Regulation of Osteoclast Differentiation by Cytokine Networks

Dulshara Sachini Amarasekara; Hyeongseok Yun; Sumi Kim; Nari Lee; Hyunjong Kim; Jaerang Rho

doi:10.4110/in.2018.18.e8

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Amarasekara, Yun, Kim, Lee, Kim, and Rho: Regulation of Osteoclast Differentiation by Cytokine Networks

Review Article

Immune Netw 2018;18(1):e8.

Published online: 4 February 2018

DOI: https://doi.org/10.4110/in.2018.18.e8

Regulation of Osteoclast Differentiation by Cytokine Networks

Dulshara Sachini Amarasekara, Hyeongseok Yun, Sumi Kim, Nari Lee, Hyunjong Kim, Jaerang Rho^*

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.

Received 4 December 2017 Revised 2 February 2018 Accepted 3 February 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.

Keywords: Cytokines, Osteoclast differentiation factor, Osteoclastogenesis, Osteoimmunology

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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-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.

Table 1.

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)

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