TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand

Lam, Jonathan; Takeshita, Satoshi; Barker, Jane E.; Kanagawa, Osami; Ross, F. Patrick; Teitelbaum, Steven L.

doi:10.1172/jci11176

Cited by 1,285 publications

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“…Moreover, inhibition of TNF-a by neutralizing antibodies or soluble receptors effectively blocks local bone destruction in arthritic joints [23]. Pro-osteoclastogenic and bone resorptive effects of TNF-a require the presence of at least tiny amounts of M-CSF and RANKL, which are both essential for osteoclast differentiation [5]. TNF-a also induces the expression of IL-1, which has been identified as an important mediator for osteoclast formation.…”

Section: Discussionmentioning

confidence: 99%

“…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 TNF-a and IL-1, which are preferentially linked to cells of the innate immune system, adaptive immunity, particularly T cells, link immune activation to bone loss [7]. Activated T cells express RANKL and among the various T-cell lineages Th17 cells appear to have consistent pro-osteoclastogenic properties [8].…”

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confidence: 99%

“…This tight link between immune and inflammatory processes and bone is mediated by pro-inflammatory cytokines, which disturbs the fine balance of bone resorption and bone formation [19]. TNF-a for instance is not only a key mediator of inflammatory processes in diseases like RA but also increases the differentiation of boneresorbing osteoclasts [5,20], while blocking the activity of boneforming osteoblasts [21]. Bone loss is strongly accelerated in diseases associated with increased TNF-a production such as RA, ankylosing spondylitis and inflammatory bowel disease [22].…”

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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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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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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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“…Of particular interest in this context is the fact that IL-1␣ A final important issue is how the distinct inflammatory milieu in the inflamed SpA joint translates into differences in phenotype and disease progression as compared with that in the inflamed RA joint. In RA, TNF␣ and IL-1␤ are important drivers of bone and cartilage damage (46)(47)(48)(49)(50). Although lower levels of these cytokines in the inflamed SpA joint may contribute to the preservation of tissue integrity, no clear differences in downstream destructive processes have yet been demonstrated between SpA and RA (34,46,51).…”

Section: Discussionmentioning

confidence: 99%

Absence of a classically activated macrophage cytokine signature in peripheral spondylarthritis, including psoriatic arthritis

Vandooren¹,

Noordenbos²,

Ambarus³

et al. 2009

Arthritis & Rheumatism

154

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Objective. Peripheral spondylarthritis (SpA) is characterized by macrophages that express CD163, a marker of alternative activation (M2). The purpose of this study was to assess whether this differential infiltration with macrophage subsets was associated with a different local inflammatory milieu in SpA as compared with rheumatoid arthritis (RA).Methods Conclusion. The local inflammatory milieu is clearly different in SpA as compared with RA peripheral arthritis. Synovitis in SpA, including that in PsA, is characterized by a selective decrease in M1-derived proinflammatory mediators, such as TNF␣ and IL-1␤.

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“…It has been further shown that human wear particleassociated macrophages isolated directly from periprosthetic tissues surrounding loosened implants can differentiate into multinucleated cells displaying all the functional and cytochemical characteristics of osteoclasts [26]. Lam et al [32] have demonstrated that TNFa induction of osteoclastogenesis occurs as a result of direct stimulation of macrophages that are exposed to a stromal environment, expressing permissive levels of RANKL (receptor activator of NF-KB ligand), which signals through the transcription factor NF-KB. Based on these findings it was concluded that TNFa alone does not induce osteoclast formation.…”

Section: B Baurnann Et Al I Journal Of Orthopaedc Research 23 (2005)mentioning

confidence: 99%

Activation of NF-KB signalling and TNFα-expression in THP-1 macrophages by TiAlV- and polyethylene-wear particles

et al. 2005

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Wear particles are believed to induce periprosthetic inflammation which contributes to periprosthetic osteolysis. TNFu plays a pivotal role in the pathogenesis of this process. The molecular mechanisms leading to the development of periprosthetic inflammation with upregulated TNFa expression in monocytic cells in response to different wear particles have yet to be defined. 1n:this study we evaluated the effects of polyethylene-and TiAIV-particles on activation of NF-KB signalling pathways and TNFa biosynthesis and release in monocytic cells with respect to periprosthetic osteoclastogenesis. THP-1 monocytic cells were differentiated to macrophage-like cells and exposed to LPS-detoxified polyethylene and prosthesis-derived TiAlV-particles. TNFa release was analyzed in culture supernatant by ELISA. NF-KB activation was examined by electrophoretic mobility shift assay (EMSA), and NF-KB target promoter activities including transactivation of the TNFa promoter were determined by luciferase reporter gene assays. Differentiated THP-1 macrophages were exposed to increasing numbers of particles for 0, 60, 180 and 360 min. Both, polyethylene-and TiAIV-particles induced a significant activation of both NF-KB and TNFa promoters at 180 min. A significant TNFu release was detected after 360 min exposure to polyethylene-and TiAlV-particles in a dose dependent manner. In comparison, LPS induced a much greater activation of NF-KB and TNFa promoters, and TNFa secretion into the supernatant was strongly induced. These results provide evidence that induction of the NF-KB signal transduction pathway in macrophages plays a major role in initiating and mediating the inflammatory response leading to periprosthetic osteolysis.

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TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand

Cited by 1,285 publications

References 28 publications

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

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

Absence of a classically activated macrophage cytokine signature in peripheral spondylarthritis, including psoriatic arthritis

Activation of NF-KB signalling and TNFα-expression in THP-1 macrophages by TiAlV- and polyethylene-wear particles

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