Regulation of Osteoclast Differentiation by Cytokine Networks

Abstract

Cytokines play a pivotal role in maintaining bone homeostasis. Osteoclasts (OCs), the sole bone resorbing cells, are regulated by numerous cytokines. Macrophage colony-stimulating factor and receptor activator of NF-κB ligand play a central role in OC differentiation, which is also termed osteoclastogenesis. Osteoclastogenic cytokines, including tumor necrosis factor-α, IL-1, IL-6, IL-7, IL-8, IL-11, IL-15, IL-17, IL-23, and IL-34, promote OC differentiation, whereas anti-osteoclastogenic cytokines, including interferon (IFN)-α, IFN-β, IFN-γ, IL-3, IL-4, IL-10, IL-12, IL-27, and IL-33, downregulate OC differentiation. Therefore, dynamic regulation of osteoclastogenic and anti-osteoclastogenic cytokines is important in maintaining the balance between bone-resorbing OCs and bone-forming osteoblasts (OBs), which eventually affects bone integrity. This review outlines the osteoclastogenic and anti-osteoclastogenic properties of cytokines with regard to osteoimmunology, and summarizes our current understanding of the roles these cytokines play in osteoclastogenesis.

Keywords: Cytokines; Osteoclast differentiation factor; Osteoclastogenesis; Osteoimmunology.

Figure 1

Schematic representation of OC differentiation and activation. HSCs undergo differentiation into OC precursors depending on the presence of PU.1 and the MITF transcription factors activated by M-CSF signaling. The differentiation of OC precursors into mononuclear and multinucleated OCs is further modulated by RANKL and M-CSF signaling. Bone-resorbing multinucleated OCs derived from the fusion of mononuclear OCs express OC differentiation markers such as DC-STAMP, Atp6v0d2, β3 integrin, cathepsin K, and OSTM1. Atp6v0d2, v-ATPase subunit d2; DC-STAMP, dendritic cell-specific transmembrane protein; HSCs, hematopoietic stem cell; MITF, microphthalmia transcription factor; OSTM1, osteopetrosis-associated transmembrane protein 1.

Figure 2

Signaling networks in osteoclastogenesis. Osteoclastogenesis is principally stimulated by RANKL and M-CSF. During the early stage of OC differentiation, M-CSF signaling induces Akt and ERK activation leading to OC proliferation and differentiation. Then, RANKL induces NF-κB, AP-1, CREB, MITF and NFATc1 activation via TRAF6 recruitment and the MAPKs, Akt, Vav3 and c-Src signaling cascades to promote the differentiation of OC precursors into mature OCs. RANKL signaling is further strengthened by TREM2- or OSCAR-mediated costimulatory signaling pathway through the induction of DAP12/FcRγ-Syk-PLCγ signaling cascades that activate calcium signaling and NFATc1 induction. Grb2, growth factor receptor bound protein 2; TAK1, transforming growth factor-β kinase 1; TAB, transforming growth factor-β kinase 1 binding protein; NEMO, NF-κB essential modulator; IKK, inhibitor of IκB kinase; DAP12, DNAX-activating protein 12; FcRγ, Fc receptor common γ subunit; BLNK, B-cell linker protein; SLP-76, SH2 domain-containing leukocyte protein of 76 kDa; CaMKIV, Ca2⁺/calmodulin-dependent protein kinase IV; CREB, cyclic adenosine monophosphate response element-binding protein; MITF, microphthalmia transcription factor.