New roles of osteoblasts involved in osteoclast differentiation

Figure 1 Regulation of osteoclast differentiation by osteoblasts through macrophage colony-stimulating factor, receptor activator of nuclear factor-κB ligand, and osteoprotegerin production. Osteoblasts express two cytokines essential for osteoclast differentiation, macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). Osteoblasts constitutively express M-CSF. On the other hand, osteoblasts express RANKL as a membrane-associated form in response to bone resorption-stimulating factors such as 1α,25-dihydroxyvitamin D3 [1α,25(OH)₂D₃], parathyroid hormone (PTH), prostaglandin E₂ (PGE₂), and interleukin 11 (IL-11). Osteoclast precursors express c-Fms (M-CSF receptor) and RANK (RANKL receptor) and differentiate into osteoclasts in the presence of M-CSF and RANKL. Osteoblasts also produce osteoprotegerin (OPG), which inhibits osteoclastogenesis by blocking the RANKL-RANK interaction.

Figure 2 In vivo dynamics of osteoclast precursors. Cells expressing both receptor activator of nuclear factor-κB (RANK) and c-Fms are cell cycle-arrested quiescent osteoclast precursors (QOPs) in vivo. QOPs are detected in hematopoietic organs such as the spleen and bone. macrophage colony-stimulating factor (M-CSF) and/or interleukin 34 (IL-34) appear to be involved in the differentiation of hematopoietic progenitor cells into QOPs. Some QOPs circulate to find bone. Osteoblasts play a role in the homing of QOPs to bone. QOPs in bone differentiate into osteoclasts without cell cycle progression in response to M-CSF/IL-34 and RANK ligand.

Figure 3 Role of Wnt5a-receptor tyrosine kinase-like orphan receptor 2 signaling in osteoclast precursors. Receptor activator of nuclear factor-κB (RANK) expression in osteoclast precursors is much stronger than that in bone marrow and the spleen. Osteoblasts express Wnt5a, while osteoclast precursors express receptor tyrosine kinase-like orphan receptor 2 (Ror2), a co-receptor of Wnt5a. Wnt5a produced by osteoblasts enhances RANK expression in osteoclast precursors through Ror2. Wnt5a up-regulates RANK expression through the recruitment of c-Jun to Sp1 sites of the RANK promoter. The up-regulation of RANK expression in osteoclast precursors increases their sensitivity to RANK ligand. JNK: c-Jun N-terminal kinase.

Figure 4 Role of semaphorin 3A in osteoclast differentiation. Semaphorin 3A (Sema3A) produced by osteoblasts usually binds to the receptor complex of Nrp1 and Plexin-A1 in osteoclast precursors. Sema3A inhibits differentiation of osteoclast precursors into osteoclasts through the suppression of immunoreceptor tyrosine-based activation motifs (ITAM) signaling. Receptor activator of nuclear factor-κB ligand (RANKL) stimulation rapidly suppresses Nrp1 expression in osteoclast precursors. Plexin-A1 then makes a complex with triggering receptor expressed on myeloid cells 2 (TREM-2) and DNAX-activating protein of 12 kDa (DAP12). Sema6D or 6C, transmembrane semaphorins, binds to the receptor complex and stimulates ITAM signals in osteoclast precursors to enhance RANK signaling.