Activation of p38 mitogen‐activated protein kinase is crucial in osteoclastogenesis induced by tumor necrosis factor

Matsumoto, Masahito; Sudo, Tatsuhiko; Maruyama, Masumi; Osada, Hiroyuki; Tsujimoto, Masafumi

doi:10.1016/s0014-5793(00)02231-6

Cited by 77 publications

(55 citation statements)

References 30 publications

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“…Although DcR3 can trigger ERK and p38 MAPK signals, it did not activate JNK phosphorylation within 1 h incubation. Consistent with previous reports, 16,[41][42][43] we confirmed the ability of RANKL and M-CSF to activate all three types of MAPKs. The differential effect on JNK activation again suggests distinct signaling mechanisms transduced by DcR3 and M-CSF/RANKL.…”

Section: Discussionsupporting

confidence: 93%

“…In addition to the pivotal role of ERK and p38 MAPK in the upregulation of TNF-a gene expression, both signaling pathways are also involved in the osteoclastogenesis induced by TNF-a. 16,17 Thus, we suggest that both MAPKs contribute to DcR3-mediated response in two sequential events. The first event is the mediation of DcR3-induced reverse signal transduction (see below) in transcription of the TNF-a gene.…”

Section: Discussionmentioning

confidence: 76%

“…For differentiation of osteoclasts, RAW264.7 cells (2 Â 10 3 cells/96-well) were cultured in the presence of 20 ng/ml M-CSF and 50 ng/ml RANKL for 5 days as previously described. 16 The medium was replaced every 3 days.…”

Section: Cell Culturementioning

confidence: 99%

“…2,7,8 In addition to M-CSF and RANKL, various cytokines and hormones have been shown to play roles in the differentiation of pluripotent osteoclast progenitors into mature multinucleated osteoclasts, 5,9 such as interleukin-1b (IL-1b), 10 interleukin-6 (IL-6), 11 interleukin-11, 12 transforming growth factor-b (TGF-b), 13 1a, 25-dihydroxyvitamin D 3, 14 glucocorticoids, 5 and tumor necrosis factor-a (TNF-a). 12,[15][16][17] The pleiotropic cytokine TNF-a has been implicated in the pathogenesis of osteoclastogenesis via the activation of TNF receptor 1 (TNFR1). 15,18,19 Decoy receptor 3 (DcR3) is a member of the TNF receptor superfamily and has been shown to be the decoy receptor for Fas ligand (FasL), 20 LIGHT, 21 and TL1A.…”

Section: Introductionmentioning

confidence: 99%

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Decoy receptor 3 (DcR3) induces osteoclast formation from monocyte/macrophage lineage precursor cells

Yang

Wang

Hsieh³

et al. 2004

Cell Death Differ

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Recent evidence indicates that the decoy receptor 3 (DcR3) of the TNF receptor superfamily, which initially though prevents cytokine responses of FasL, LIGHT and TL1A by binding and neutralization, can modulate monocyte function through reverse signaling. We show in this work that DcR3 can induce osteoclast formation from human monocytes, murine RAW264.7 macrophages, and bone marrow cells. DcR3-differentiated cells exhibit characteristics unique for osteoclasts, including polynuclear giant morphology, bone resorption, TRAP, CD51/61, and MMP-9 expression. Consistent with the abrogation of osteoclastogenic effect of DcR3 by TNFRFc, DcR3 treatment can induce osteoclastogenic cytokine TNF-a release through ERK and p38 MAPK signaling pathways. We conclude that DcR3 via coupling reverse signaling of ERK and p38 MAPK and stimulating TNF-a synthesis is a critical regulator of osteoclast formation. This action of DcR3 might play an important role in significant osteoclastic activity in osteolytic bone metastases.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 76%

Section: Cell Culturementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Decoy receptor 3 (DcR3) induces osteoclast formation from monocyte/macrophage lineage precursor cells

Yang

Wang

Hsieh³

et al. 2004

Cell Death Differ

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“…First, activation of p38 MAPK is a key signal for osteoclastogenesis. Thus, activation of p38 MAPK is important for the differentiation of mature osteoclasts from their precursors (28); this observation is also relevant for TNF-mediated osteoclastogenesis in relation to bone loss as a result of the inflammatory process involved in arthritis. The second principle is based on the role of osteoclasts in inflammatory bone destruction.…”

Section: Discussionmentioning

confidence: 99%

Activation of p38 MAPK is a key step in tumor necrosis factor–mediated inflammatory bone destruction

Zwerina¹,

Hayer²,

Redlich³

et al. 2006

Arthritis & Rheumatism

133

107

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Objective. To investigate whether activation of p38 MAPK is a crucial signaling factor in inflammatory bone destruction mediated by tumor necrosis factor (TNF). Mice overexpressing TNF were treated with 2 different inhibitors of p38 MAPK, and the effect of this treatment on joint inflammation and structural damage was assessed.Methods. Human TNF-transgenic mice received systemic treatment with 2 different p38 MAPK inhibitors (RO4399247 and AVE8677). Treatment was started at the time of symptom onset and lasted for 6 weeks. Mice were assessed for clinical signs of arthritis, bone erosion, and cartilage damage. In addition, the effect of these inhibitors on osteoclast generation in vitro and in vivo was assessed.Results. Both p38 MAPK inhibitors significantly reduced clinical signs of TNF-mediated arthritis. This was attributable to reducing synovial inflammation by 50% without affecting the cellular composition of the infiltrate. Synovial expression of interleukin-1 and RANKL was reduced upon p38 MAPK blockade, and activation of the molecular target MAPK-activated protein kinase 2 (MAPKAP-2) was also inhibited. Proteoglycan loss of articular cartilage was reduced by 50%, although p38 MAPK inhibition did not change matrix molecule synthesis by cultivated chondrocytes. Importantly, bone loss was almost completely prevented by p38 MAPK inhibition. The numbers of synovial osteoclasts and precursors were dramatically reduced, and both p38 MAPK inhibitors also inhibited in vitro osteoclastogenesis at micromolar concentrations and blocked activation of MAPKAP-2 as well as differentiation markers in cultured osteoclast precursors.Conclusion. These results suggest the major importance of p38 MAPK for TNF-mediated inflammatory bone destruction in arthritis and suggest that inhibition of p38 MAPK might be an important tool for reducing structural damage in rheumatoid arthritis.

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Prevention of the onset and progression of collagen‐induced arthritis in rats by the potent p38 mitogen‐activated protein kinase inhibitor FR167653

Nishikawa¹,

Myoui²,

Tomita³

et al. 2003

Arthritis & Rheumatism

168

110

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Objective. FR167653 is a potent inhibitor of p38 mitogen-activated protein kinase (MAPK) and inhibits tumor necrosis factor ␣ (TNF␣) and interleukin-1␤ (IL-1␤) production in inflammatory cells. In this study we investigated the effect of FR167653 on collageninduced arthritis (CIA).Methods. Rats with CIA were subcutaneously injected with FR167653 (32 mg/kg/day) starting on the day of the booster injection (day 7) in the prophylactic treatment group and after the onset of arthritis (day 21) in the therapeutic treatment group. Hind-paw swelling, body weight, radiographic and histologic scores, and osteoclast number were evaluated. Cytokine levels in the serum and tissue were assessed by enzyme-linked immunosorbent assays. Flow cytometric analysis of T lymphocytes from bone marrow was performed. The effect of FR167653 on in vitro osteoclast formation induced by soluble receptor activator of nuclear factor B ligand (sRANKL) and TNF␣ was examined.Results. Swelling of hind paws and loss of weight occurred in the CIA rats, but this was not evident in the prophylactic treatment group. Therapeutic treatment also significantly reduced paw swelling. The mean radiographic and histologic scores as well as the osteoclast numbers were significantly lower in the treatment group than in the CIA rats without treatment. FR167653 treatment reduced the serum levels of TNF␣ and IL-1␤, lowered the IL-1␤ concentration in the ankle joints, and decreased the CD4؊,CD8a؉ T cell population in bone marrow. Furthermore, FR167653 inhibited the osteoclast-like cell differentiation induced by both sRANKL and TNF␣ in vitro.Conclusion. FR167653 prevents the onset of arthritis in a prophylactic treatment model and suppresses the progression of joint destruction in a therapeutic treatment model, suggesting that p38 MAPK is a potential therapeutic target for rheumatoid arthritis.

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Activation of p38 mitogen‐activated protein kinase is crucial in osteoclastogenesis induced by tumor necrosis factor

Cited by 77 publications

References 30 publications

Decoy receptor 3 (DcR3) induces osteoclast formation from monocyte/macrophage lineage precursor cells

Decoy receptor 3 (DcR3) induces osteoclast formation from monocyte/macrophage lineage precursor cells

Activation of p38 MAPK is a key step in tumor necrosis factor–mediated inflammatory bone destruction

Prevention of the onset and progression of collagen‐induced arthritis in rats by the potent p38 mitogen‐activated protein kinase inhibitor FR167653

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