T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ

Takayanagi, Hiroshi; Ogasawara, Kunio; Hida, Shigeaki; Chiba, Tomoki; Murata, Shigeo; Sato, Kojiro; Takaoka, Akinori; Yokochi, Taeko; Oda, Hiromi; Tanaka, Keiji; Nakamura, Kozo; Taniguchi, Tadatsugu

doi:10.1038/35046102

Cited by 1,244 publications

(1,061 citation statements)

References 29 publications

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“…In addition, cytokines may further modulate the fate of monocytes/macrophages that interact with activated T cells. IFN-c from Th1 cells strongly inhibits osteoclast differentiation and induces type 1 macrophages (M1), potent effector cells that kill microbes and produce proinflammatory cytokines [1,37]. GM-CSF and IL-4 from Th2 cells also inhibit osteoclastogenesis and induce type 2 macrophages (M2) that refrain inflammatory responses and promote tissue remodeling [1,38,39].…”

Section: Discussionmentioning

confidence: 99%

The 4–1BB ligand and 4–1BB expressed on osteoclast precursors enhance RANKL‐induced osteoclastogenesis via bi‐directional signaling

et al. 2008

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The 4-1BB is a costimulatory molecule similar to the receptor activator of NF-jB ligand (RANKL), both of which are key factors for the differentiation of osteoclasts and are expressed mainly by activated T cells. The 4-1BB shares common signaling pathways with RANK, suggesting a potential role in osteoclastogenesis. In this study, the role of 4-1BB and 4-1BB ligand (4-1BBL) in osteoclastogenesis was investigated using 4-1BB -/-and 4-1BB +/+ mice. Osteoclast precursors normally express 4-1BB and 4-1BBL after exposure to RANKL, which was confirmed by semi-quantitative RT-PCR and flow cytometry. The 4-1BB -/-mice had a slightly increased bone mass accompanied by a reduced osteoclastogenic ability of 4-1BB -/-bone marrow-derived macrophages (BMM) ex vivo. In addition, 4-1BB -/-BMM demonstrated hypophosphorylation of JNK and p38 and decreased induction of c-Fos in response to RANKL stimulation. Retroviral transduction of wild-type as well as partiallength 4-1BB, which lacks TNF receptor-associated factor 2-binding sites for signaling, restored the osteoclastogenic ability of 4-1BB -/-BMM. Furthermore, both recombinant 4-1BB and 4-1BBL enhanced RANKL-induced osteoclastogenesis by 4-1BB +/+ BMM and the induction of c-Fos and NFATc1.Together, these results indicate that 4-1BBL and 4-1BB expressed on osteoclast precursors enhance RANKL-induced osteoclastogenesis via bi-directional signaling, findings that may delineate the complex nature of the 4-1BBL and 4-1BB interaction.

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Section: Discussionmentioning

confidence: 99%

The 4–1BB ligand and 4–1BB expressed on osteoclast precursors enhance RANKL‐induced osteoclastogenesis via bi‐directional signaling

et al. 2008

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“…Interferon-␥, on the other hand, interferes with the signaling of RANKL by reducing TRAF6 expression in a selective manner. Therefore, inhibition of the transcription pathways induced by RANKL decreases RANKL-mediated osteoclast formation (51).…”

Section: Cytokines and The Rank/rankl/opg Systemmentioning

confidence: 99%

The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: New insights from animal models

Neumann

Müller‐Ladner

2005

Arthritis & Rheumatism

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“…Additionally, mast cells are a source for IL-17 in the joints of patients with rheumatoid arthritis [10]. In contrast, cytokines linked to Th2 cells such as IL-4 effectively block osteoclast differentiation and also IL-12 and IFN-g, which are the cytokine signature of Th1 cells are potent inhibitors of osteoclasts [11][12][13]. Recently, Treg cells have been shown to directly inhibit osteoclast differentiation at least in vitro [14].…”

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confidence: 99%

Anti IL‐17A therapy inhibits bone loss in TNF‐α‐mediated murine arthritis by modulation of the T‐cell balance

et al. 2011

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Tumour necrosis factor alpha (TNF-a) is a major inducer for inflammation and bone loss. Here, we investigated whether interleukin (IL)-17 plays a role in TNF-a-mediated inflammation and bone resorption. Human TNF-a transgenic (hTNFtg) mice were treated with a neutralizing anti-IL-17A antibody and assessed for inflammation, cartilage and bone damage. T-cell transcription factors and lymphokine patterns were measured in the LNs. IL-17A inhibition in the absence of IL-1 was also evaluated by treating hTNFtg/IL-1 À/À mice with an IL-17A neutralizing antibody. IL-17A neutralization had only minor effects on TNF-a-induced inflammation but effectively reduced local and systemic bone loss by blocking osteoclast differentiation in vivo. Effects were based on a shift to bone-protective T-cell responses such as enhanced Th2 differentiation, IL-4 and IL-12 expression and Treg cell numbers. Whereas inflammation in hTNFtg/IL-1 À/À mice was highly sensitive to IL-17A blockade, no shift in the T-cell lineages and no additional benefit on bone mass were observed in response to IL-17A neutralization. We thus conclude that IL-17A is a key mediator of TNF-a-induced bone loss by closely interacting with IL-1 in blocking bone protective T-cell responses.Key words: Arthritis . Cytokine . IL-17 . Osteoclast . T cells IntroductionBone is continuously remodelled in life by the interaction between bone resorbing cells, termed osteoclasts, with boneforming cells, termed osteoblasts [1]. Bone resorption and bone formation are usually in physiological balance, maintaining a stable bone mass. An imbalance between bone resorption and bone formation leads to bone loss and several factors such as age, oestrogen deficiency or drug therapy alter this fine balance between osteoclasts and osteoblasts in favour of the former. Immune activation and inflammation is one the pivotal condi-Ã These authors contributed equally to this work. 413tions perturbing this fine balance of bone remodelling ultimately leading to enhanced bone loss [2]. Autoimmune inflammatory diseases, such as chronic arthritis are characterized by activation of the innate and adaptive immune system eliciting profound local and systemic bone loss. Progressive destruction of the joints is associated with pain, functional impairment and low quality of life. In addition, loss of systemic bone mass causes osteoporosis and increased fracture risk in patients with inflammatory arthritis [3]. This tight link between inflammation and bone loss is mediated by inducible expression of factors, such as M-CSF and RANKL, which are essential for osteoclast differentiation [4]. In addition, inflammatory cytokines produced by monocytes and resident mesenchymal cells are of key importance for osteoclast formation, as they regulate expression of RANKL and also sensitize monocytes for osteoclast differentiation. In this context, TNF-a, and IL-1 are of particular key importance for osteoclast formation and bone resorption in inflammatory tissue [5,6].Aside from classical pro-inflammatory mediators like ...

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T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ

Cited by 1,244 publications

References 29 publications

The 4–1BB ligand and 4–1BB expressed on osteoclast precursors enhance RANKL‐induced osteoclastogenesis via bi‐directional signaling

The 4–1BB ligand and 4–1BB expressed on osteoclast precursors enhance RANKL‐induced osteoclastogenesis via bi‐directional signaling

The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: New insights from animal models

Anti IL‐17A therapy inhibits bone loss in TNF‐α‐mediated murine arthritis by modulation of the T‐cell balance

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