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Cited by 280Bone Metabolism and DiseasesRheumatoid Arthritis Research and TherapiesOsteomyelitis and Bone Disorders Research

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Regulation of TNF-Induced Osteoclast Differentiation

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Yao, Zhenqiang, Getting, Stephen J., Locke, Ian C.·2021·Cells
DOI 10.3390/cells11010132PMC PMC8750957
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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.

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Figures

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 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.CC BY · PubMed Central
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 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.CC BY · PubMed Central
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.
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.CC BY · PubMed Central

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Metadata

Authors
Yao, Z., Getting, S. J., & Locke, I. C.
Affiliations
  • University of Rochester Medicine (US)
  • University of Westminster (GB)
Corresponding author
Yao, Zhenqiang
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2021-12-31
Volume
11
Issue
1
Pages
132
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells11010132
PMC
PMC8750957
OpenAlex
W4205952184
Cited by
280
References
201
Citations by year
2026: 45 · 2025: 87 · 2024: 69 · 2023: 54 · 2022: 25
FWCI
3.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • WestminsterResearch (University of Westminster) (acceptedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute on Aging (AG049994)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
  • Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
Keywords
TNF-α, osteoclastogenesis, TNF receptor-associated factors, NF-κB signaling, NFATc1, TRAF3, interleukin-1, TGF-β1, osteoporosis, rheumatoid arthritis, bone loss, antiresorptive agents, Jagged1, macrophages
MeSH terms
Animals, Arthritis, Rheumatoid, Cell Differentiation, Humans, Osteoclasts, Osteoporosis, Tumor Necrosis Factor-alpha, Signal Transduction

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