cells. Osteoclast formation by TNFα was inhibited by antibodies against TNF receptor type 1 and 2 (TNFR1 and TNFR2), but not by OPG/OCIF, indicating that differentiation of M-BMMφ into osteoclasts by TNFα occurs by a mechanism independent of the ODF/RANKL-RANK interaction. IL-1 failed to induce differentiation of M-BMMφ into osteoclasts. More recently, we found that lipopolysaccharides (LPS)-induced bone loss did not occur in knockout mice of EP4, a subtype of PGE2 receptor. This indicates that EP4 signals are involved in the LPS-induced bone resorption. LPS appeared to induce osteoclast formation by two different pathways: one is an ODF/RANK-independent pathway involving TNFα. LPS induces TNFα production through toll-like receptor 4 (TLR4) in macrophages, which in turn directly acts on osteoclast progenitors through TNFR1 and TNFR2 to induce osteoclast differentiation. In this pathway, osteoblasts did not appear to be involved. The other pathway is the classical ODF/RANKL-dependent pathway. In the classical pathway, LPS induces PGE2 production through TLR4 in osteoblasts and macrophages, which in turn induces ODF/RANKL through EP4 in osteoblasts. ODF then binds ODF receptor (RANK) in osteoclast progenitors by cell-cell contact, which stimulates osteoclast differentiation. We conclude that osteoblasts/stromal cells are involved in not only physiological, but also pathological bone resorption via ODF/RANKL.