Titanium particle‑mediated osteoclastogenesis may be attenuated via bidirectional ephrin‑B2/eph‑B4 signaling in vitro

Ge,Yu‑Wei; Liu,Zhi‑Qing; Sun,Zhen‑Yu; Yu,De‑Gang; Feng,Kai; Zhu,Zhen‑An; Mao,Yuan‑Qing

doi:10.3892/ijmm.2018.3780

Titanium particle‑mediated osteoclastogenesis may be attenuated via bidirectional ephrin‑B2/eph‑B4 signaling in vitro

Authors:
- Yu‑Wei Ge
- Zhi‑Qing Liu
- Zhen‑Yu Sun
- De‑Gang Yu
- Kai Feng
- Zhen‑An Zhu
- Yuan‑Qing Mao
View Affiliations

Affiliations: Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
Published online on: July 17, 2018 https://doi.org/10.3892/ijmm.2018.3780
Pages: 2031-2041
Copyright: © Ge et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study investigated the role of bidirectional ephrin‑B2/erythropoietin‑producing human hepatocellular receptor 4 (ephB4) signaling in the regulation of wear particle‑mediated osteoclastogenesis in vitro. Mouse bone marrow macrophages (BMMs) were induced into osteoclasts by receptor activator of nuclear factor‑κB ligand (RANKL, 50 ng/ml). EphB4‑Fc, an osteoblast membrane surface receptor (4 µg/ml), was used to stimulate the ephrin‑B2 ligand of osteoclasts in the presence and absence of titanium (Ti). Tartrate‑resistant acid phosphatase (TRAP) staining was used to detect the number of osteoclasts, and phalloidin staining was used to examine the cytoskeletons of the osteoclasts. A bone pit absorption experiment was used to measure osteoclast function. Reverse transcription quantitative polymerase chain reaction and western blot analysis were used to examine osteoclastogenesis. ELISAs were used to detect the production of inflammatory factors. The data demonstrated that Ti significantly promoted the differentiation of BMMs into mature osteoclasts in the presence of RANKL and significantly promoted expression of the ephrin‑B2, nuclear factor of activated T‑cells 1 (NFATc1), TRAP, Fos proto‑oncogene, AP‑1 transcription factor subunit (C‑FOS), and matrix metalloproteinase 9 (MMP9) genes. Phalloidin and TRAP staining revealed that following the addition of ephB4‑Fc, the number, size and cytoskeletal elements of osteoclasts were significantly decreased compared with those in the titanium particle group without ephB4‑Fc. Compared with the titanium particle group, the bone pit absorption experiment revealed significantly decreased absorption pit areas in the titanium particle+ephB4‑Fc group. The expression of the NFATc1, TRAP, C‑FOS and MMP9 genes was markedly decreased in the ephB4‑Fc group; however, the expression of the ephrin‑B2 gene was increased compared with the Ti particle group without ephB4‑Fc after 5 days. Production of inflammatory cytokines was inhibited by Ti particles through bidirectional signals. Addition of ephB4‑Fc inhibited the osteoclast‑mediated formation of Ti particles via bidirectional ephrin‑B2/ephB4 signaling. Activation of this bidirectional signaling pathway may be a potential clinical treatment for osteolysis surrounding prostheses.

View Figures

View References

1	Liu F, Zhu Z, Mao Y, Liu M, Tang T and Qiu S: Inhibition of titanium particle-induced osteoclastogenesis through inactivation of NFATc1 by VIVIT peptide. Biomaterials. 30:1756–1762. 2009. View Article : Google Scholar : PubMed/NCBI
2	Liu X, Zhu S, Cui J, Shao H, Zhang W, Yang H, Xu Y, Geng D and Yu L: Strontium ranelate inhibits titanium-particle-induced osteolysis by restraining inflammatory osteoclastogenesis in vivo. Acta Biomater. 10:4912–4918. 2014. View Article : Google Scholar : PubMed/NCBI
3	Geng D, Wu J, Shao H, Zhu S, Wang Y, Zhang W, Ping Z, Hu X, Zhu X, Xu Y and Yang H: Pharmaceutical inhibition of glycogen synthetase kinase 3 beta suppresses wear debris-induced osteolysis. Biomaterials. 69:12–21. 2015. View Article : Google Scholar : PubMed/NCBI
4	Gallo J, Goodman SB, Konttinen YT, Wimmer MA and Holinka M: Osteolysis around total knee arthroplasty: A review of pathogenetic mechanisms. Acta Biomater. 9:8046–8058. 2013. View Article : Google Scholar : PubMed/NCBI
5	Liu X, Qu X, Wu C, Zhai Z, Tian B, Li H, Ouyang Z, Xu X, Wang W, Fan Q, et al: The effect of enoxacin on osteoclastogenesis and reduction of titanium particle-induced osteolysis via suppression of JNK signaling pathway. Biomaterials. 35:5721–5730. 2014. View Article : Google Scholar : PubMed/NCBI
6	Vallés G, Pérez C, Boré A, Martín-Saavedra F, Saldaña L and Vilaboa N: Simvastatin prevents the induction of interleukin-6 gene expression by titanium particles in human osteoblastic cells. Acta Biomater. 9:4916–4925. 2013. View Article : Google Scholar
7	Nich C, Takakubo Y, Pajarinen J, Ainola M, Salem A, Sillat T, Rao AJ, Raska M, Tamaki Y, Takagi M, et al: Macrophages-Key cells in the response to wear debris from joint replacements. J Biomed Mater Res A. 101:3033–3045. 2013. View Article : Google Scholar : PubMed/NCBI
8	Pajarinen J, Kouri VP, Jämsen E, Li TF, Mandelin J and Konttinen YT: The response of macrophages to titanium particles is determined by macrophage polarization. Acta Biomater. 9:9229–9240. 2013. View Article : Google Scholar : PubMed/NCBI
9	Lee HG, Minematsu H, Kim KO, Celil Aydemir AB, Shin MJ, Nizami SA, Chung KJ, Hsu AC, Jacobs CR and Lee FY: Actin and ERK1/2-CEBPβ signaling mediates phagocytosis-induced innate immune response of osteoprogenitor cells. Biomaterials. 32:9197–9206. 2011. View Article : Google Scholar : PubMed/NCBI
10	Huang JB, Ding Y, Huang DS, Zeng WK, Guan ZP and Zhang ML: rna interference targeting p110β reduces tumor necrosis factor-alpha production in cellular response to wear particles in vitro and osteolysis in vivo. Inflammation. 36:1041–1054. 2013. View Article : Google Scholar : PubMed/NCBI
11	Liu FX, Wu CL, Zhu ZA, Li MQ, Mao YQ, Liu M, Wang XQ, Yu DG and Tang TT: Calcineurin/NFAT pathway mediates wear particle-induced TNF-alpha release and osteoclastogenesis from mice bone marrow macrophages in vitro. Acta Pharmacol Sin. 34:1457–1466. 2013. View Article : Google Scholar : PubMed/NCBI
12	Kim JA, Ihn HJ, Park JY, Lim J, Hong JM, Kim SH, Kim SY, Shin HI and Park EK: Inhibitory effects of triptolide on titanium particle-induced osteolysis and receptor activator of nuclear factor-κB ligand-mediated osteoclast differentiation. Int Orthop. 39:173–182. 2015. View Article : Google Scholar
13	Zhao C, Irie N, Takada Y, Shimoda K, Miyamoto T, Nishiwaki T, Suda T and Matsuo K: Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab. 4:111–121. 2006. View Article : Google Scholar : PubMed/NCBI
14	Henriksen K, Neutzsky-Wulff AV, Bonewald LF and Karsdal MA: Local communication on and within bone controls bone remodeling. Bone. 44:1026–1033. 2009. View Article : Google Scholar : PubMed/NCBI
15	Deng L, Wang Y, Peng Y, Wu Y, Ding Y, Jiang Y, Shen Z and Fu Q: Osteoblast-derived microvesicles: A novel mechanism for communication between osteoblasts and osteoclasts. Bone. 79:37–42. 2015. View Article : Google Scholar : PubMed/NCBI
16	Matsuo K and Otaki N: Bone cell interactions through Eph/ephrin: Bone modeling, remodeling and associated diseases. Cell Adh Migr. 6:148–156. 2012. View Article : Google Scholar : PubMed/NCBI
17	Matsuo K: Eph and ephrin interactions in bone. Adv Exp Med Biol. 658:95–103. 2010. View Article : Google Scholar
18	Luiz de Freitas PH, Li M, Ninomiya T, Nakamura M, Ubaidus S, Oda K, Udagawa N, Maeda T, Takagi R and Amizuka N: Intermittent PTH administration stimulates pre-osteoblastic proliferation without leading to enhanced bone formation in osteoclast-less c-fos(−/−) mice. J Bone Miner Res. 24:1586–1597. 2009. View Article : Google Scholar : PubMed/NCBI
19	Fan WB, Zhao JN and Bao NR: Effects of bidirectional EphB4-EphrinB2 signaling on bone remodeling. Zhongguo Gu Shang. 26:705–708. 2013.In Chinese. PubMed/NCBI
20	Zuo C, Huang Y, Bajis R, Sahih M, Li YP, Dai K and Zhang X: Osteoblastogenesis regulation signals in bone remodeling. Osteoporos Int. 23:1653–1663. 2012. View Article : Google Scholar : PubMed/NCBI
21	von Knoch M, Jewison DE, Sibonga JD, Sprecher C, Morrey BF, Loer F, Berry DJ and Scully SP: The effectiveness of polyethylene versus titanium particles in inducing osteolysis in vivo. J Orthop Res. 22:237–243. 2004. View Article : Google Scholar : PubMed/NCBI
22	Lee SS, Woo CH, Chang JD and Kim JH: Roles of Rac and cytosolic phospholipase A2 in the intracellular signalling in response to titanium particles. Cell Signal. 15:339–345. 2003. View Article : Google Scholar : PubMed/NCBI
23	Takyar FM, Tonna S, Ho PW, Crimeen-Irwin B, Baker EK, Martin TJ and Sims NA: EphrinB2/EphB4 inhibition in the osteoblast lineage modifies the anabolic response to parathyroid hormone. J Bone Miner Res. 28:912–925. 2013. View Article : Google Scholar
24	Ouyang Z, Zhai Z, Li H, Liu X, Qu X, Li X, Fan Q, Tang T, Qin A and Dai K: Hypericin suppresses osteoclast formation and wear particle-induced osteolysis via modulating ERK signalling pathway. Biochem Pharmacol. 90:276–287. 2014. View Article : Google Scholar : PubMed/NCBI
25	Zhang Y, Wang XC, Bao XF, Hu M and Yu WX: Effects of Porphyromonas gingivalis lipopolysaccharide on osteoblast-osteoclast bidirectional EphB4-EphrinB2 signaling. Exp Ther Med. 7:80–84. 2014. View Article : Google Scholar
26	Wu C, Wang W, Tian B, Liu X, Qu X, Zhai Z, Li H, Liu F, Fan Q, Tang T, et al: Myricetin prevents titanium particle-induced osteolysis in vivo and inhibits RANKL-induced osteoclastogenesis in vitro. Biochem Pharmacol. 93:59–71. 2015. View Article : Google Scholar
27	Shao H, Shen J, Wang M, Cui J, Wang Y, Zhu S, Zhang W, Yang H, Xu Y and Geng D: Icariin protects against titanium particle-induced osteolysis and inflammatory response in a mouse calvarial model. Biomaterials. 60:92–99. 2015. View Article : Google Scholar : PubMed/NCBI
28	Zhai Z, Qu X, Li H, Yang K, Wan P, Tan L, Ouyang Z, Liu X, Tian B, Xiao F, et al: The effect of metallic magnesium degradation products on osteoclast-induced osteolysis and attenuation of NF-κB and NFATc1 signaling. Biomaterials. 35:6299–6310. 2014. View Article : Google Scholar : PubMed/NCBI
29	Matsuo K and Irie N: Osteoclast-osteoblast communication. Arch Biochem Biophys. 473:201–209. 2008. View Article : Google Scholar : PubMed/NCBI
30	Chen X, Wang Z, Duan N, Zhu G, Schwarz EM and Xie C: Osteoblast-osteoclast interactions. Connect Tissue Res. 59:99–107. 2018. View Article : Google Scholar
31	Martin TJ, Allan EH, Ho PW, Gooi JH, Quinn JM, Gillespie MT, Krasnoperov V and Sims NA: Communication between ephrinB2 and EphB4 within the osteoblast lineage. Adv Exp Med Biol. 658:51–60. 2010. View Article : Google Scholar
32	Gooi JH, Pompolo S, Karsdal MA, Kulkarni NH, Kalajzic I, McAhren SH, Han B, Onyia JE, Ho PW, Gillespie MT, et al: Calcitonin impairs the anabolic effect of PTH in young rats and stimulates expression of sclerostin by osteocytes. Bone. 46:1486–1497. 2010. View Article : Google Scholar : PubMed/NCBI
33	Benson MD, Opperman LA, Westerlund J, Fernandez CR, San Miguel S, Henkemeyer M and Chenaux G: Ephrin-B stimulation of calvarial bone formation. Dev Dyn. 241:1901–1910. 2012. View Article : Google Scholar : PubMed/NCBI
34	Arthur A, Panagopoulos RA, Cooper L, Menicanin D, Parkinson IH, Codrington JD, Vandyke K, Zannettino AC, Koblar SA, Sims NA, et al: EphB4 enhances the process of endochondral ossification and inhibits remodeling during bone fracture repair. J Bone Miner Res. 28:926–935. 2013. View Article : Google Scholar
35	Allan EH, Häusler KD, Wei T, Gooi JH, Quinn JM, Crimeen-Irwin B, Pompolo S, Sims NA, Gillespie MT, Onyia JE and Martin TJ: EphrinB2 regulation by PTH and PTHrP revealed by molecular profiling in differentiating osteoblasts. J Bone Miner Res. 23:1170–1181. 2008. View Article : Google Scholar : PubMed/NCBI
36	Hirai H, Maru Y, Hagiwara K, Nishida J and Takaku F: A novel putative tyrosine kinase receptor encoded by the eph gene. Science. 238:1717–1720. 1987. View Article : Google Scholar : PubMed/NCBI
37	Wang L, Zhang J, Wang C, Qi Y, Du M, Liu W, Yang C and Yang P: Low concentrations of TNF-alpha promote osteogenic differentiation via activation of the ephrinB2-EphB4 signalling pathway. Cell Prolif. 50:2017. View Article : Google Scholar
38	Li C, Shi C, Kim J, Chen Y, Ni S, Jiang L, Zheng C, Li D, Hou J, Taichman RS and Sun H: Erythropoietin promotes bone formation through EphrinB2/EphB4 signaling. J Dent Res. 94:455–463. 2015. View Article : Google Scholar : PubMed/NCBI