Combination of Tumor Necrosis Factor α and Interleukin‐6 Induces Mouse Osteoclast‐like Cells With Bone Resorption Activity Both In Vitro and In Vivo

Kazuhiro Yokota; Kojiro Sato; Takashi Miyazaki; Hideki Kitaura; Hisako Kayama; Fumihiko Miyoshi; Yasuto Araki; Yuji Akiyama; Kiyoshi Takeda; Toshihide Mimura

doi:10.1002/art.38218

journal article Dec 30, 2013

Combination of Tumor Necrosis Factor α and Interleukin‐6 Induces Mouse Osteoclast‐like Cells With Bone Resorption Activity Both In Vitro and In Vivo

Kazuhiro Yokota Kojiro Sato Takashi Miyazaki Hideki Kitaura Hisako Kayama Fumihiko Miyoshi Yasuto Araki Yuji Akiyama Kiyoshi Takeda Toshihide Mimura

Arthritis & Rheumatology Vol. 66 No. 1 pp. 121-129 · Wiley

View at Publisher Save 10.1002/art.38218

Abstract

ObjectiveTo clarify the function of osteoclast‐like multinuclear cells differentiated from bone marrow–derived macrophages (BMMs) by a combination of tumor necrosis factor α (TNFα) and interleukin‐6 (IL‐6), and to investigate the molecular mechanisms underlying the differentiation.MethodsBMMs were stimulated by TNFα and/or IL‐6. The cells were then compared with conventional osteoclasts differentiated in vitro by RANKL. An in vitro pit formation assay on dentine slices and an in vivo resorption assay of calvarial bones were performed. We also evaluated the activities and expression levels of NF‐κB, c‐Fos, and NF‐ATc1, which are essential to the differentiation of conventional osteoclasts. Small interfering RNA was used to knock down c‐Fos. The effects of genetic ablation of STAT‐3 and pharmacologic inhibitors of NF‐AT, JAK, and ERK were also studied.ResultsOsteoclast‐like cell differentiation depended on TNFα and IL‐6 and was not inhibited by osteoprotegerin. These differentiated cells were associated with both in vitro and in vivo bone resorption activity. TNFα and IL‐6 had a synergistic effect on the activity and expression of c‐Fos. Knockdown of c‐Fos inhibited the expression of NF‐ATc1 and the differentiation of osteoclast‐like cells. All of these inhibitors blocked differentiation of the cells in vitro, but surprisingly, the conditional knockout of STAT‐3 did not. Tofacitinib also inhibited the bone destruction caused by TNFα and IL‐6 in vivo.ConclusionOur results demonstrate that a combination of the inflammatory cytokines TNFα and IL‐6 can induce osteoclast‐like cells that have in vitro and in vivo bone‐resorptive activity.

Topics

No keywords indexed for this article. Browse by subject →

References

37

[1]

10.1172/jci11176

[2]

10.1073/pnas.0701971104

[3]

10.1016/s0140-6736(04)15640-7

[4]

10.1016/s1074-7613(00)80005-9

[5]

10.1038/nm1515

[6]

10.1084/jem.20061775

[7]

10.1172/jci26132

[8]

10.4049/jimmunol.1101174

[9]

10.1007/bf02411252

[10]

10.1038/ncprheum0338

[11]

10.1073/pnas.90.24.11924

[12]

10.4049/jimmunol.145.10.3297

[13]

10.1093/intimm/dxr077

[14]

10.1016/s0092-8674(00)81569-x

[15]

10.1084/jem.20050978

[16]

10.1111/j.1749-6632.2011.06283.x

[17]

10.1016/s1534-5807(02)00369-6

[18]

10.1101/gad.11.24.3482

[19]

10.1038/nm1197-1285

[20]

10.1016/0092-8674(92)90592-z

[21]

10.1038/360741a0

[22]

10.1111/j.1356-9597.2004.00715.x

[23]

10.1016/j.jmb.2009.01.041

[24]

10.1016/s0140-6736(12)61424-x

[25]

10.1023/a:1008942828960

[26]

10.4049/jimmunol.161.9.4652

[27]

10.1042/bj3350557

[28]

10.1016/j.molcel.2006.08.005

[29]

10.1210/en.2007-1719

[30]

10.1016/j.cca.2012.05.007

[31]

Yoshida M "Methotrexate suppresses inflammatory agonist induced interleukin 6 synthesis in osteoblasts" J Rheumatol (2005)

[32]

10.1186/ar1857

[33]

10.1172/jci200523394

[34]

10.4049/jimmunol.173.8.4838

[35]

10.1084/jem.191.2.275

[36]

10.1016/s0736-0266(02)00106-7

[37]

10.1359/jbmr.0809010

Cited By

152

Necrotic-cell–activated macrophages drive an ERK–Bcl-xL survival pathway in osteoclasts and confer bisphosphonate resistance

Kazuya Uehara, Keiichi Kato · 2026

Biochemical and Biophysical Researc...

Porphyromonas gingivalis outer membrane vesicles promote alveolar bone resorption by increasing the local RANKL/OPG ratio in experimental periodontitis model rats

Daisuke Nakamura, Yuji Inagaki · 2026

Scientific Reports

Optimal Se content on P/G-EGCG@Se nanofibers reverses muscle-derived IL-6- induced osteogenesis depression

Weichao Gui, Yan Deng · 2026

Biomaterials Advances

The Multiple Biological Functions of Dipeptidyl Peptidase-4 in Bone Metabolism

Qiu Yang, Bing Fu · 2022

Frontiers in Endocrinology

The Role of T Helper 17 Cells and Other IL-17-Producing Cells in Bone Resorption and Remodeling

Wen-Xing Liu, Zhi-Jun Li · 2015

International Reviews of Immunology

Metrics

152

Citations

37

References

Details

Published: Dec 30, 2013
Vol/Issue: 66(1)
Pages: 121-129
License: View

Authors

K

Kazuhiro Yokota

Saitama Medical University Saitama Japan

K

Kojiro Sato

Saitama Medical University Saitama Japan

T

Takashi Miyazaki

Saitama Medical University Saitama Japan

H

Hideki Kitaura

Tohoku University Sendai Japan

H

Hisako Kayama

Osaka University Osaka Japan

F

Fumihiko Miyoshi

Saitama Medical University Saitama Japan

Y

Yasuto Araki

Saitama Medical University Saitama Japan

Y

Yuji Akiyama

Saitama Medical University Saitama Japan

K

Kiyoshi Takeda

Osaka University Osaka Japan

T

Toshihide Mimura

Saitama Medical University Saitama Japan

Cite This Article

Kazuhiro Yokota, Kojiro Sato, Takashi Miyazaki, et al. (2013). Combination of Tumor Necrosis Factor α and Interleukin‐6 Induces Mouse Osteoclast‐like Cells With Bone Resorption Activity Both In Vitro and In Vivo. Arthritis & Rheumatology, 66(1), 121-129. https://doi.org/10.1002/art.38218

Combination of Tumor Necrosis Factor α and Interleukin‐6 Induces Mouse Osteoclast‐like Cells With Bone Resorption Activity Both In Vitro and In Vivo

You May Also Like