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Review
. 2021 Dec 31;11(1):132.
doi: 10.3390/cells11010132.

Regulation of TNF-Induced Osteoclast Differentiation

Zhenqiang Yao  1 , Stephen J Getting  2 , Ian C Locke  2
Affiliations
Review

Regulation of TNF-Induced Osteoclast Differentiation

Zhenqiang Yao et al. Cells. .

Abstract

Increased osteoclast (OC) differentiation and activity is the critical event that results in bone loss and joint destruction in common pathological bone conditions, such as osteoporosis and rheumatoid arthritis (RA). RANKL and its decoy receptor, osteoprotegerin (OPG), control OC differentiation and activity. However, there is a specific concern of a rebound effect of denosumab discontinuation in treating osteoporosis. TNFα can induce OC differentiation that is independent of the RANKL/RANK system. In this review, we discuss the factors that negatively and positively regulate TNFα induction of OC formation, and the mechanisms involved to inform the design of new anti-resorptive agents for the treatment of bone conditions with enhanced OC formation. Similar to, and being independent of, RANKL, TNFα recruits TNF receptor-associated factors (TRAFs) to sequentially activate transcriptional factors NF-κB p50 and p52, followed by c-Fos, and then NFATc1 to induce OC differentiation. However, induction of OC formation by TNFα alone is very limited, since it also induces many inhibitory proteins, such as TRAF3, p100, IRF8, and RBP-j. TNFα induction of OC differentiation is, however, versatile, and Interleukin-1 or TGFβ1 can enhance TNFα-induced OC formation through a mechanism which is independent of RANKL, TRAF6, and/or NF-κB. However, TNFα polarized macrophages also produce anabolic factors, including insulin such as 6 peptide and Jagged1, to slow down bone loss in the pathological conditions. Thus, the development of novel approaches targeting TNFα signaling should focus on its downstream molecules that do not affect its anabolic effect.

Keywords: TNF receptor-associated factor 3 (TRAF3); interferon-regulatory factor 8 (IRF8); interleukin-1β (IL-1β); nuclear factor-kappa B (NF-κB); osteoclast; osteoprotegerin (OPG); receptor activator of NF-κB ligand (RANKL); recombination signal–binding protein jκ (RBPjκ); transforming growth factor-β1 (TGF-β1); tumor necrosis factor alpha (TNFα).

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Conflict of interest statement

The authors declare no conflict of interest. The content is solely the responsibility of the authors, and does not necessarily represent the official views of the funding source.

Figures

Figure 1
Figure 1
Key factors that mediate TNF-induced OC differentiation. (1) Similar to, and independent of, RANKL, TNFα sequentially activates NF-κB p50 and p52, then c-Fos, followed by NFATc1 to induce OC differentiation; (2) TNFα pre-activated OCPs expressing c-Fos attach to bone, and (3) are stimulated by bone matrix proteins, such as dentin sialoprotein (DSP), to produce IL-1β, which mediates the terminal differentiation of pre-activated OCPs into mature OCs to degrade bone.
Figure 2
Figure 2
NF-κB signaling pathway. (1) Canonical NF-κB activation. Cytokines, such as RANKL and TNFα, induce canonical signaling by recruiting TRAF6 and TRAF2/5, respectively, to their receptors to activate a complex consisting of IKK-α, IKK-β, and IKK-γ (NEMO), which induces phosphorylation and degradation of IκB-α, and the release of p65/p50 heterodimers, which translocate to the nucleus to activate the target gene expression. (2) Non-canonical NF-κB activation. In unstimulated cells, the TRAF3–TRA2 complex results in constitutive NIK degradation, and thus, p100 binds RelB to be remained trapped in cytoplasm. Cytokines, such as CD40L and RANKL, recruit cIAP to the TRAF2–TRA3 complex, resulting in TRAF3 ubiquitin degradation, and allowing newly synthesized NIK accumulation. NIK then phosphorylates IKK-α, which leads to proteasomal processing of p100 to p52, releasing RelB:p52 heterodimers for translocation to the nucleus. TNFα does not degrade TRAF3, and thus, NIK is degraded, leading to the accumulation of p100 in the cytoplasm of osteoclast precursors to limit their differentiation.
Figure 3
Figure 3
Notch signaling regulation of OC differentiation. Notch ligand binding to Notch receptors results in the cleavage and release of Notch NICD. As a result, NICD translocates into the nucleus, where it associates with RBPjκ and NF-κB to regulate the transcription of genes that control OC differentiation. NICD association with RBPjκ inhibits the expression of NFATc1 by attenuating c-Fos, and suppressing Blimp1, and promotes IRF8 expression. Notch also inhibits cFms expression, but associates with NF-κB RelA to promote NFATc1 expression. In addition, Notch inhibits OC differentiation, indirectly downregulating RANKL, while promoting OPG expression by MPCs and osteocytes.
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References

    1. Garnero P., Shih W.J., Gineyts E., Karpf D.B., Delmas P.D. Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J. Clin. Endocrinol. Metab. 1994;79:1693–1700. doi: 10.1210/jcem.79.6.7989477. - DOI - PubMed
    1. Garnero P., Sornay-Rendu E., Chapuy M.C., Delmas P.D. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J. Bone Miner. Res. 1996;11:337–349. doi: 10.1002/jbmr.5650110307. - DOI - PubMed
    1. Eriksen E.F., Hodgson S.F., Eastell R., Riggs B.L., Cedel S.L., O’Fallon W.M. Cancellous bone remodeling in type i (postmenopausal) osteoporosis: Quantitative assessment of rates of formation, resorption, and bone loss at tissue and cellular levels. J. Bone Miner. Res. 1990;5:311–319. doi: 10.1002/jbmr.5650050402. - DOI - PubMed
    1. Redlich K., Hayer S., Maier A., Dunstan C.R., Tohidast-Akrad M., Lang S., Türk B., Pietschmann P., Woloszczuk W., Haralambous S., et al. Tumor necrosis factor α-mediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin. Arthritis Rheum. 2002;46:785–792. doi: 10.1002/art.10097. - DOI - PubMed
    1. Redlich K., Hayer S., Ricci R., David J.-P., Tohidast-Akrad M., Kollias G., Steiner G., Smolen J.S., Wagner E.F., Schett G. Osteoclasts are essential for TNF-α–mediated joint destruction. J. Clin. Investig. 2002;110:1419–1427. doi: 10.1172/JCI0215582. - DOI - PMC - PubMed

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