RANKing c-Jun in osteoclast development

Teitelbaum, Steven L.

doi:10.1172/jci200422644

Cited by 79 publications

(27 citation statements)

References 21 publications

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“…Gene expression of RANK and RANKL was rather moderate in osteolytic tissue, which was somewhat unexpected because RANKL and its interaction with RANK on osteoclast precursors were implied as major inducers of bone resorption in chronic inflammatory diseases or in patients with bone tumours or bone metastases (10,17). Low numbers of transcripts, however, do not rule out a participation of RANK-RANKL, especially because RANK is constitutively expressed by osteoclast precursors and only modestly upregulated.…”

Section: Discussionmentioning

confidence: 98%

Osteoclast Generation and Cytokine Profile at Prosthetic Interfaces: A Study on Tissue of Patients with Aseptic Loosening or Implant-Associated Infections

et al. 2014

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Aseptic loosening of implants or loosening due to persistent bacterial infection remains a severe complication in orthopaedic surgery. To investigate underlying cellular and molecular mechanisms, particularly with regard to bone loss, tissue samples of patients requiring surgery were examined. By histological methods and by quantitative RT-PCR, respectively, infiltration of leukocytes, expression of osteoclast-typical genes and of proinflammatory cytokines was determined. Samples were taken directly from osteolytic sites and for comparison from adjacent sites, distant sites and from muscle. At osteolytic sites, cathepsin K and the metalloproteinases MMPI and MMP9 were found, as was expression of inflammation-related cytokines, particularly of interleukin (IL)-lO, CXCL8, SlOOA9 and a very moderate expression of receptor activator of NfKB ligand (RANKL) and tumour necrosis factor (TNF)

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Section: Discussionmentioning

confidence: 98%

Osteoclast Generation and Cytokine Profile at Prosthetic Interfaces: A Study on Tissue of Patients with Aseptic Loosening or Implant-Associated Infections

et al. 2014

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“…3c). NFATc1 is a terminal transcription factor that plays a critical and fundamental role in osteoclast development, and a lack of this factor leads to arrest of osteoclastogenesis (Teitelbaum 2004). Luteolin strongly impaired the RANKL-stimulated expression of NFATc1 protein.…”

Section: Luteolin Does Not Affect Rankl-induced Signal Cascades But Dmentioning

confidence: 99%

Inhibitory effect of luteolin on osteoclast differentiation and function

et al. 2009

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Osteoclasts are multinucleated cells that play a crucial role in bone resorption, and are formed by the fusion of mononuclear osteoclasts derived from osteoclast precursors of the macrophage lineage. Compounds that specifically target functional osteoclasts would be ideal candidates for anti-resorptive agents for clinical applications. In the present study, we investigated the effects of luteolin, a flavonoid, on the regulation of receptor activator of nuclear factorjB ligand (RANKL)-induced osteoclastogenesis, functions and signaling pathway. Addition of luteolin to a coculture system of mouse bone marrow cells and ST2 cells in the presence of 10 -8 M 1a,25(OH) 2 D 3 caused significant inhibition of osteoclastogenesis. Luteolin had no effects on the 1a,25(OH) 2 D 3 -induced expressions of RANKL, osteoprotegerin and macrophage colony-stimulating factor mRNAs. Next, we examined the direct effects of luteolin on osteoclast precursors using bone marrow macrophages and RAW264.7 cells. Luteolin completely inhibited RANKL-induced osteoclast formation. Moreover, luteolin inhibited the bone resorption by mature osteoclasts accompanied by the disruption of their actin rings, and these effects were reversely induced by the disruption of the actin rings in mature osteoclasts. Finally, we found that luteolin inhibited RANKLinduced osteoclastogenesis through the suppression of ATF2, downstream of p38 MAPK and nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) expression, respectively. Taken together, the present results indicate that naturally occurring luteolin has inhibitory activities toward both osteoclast differentiation and functions through inhibition of RANKL-induced signaling pathway as well as actin ring disruption, respectively.

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“…The activation of MAPK signaling pathways by RANKL is an important mechanism involved in osteoclastogensis Teitelbaum, 2004). The activation of ERK, JNK, and p38 MAPKs by RANKL and their contribution to osteoclastogenesis has been demonstrated with pharmacological inhibitors and dominant-negative forms (Matsumoto et al, 2000;Wei et al, 2002).…”

Section: Dms Inhibits the Activation Of Erk But Not That Of Jnk And mentioning

confidence: 99%

Suppression of Osteoclastogenesis by N,N-Dimethyl-D-erythro-sphingosine: A Sphingosine Kinase Inhibition-Independent Action

et al. 2007

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N,N-Dimethyl-D-erythro-sphingosine (DMS) competitively inhibits sphingosine kinase (SPHK) and has been widely used to assess the role of SPHK during cellular events, including motility, proliferation, and differentiation. In the present study, the effect of DMS on the differentiation of bone marrow macrophages (BMMs) to osteoclasts was investigated. When the osteoclast precursor cells were treated with DMS, the receptor activator of nuclear factor B ligand (RANKL)-induced osteoclastogenesis was completely blocked. We were surprised to find, however, that knock-down of SPHK by small interfering RNA (siRNA) in BMMs did not reduce osteoclastogenesis. Furthermore, both overexpression of SPHK and exogenous addition of sphingosine-1-phosphate, the product of SPHK activity, failed to overcome the antiosteoclastogenic effect of DMS. These results suggest that DMS inhibited osteoclastogenesis independently of SPHK. Subsequent characterization of the DMS-mediated suppression of osteoclastogenesis revealed that DMS did not affect RANKL-induced activation of JNK, p38, NF-B, and Ca 2ϩ oscillation. On the other hand, DMS strongly inhibited two separate signaling pathways, the RANKL-induced activation of ERK and Akt, which eventually converged on the transcription factors c-Fos and NFATc1. There was significant increase in the osteoclast formation in the presence of DMS when BMMs were overexpressed with c-Fos, suggesting that c-Fos was a critical downstream target of DMS for the inhibition of osteoclastogenesis. Taken together, our data demonstrate that DMS has an antiosteoclastogenic function independently of its SPHK inhibitory activity. Considering previously reported anticancer properties of DMS, our study may also propose that DMS is an ideal drug candidate for bone metastases, for which osteoclastic bone-resorption is crucial.Bone is a complex tissue composed of several cell types. The functions of bone are accomplished by continuous tissue renewal, termed "bone remodeling," occurring throughout life in the adult skeleton. The two major cell types responsible for bone remodeling are osteoclasts and osteoblasts. The harmony between osteoclastic bone resorption and osteoblastic bone formation maintains skeletal homeostasis in adults (Walsh et al., 2006). In pathological bone resorption, this balance is tipped in favor of osteoclast formation, as seen in postmenopausal osteoporosis, autoimmune arthritis, periodontitis, and Paget's disease. Osteoclasts, the only type of cells responsible for bone resorption, are highly specialized cells originating from monocyte/macrophage lineage precursors. The single most important cytokine in the development of osteoclasts is receptor activator of nuclear factor B ligand (RANKL), whereas macrophage-colony stimulating factor (M-CSF), secreted by osteoblasts, provides the survival sigThis work was supported by the Molecular and Cellular BioDiscovery Research Program (M1-0311-00-0024) and the 21C Frontier Functional Proteomics Project Grant (FPR05C2-280) from the Korea Science and ...

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RANKing c-Jun in osteoclast development

Cited by 79 publications

References 21 publications

Osteoclast Generation and Cytokine Profile at Prosthetic Interfaces: A Study on Tissue of Patients with Aseptic Loosening or Implant-Associated Infections

Osteoclast Generation and Cytokine Profile at Prosthetic Interfaces: A Study on Tissue of Patients with Aseptic Loosening or Implant-Associated Infections

Inhibitory effect of luteolin on osteoclast differentiation and function

Suppression of Osteoclastogenesis by N,N-Dimethyl-D-erythro-sphingosine: A Sphingosine Kinase Inhibition-Independent Action

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