IFN-γ-producing human T cells directly induce osteoclastogenesis from human monocytes via the expression of RANKL

Kotake, Shigeru; Nanke, Yuki; Mogi, Makio; Kawamoto, Manabu; Furuya, Takefumi; Yago, Toru; Kobashigawa, Tsuyoshi; Togari, Akifumi; Kamatani, Naoyuki

doi:10.1002/eji.200526141

Cited by 127 publications

(100 citation statements)

References 41 publications

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“…RANKL + CD4 + PB T cells isolated from patients with early RA, if cultured with monocytes for 2 wk at a high T cell:monocyte ratio (4:1), can induce osteoclast differentiation (41). Other studies have shown that activated PB T cells induce RANKL-dependent osteoclastogenesis from adherent PBMCs if these cultures are pretreated with M-CSF (40,42). Although a direct role for T cells in inducing osteoclastogenesis remains controversial, recent studies have established an indirect role for the Th17 cell subset that up-regulates RANKL expression by osteoblasts (43).…”

Section: Discussionmentioning

confidence: 99%

Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis

Söderström

Stein

Colmenero

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

150

153

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Osteoclasts are bone-eroding cells that develop from monocytic precursor cells in the presence of receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Osteoclasts are essential for physiological bone remodeling, but localized excessive osteoclast activity is responsible for the periarticular bone destruction that characteristically occurs in patients with rheumatoid arthritis (RA). The origin of osteoclasts at sites of bone erosion in RA is unknown. Natural killer (NK) cells, as well as monocytes, are abundant in the inflamed joints of patients with RA. We show here that such NK cells express both RANKL and M-CSF and are frequently associated with CD14 + monocytes in the RA synovium. Moreover, when synovial NK cells are cocultured with monocytes in vitro, they trigger their differentiation into osteoclasts, a process dependent on RANKL and M-CSF. As in RA, NK cells in the joints of mice with collagen-induced arthritis (CIA) express RANKL. Depletion of NK cells from mice before the induction of CIA reduces the severity of subsequent arthritis and almost completely prevents bone erosion. These results suggest that NK cells may play an important role in the destruction of bone associated with inflammatory arthritis.

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Section: Discussionmentioning

confidence: 99%

Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis

Söderström

Stein

Colmenero

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

150

153

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“…46 In this regard, activated IFN-␥-producing Th1 cells themselves express RANKL, induce osteoclastogenesis, and mediate infection-stimulated alveolar bone resorption. 47,48 Additional studies will be needed to precisely determine the pathways leading to bone resorption in Th1-biased animals.…”

Section: Discussionmentioning

confidence: 99%

Th1 Immune Response Promotes Severe Bone Resorption Caused by Porphyromonas gingivalis

Stashenko

Gonçalves

Lipkin

et al. 2007

The American Journal of Pathology

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Bacterial infections of the dental pulp result in soft tissue and alveolar bone destruction. It has been suggested that Th1 responses promote disease, whereas Th2 responses are protective. However, other studies have challenged this notion. To address this question, bone destruction was evaluated in mice immunized to develop strong and polarized Th1-or Th2-biased responses to the oral pathogen Porphyromonas gingivalis. Th1 bias was confirmed by the presence of high titers of serum IgG2a and the production of high levels of interferon (IFN)-␥ and no interleukin (IL)-4 by lymph node cells stimulated with P. gingivalis antigens. In contrast, Th2-biased animals had high titer IgG1 and no IgG2a, and their lymph node cells produced high levels of IL-4 but no IFN-␥. Subsequent infection of the dental pulp with P. gingivalis caused extensive inflammation and alveolar bone destruction in Th1-biased mice, whereas Th2-biased mice and controls developed minimal lesions. Inflammatory granulomas in Th1-biased mice were heavily infiltrated with osteoclasts and had high local expression of IFN-␥, IL-1␣, and IL-1␤. Little or no IFN-␥/IL-1␣/IL-1␤ and no obvious osteoclasts were detected in lesions of Th2-biased and control groups. These results directly demonstrate that specific Th1 responses promote severe infection-stimulated alveolar bone loss.

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“…11,12) In light of this, we previously reported that diarylheptanoid hirsutenone (HTN), 1,7-bis-(3,4-dihydroxyphenyl)-4-heptene-3-one and one of the major diarylheptanoids, isolated from the bark of Alnus japonica. Cumulative evidences suggest that HTN has bioactive properties as a diarylheptanoid and plays a key role in inducing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent apoptosis and in the inhibition of T cell-dependent cytokines, such as IL-2, 4, 5, 10, 13, and IFNγ.…”

Section: )mentioning

confidence: 99%

“…9,10) In addition, an increasing body of evidence has focused on activated T cell-derived IFNγ for the induction of osteoclastogenesis, although IFNγ has also been shown to have a direct anti-osteoclastogenic effect via the suppression of RANKL signaling and the subsequent degradation of tumor necrosis factor receptor-associated factor 6 (TRAF6). 11,12) In light of this, we previously reported that diarylheptanoid hirsutenone (HTN), 1,7-bis-(3,4-dihydroxyphenyl)-4-heptene-3-one and one of the major diarylheptanoids, isolated from the bark of Alnus japonica. Cumulative evidences suggest that HTN has bioactive properties as a diarylheptanoid and plays a key role in inducing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent apoptosis and in the inhibition of T cell-dependent cytokines, such as IL-2, 4, 5, 10, 13, and IFNγ.…”

mentioning

confidence: 99%

Diarylheptanoid Hirsutenone Attenuates Osteoclastogenesis by Suppressing IFNγ and NF-κB Signaling in Th1 and Preosteoclastic Cells

Lee

Jang

Park

et al. 2017

Biological & Pharmaceutical Bulletin

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The aim of the present study was to examine the inhibitory roles and mechanisms of hirsutenone (HTN) in the regulation of osteoclastogenesis. Gene levels were compared to assure the effects of HTN on osteoclastogenesis in mouse splenocytes/CD4 T cells, mouse macrophage-like cell line RAW264.7 (preosteoclast), MG63 (osteoblast), and RPMI1788 (B cell) cells. The mechanism by which HTN regulates the degradation of tumor necrosis factor receptor-associated factor 6 (TRAF6) and inhibits inhibitor of kappaB (IκB) and nuclear factor-kappaB (NF-κB) signaling was examined by Western blotting and luciferase reporter assays. Our results demonstrated that HTN effectively downregulated the expression of interferon γ (IFNγ), interleukin-22 (IL-22), IL-1β, and tartrate-resistant acid phosphatase (TRAP) in splenocyte-/CD4 -RAW264.7 co-culture system. Moreover, receptor activator of nuclear factor-κB ligand (RANKL) and CD25 expression were also significantly inhibited in MG63 and CD4 single culture system, suggesting an additional independent effect of HTN on osteoclastogenesis. Notably, TRAF6 was markedly degraded along with a decrease in nuclear factor of activated T-cells (NFATc) and NF-κB activities in RAW264.7 cells. Finally, we concluded that HTN directly or indirectly inhibits osteoclastogenesis via the inhibition of NF-κB signaling by promoting TRAF6 degradation, and plays a crucial role in suppressing the expression of RANKL and cytokines expressed in IFNγ-producing T-helper 1 (Th1) cells. These findings suggest that HTN may be a promising therapeutic candidate for diseases resulting from bone loss.Key words osteoclastogenesis; hirsutenone; interferon γ; receptor activator of nuclear factor-κB ligand; tumor necrosis factor receptor-associated factor 6 Bone serves as an ion reservoir for the body, as well as the location of several specialized bone cells, such as osteoblasts, osteocytes, and osteoclasts, which reside within this complex tissue.1,2) Bone loss, which may induce an imbalance between bone formation and resorption, as a result of aging and after menopause, can lead to osteoporosis, which is characterized by reduced bone mass, deterioration of bone architecture, and an increased risk of fatal bone fractures.3,4) Osteoclasts (OC), the bone-resorbing cells generated from the same precursors as monocyte/macrophages, crosstalk with activated T cells to form activated osteoclasts directly by producing interleukin-7 (IL-7) and receptor activator of nuclear factor-κB ligand (RANKL), and indirectly by promoting the production of RANKL by osteoblasts and fibroblasts via the production of pro-inflammatory cytokines (i.e., IL-1, -6, -17, and interferon (IFN)-γ).5,6) Of these, interleukin-1β (IL-1β), one of the most well-known proinflammatory cytokines, has been reported as an effective stimulator of bone resorption through the upregulation of RANKL.7) In addition, IL-22 produced by activated T cells has been shown to promote osteoclastogenesis, leading to bone erosion in rheumatoid arthritis. 8)As the binding of RANKL to...

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IFN-γ-producing human T cells directly induce osteoclastogenesis from human monocytes via the expression of RANKL

Abstract: The current study explored our hypothesis that IFN-c-producing human T cells inhibit human osteoclast formation.

Cited by 127 publications

References 41 publications

Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis

Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis

Th1 Immune Response Promotes Severe Bone Resorption Caused by Porphyromonas gingivalis

Diarylheptanoid Hirsutenone Attenuates Osteoclastogenesis by Suppressing IFNγ and NF-κB Signaling in Th1 and Preosteoclastic Cells

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