in Immune Network Immune Netw 1598-2629 2092-6685 Korean Association of Immunologists 10.4110/in.2018.18.e8 in-18-e8 Review Article Regulation of Osteoclast Differentiation by Cytokine Networks AmarasekaraDulshara Sachini YunHyeongseok KimSumi LeeNari KimHyunjong RhoJaerang * Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 34134, Korea Correspondence to Jaerang Rho Department of Microbiology and Molecular Biology, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea. E-mail: jrrho@cnu.ac.kr

Conflict of Interest The authors declare no potential conflicts of interest.

 02 2018 04 02 2018 18 1 e8 04122017 02022018 03022018 Copyright © 2018 The Korean Association of Immunologists 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 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-κ B 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.

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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.

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-κ B, 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-κ B essential modulator; IKK, inhibitor of Iκ B 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.

Summary of the effects of osteoclastogenic and anti-osteoclastogenic cytokines in osteoclastogenesis.

Cytokine Action Reference
Osteoclastogenic cytokines
   RANKL Induces OC differentiation, survival, proliferation, and maturation (1-3,10–14)
   M-CSF Induces OC differentiation, survival, proliferation, and maturation (1-3,7–9)
   TNF-α Induces RANKL and RANK expression; stimulates OC differentiation (18–28)
   IL-1a Induces RANKL and OC marker expression; activates MITF induction (33)
   IL-1b Induces RANKL expression and OC differentiation (30–32)
   IL-6 Induces RANKL and OC marker expression (36–38)
   IL-7 Induces RANKL and TNF-α expression; activates STAT5 (41–45)
   IL-8 Induces RANK-mediated NFATc1 activation (47–49)
   IL-11 Induces OC differentiation; increases OC progenitor cells (39,51,52)
   IL-15 Induces TNF-α and RANKL expression; stimulates OC differentiation (53,54)
   IL-17 Induces RANKL, TNF-α, IL-1, and IL-6 expression (55–60)
   IL-23 Induces RANKL and RANK expression; stimulates IL-17 producing Th17 cell expansion (63–65)
   IL-34 Induces OC differentiation; activates STAT3/Smad7 signaling pathway (28,66–68)
Anti-osteoclastogenic cytokines
   OPG Inhibits OC differentiation (a decoy receptor of RANKL) (1–3,5)
   IFN-α Downregulates c-Fos expression (83,84)
   IFN-β Inhibits RANK- and TLR5-mediated OC differentiation; downregulates JAK1/STAT3/c-Fos signaling pathway (85–89)
   IFN-γ Inhibits RANKL- and TNF-α-induced OC differentiation; stimulates OC apoptosis (94–96)
   IL-3 Downregulates c-Fms, PU.1, c-Fos, and TNFR expression (100–102)
   IL-4 Inhibits RANKL-induced NFATc1 induction; downregulates TNF-α, IL-1, IL-6, and RANKL expression (103–107)
   IL-10 IL-12 Downregulates NFATc1, IL-1, TNF-α, and IL-6 production; induces OPG expression Inhibits RANKL- and TNF-α-induced OC differentiation (108-110)(112–114)
   IL-27 Inhibits RANKL-induced signaling pathway; downregulates IL-17-mediated Th17 cell differentiation (117–121)
   IL-33 differentiation Inhibits RANKL-induced OC differentiation; induces OC apoptosis (122–124)