New roles of osteoblasts involved in osteoclast differentiation

Abstract

Bone-resorbing osteoclasts are formed from a monocyte/macrophage lineage under the strict control of bone-forming osteoblasts. So far, macrophage colony-stimulating factor (M-CSF), receptor activator of nuclear factor-κB ligand (RANKL), and osteoprotegerin (OPG) produced by osteoblasts play major roles in the regulation of osteoclast differentiation. Recent studies have shown that osteoblasts regulate osteoclastogenesis through several mechanisms independent of M-CSF, RANKL, and OPG production. Identification of osteoclast-committed precursors in vivo demonstrated that osteoblasts are involved in the distribution of osteoclast precursors in bone. Interleukin 34 (IL-34), a novel ligand for c-Fms, plays a pivotal role in maintaining the splenic reservoir of osteoclast-committed precursors in M-CSF deficient mice. IL-34 is also able to act as a substitute for osteoblast-producing M-CSF in osteoclastogenesis. Wnt5a, produced by osteoblasts, enhances osteoclast differentiation by upregulating RANK expression through activation of the non-canonical Wnt pathway. Semaphorin 3A produced by osteoblasts inhibits RANKL-induced osteoclast differentiation through the suppression of immunoreceptor tyrosine-based activation motif signals. Thus, recent findings show that osteoclast differentiation is tightly regulated by osteoblasts through several different mechanisms. These newly identified molecules are expected to be promising targets of therapeutic agents in bone-related diseases.

Keywords: Interleukin 34; Osteoblast; Osteoclast; Receptor activator of nuclear factor-κB ligand; Semaphorin 3A; Wnt5a.

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.