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C-X-C Motif Chemokine 12 Enhances Lipopolysaccharide-Induced Osteoclastogenesis and Bone Resorption In Vivo

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Abstract

C-X-C motif chemokine 12 (CXCL12) belongs to the family of CXC chemokines. Lipopolysaccharide (LPS) induces inflammation-induced osteoclastogenesis and bone resorption, and in recent years, stimulatory effects of CXCL12 on bone resorption have also been reported. In the present study, we investigated the effects of CXCL12 on LPS-induced osteoclastogenesis and bone resorption. LPS was administered with or without CXCL12 onto mouse calvariae by daily subcutaneous injection. Numbers of osteoclasts and bone resorption were significantly elevated in mice co-administered LPS and CXCL12 compared with mice administered LPS alone. Moreover, receptor activator of NF-kB ligand (RANKL) and tumor necrosis factor-α (TNF-α) mRNA levels were higher in mice co-administered LPS and CXCL12 compared with mice administered LPS alone. These in vitro results confirmed a direct stimulatory effect of CXCL12 on RANKL- and TNF-α-induced osteoclastogenesis. Furthermore, TNF-α and RANKL mRNA levels were elevated in macrophages and osteoblasts, respectively, co-treated in vitro with CXCL12 and LPS, in comparison with cells treated with LPS alone. Our results suggest that CXCL12 enhances LPS-induced osteoclastogenesis and bone resorption in vivo through a combination of increasing LPS-induced TNF-α production by macrophages, increasing RANKL production by osteoblasts, and direct enhancement of osteoclastogenesis.

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References

  1. Crotti TN, Dharmapatni AA, Alias E, Haynes DR (2015) Osteoimmunology: major and costimulatory pathway expression associated with chronic inflammatory induced bone loss. J Immunol Res 2015:281287. https://doi.org/10.1155/2015/281287

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Teitelbaum SL (2007) Osteoclasts: what do they do and how do they do it? Am J Pathol 170(2):427–435. https://doi.org/10.2353/ajpath.2007.060834

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Azuma Y, Kaji K, Katogi R, Takeshita S, Kudo A (2000) Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J Biol Chem 275(7):4858–4864

    Article  PubMed  CAS  Google Scholar 

  4. Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Morinaga T, Higashio K, Martin TJ, Suda T (2000) Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med 191(2):275–286

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Fuller K, Murphy C, Kirstein B, Fox SW, Chambers TJ (2002) TNFalpha potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL. Endocrinology 143(3):1108–1118. https://doi.org/10.1210/endo.143.3.8701

    Article  PubMed  CAS  Google Scholar 

  6. Kitaura H, Sands MS, Aya K, Zhou P, Hirayama T, Uthgenannt B, Wei S, Takeshita S, Novack DV, Silva MJ, Abu-Amer Y, Ross FP, Teitelbaum SL (2004) Marrow stromal cells and osteoclast precursors differentially contribute to TNF-alpha-induced osteoclastogenesis in vivo. J Immunol 173(8):4838–4846

    Article  PubMed  CAS  Google Scholar 

  7. Kitaura H, Zhou P, Kim HJ, Novack DV, Ross FP, Teitelbaum SL (2005) M-CSF mediates TNF-induced inflammatory osteolysis. J Clin Invest 115(12):3418–3427. https://doi.org/10.1172/JCI26132

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Li P, Schwarz EM, O’Keefe RJ, Ma L, Boyce BF, Xing L (2004) RANK signaling is not required for TNFalpha-mediated increase in CD11(hi) osteoclast precursors but is essential for mature osteoclast formation in TNFalpha-mediated inflammatory arthritis. J Bone Miner Res 19(2):207–213. https://doi.org/10.1359/JBMR.0301233

    Article  PubMed  CAS  Google Scholar 

  9. Abu-Amer Y, Ross FP, Edwards J, Teitelbaum SL (1997) Lipopolysaccharide-stimulated osteoclastogenesis is mediated by tumor necrosis factor via its P55 receptor. J Clin Invest 100(6):1557–1565. https://doi.org/10.1172/JCI119679

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Dumitrescu AL, Abd-El-Aleem S, Morales-Aza B, Donaldson LF (2004) A model of periodontitis in the rat: effect of lipopolysaccharide on bone resorption, osteoclast activity, and local peptidergic innervation. J Clin Periodontol 31(8):596–603. https://doi.org/10.1111/j.1600-051X.2004.00528.x

    Article  PubMed  CAS  Google Scholar 

  11. Bostanci N, Allaker RP, Belibasakis GN, Rangarajan M, Curtis MA, Hughes FJ, McKay IJ (2007) Porphyromonas gingivalis antagonises Campylobacter rectus induced cytokine production by human monocytes. Cytokine 39(2):147–156. https://doi.org/10.1016/j.cyto.2007.07.002

    Article  PubMed  CAS  Google Scholar 

  12. Kitaura H, Kimura K, Ishida M, Kohara H, Yoshimatsu M, Takano-Yamamoto T (2013) Immunological reaction in TNF-alpha-mediated osteoclast formation and bone resorption in vitro and in vivo. Clin Dev Immunol 2013:181849. https://doi.org/10.1155/2013/181849

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Zou W, Bar-Shavit Z (2002) Dual modulation of osteoclast differentiation by lipopolysaccharide. J Bone Miner Res 17(7):1211–1218. https://doi.org/10.1359/jbmr.2002.17.7.1211

    Article  PubMed  CAS  Google Scholar 

  14. Kikuchi T, Matsuguchi T, Tsuboi N, Mitani A, Tanaka S, Matsuoka M, Yamamoto G, Hishikawa T, Noguchi T, Yoshikai Y (2001) Gene expression of osteoclast differentiation factor is induced by lipopolysaccharide in mouse osteoblasts via Toll-like receptors. J Immunol 166(5):3574–3579

    Article  PubMed  CAS  Google Scholar 

  15. Lee J, Park C, Kim HJ, Lee YD, Lee ZH, Song YW, Kim HH (2017) Stimulation of osteoclast migration and bone resorption by C-C chemokine ligands 19 and 21. Exp Mol Med 49(7):e358. https://doi.org/10.1038/emm.2017.100

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Yu X, Huang Y, Collin-Osdoby P, Osdoby P (2004) CCR1 chemokines promote the chemotactic recruitment, RANKL development, and motility of osteoclasts and are induced by inflammatory cytokines in osteoblasts. J Bone Miner Res 19(12):2065–2077. https://doi.org/10.1359/JBMR.040910

    Article  PubMed  CAS  Google Scholar 

  17. Votta BJ, White JR, Dodds RA, James IE, Connor JR, Lee-Rykaczewski E, Eichman CF, Kumar S, Lark MW, Gowen M (2000) CKbeta-8 [CCL23], a novel CC chemokine, is chemotactic for human osteoclast precursors and is expressed in bone tissues. J Cell Physiol 183 (2):196–207

    Article  PubMed  CAS  Google Scholar 

  18. Pawig L, Klasen C, Weber C, Bernhagen J, Noels H (2015) Diversity and inter-connections in the CXCR4 Chemokine receptor/ligand family: molecular perspectives. Front Immunol 6:429. https://doi.org/10.3389/fimmu.2015.00429

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Schrader AJ, Lechner O, Templin M, Dittmar KE, Machtens S, Mengel M, Probst-Kepper M, Franzke A, Wollensak T, Gatzlaff P, Atzpodien J, Buer J, Lauber J (2002) CXCR4/CXCL12 expression and signalling in kidney cancer. Br J Cancer 86(8):1250–1256. https://doi.org/10.1038/sj.bjc.6600221

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, Bronson RT, Springer TA (1998) Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci USA 95(16):9448–9453

    Article  PubMed  CAS  Google Scholar 

  21. Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA (1996) A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med 184(3):1101–1109

    Article  PubMed  CAS  Google Scholar 

  22. Kincade PW (2010) Plasticity of supporting cells in a stem cell factory. Immunity 33(3):291–293. https://doi.org/10.1016/j.immuni.2010.09.003

    Article  PubMed  CAS  Google Scholar 

  23. Pramanik R, Sheng X, Ichihara B, Heisterkamp N, Mittelman SD (2013) Adipose tissue attracts and protects acute lymphoblastic leukemia cells from chemotherapy. Leuk Res 37(5):503–509. https://doi.org/10.1016/j.leukres.2012.12.013

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Okada K, Kawao N, Yano M, Tamura Y, Kurashimo S, Okumoto K, Kojima K, Kaji H (2016) Stromal cell-derived factor-1 mediates changes of bone marrow stem cells during the bone repair process. Am J Physiol Endocrinol Metab 310(1):E15–E23. https://doi.org/10.1152/ajpendo.00253.2015

    Article  Google Scholar 

  25. Teixido J, Martinez-Moreno M, Diaz-Martinez M, Sevilla-Movilla S (2018) The good and bad faces of the CXCR4 chemokine receptor. Int J Biochem Cell Biol 95:121–131. https://doi.org/10.1016/j.biocel.2017.12.018

    Article  PubMed  CAS  Google Scholar 

  26. Luo T, Liu H, Feng W, Liu D, Du J, Sun J, Wang W, Han X, Guo J, Amizuka N, Li X, Li M (2017) Adipocytes enhance expression of osteoclast adhesion-related molecules through the CXCL12/CXCR4 signalling pathway. Cell Prolif. https://doi.org/10.1111/cpr.12317

    Article  PubMed  Google Scholar 

  27. Dong Y, Liu H, Zhang X, Xu F, Qin L, Cheng P, Huang H, Guo F, Yang Q, Chen A (2016) Inhibition of SDF-1alpha/CXCR4 signalling in subchondral bone attenuates post-traumatic osteoarthritis. Int J Mol Sci. https://doi.org/10.3390/ijms17060943

    Article  PubMed  PubMed Central  Google Scholar 

  28. McHugh KP, Hodivala-Dilke K, Zheng MH, Namba N, Lam J, Novack D, Feng X, Ross FP, Hynes RO, Teitelbaum SL (2000) Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 105(4):433–440. https://doi.org/10.1172/JCI8905

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Takeshita S, Kaji K, Kudo A (2000) Identification and characterization of the new osteoclast progenitor with macrophage phenotypes being able to differentiate into mature osteoclasts. J Bone Miner Res 15(8):1477–1488. https://doi.org/10.1359/jbmr.2000.15.8.1477

    Article  PubMed  CAS  Google Scholar 

  30. Kimura K, Kitaura H, Fujii T, Hakami ZW, Takano-Yamamoto T (2012) Anti-c-Fms antibody inhibits lipopolysaccharide-induced osteoclastogenesis in vivo. FEMS Immunol Med Microbiol 64(2):219–227. https://doi.org/10.1111/j.1574-695X.2011.00888.x

    Article  PubMed  CAS  Google Scholar 

  31. Saeed J, Kitaura H, Kimura K, Ishida M, Sugisawa H, Ochi Y, Kishikawa A, Takano-Yamamoto T (2016) IL-37 inhibits lipopolysaccharide-induced osteoclast formation and bone resorption in vivo. Immunol Lett 175:8–15. https://doi.org/10.1016/j.imlet.2016.04.004

    Article  PubMed  CAS  Google Scholar 

  32. Ishida M, Kitaura H, Kimura K, Sugisawa H, Aonuma T, Takada H, Takano-Yamamoto T (2015) Muramyl dipeptide enhances lipopolysaccharide-induced osteoclast formation and bone resorption through increased RANKL expression in stromal cells. J Immunol Res 2015:132765. https://doi.org/10.1155/2015/132765

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Bakker AD, Klein-Nulend J (2012) Osteoblast isolation from murine calvaria and long bones. Methods Mol Biol 816:19–29. https://doi.org/10.1007/978-1-61779-415-5_2

    Article  PubMed  CAS  Google Scholar 

  34. Kanbe K, Takagishi K, Chen Q (2002) Stimulation of matrix metalloprotease 3 release from human chondrocytes by the interaction of stromal cell-derived factor 1 and CXC chemokine receptor 4. Arthritis Rheum 46(1):130–137

    Article  PubMed  CAS  Google Scholar 

  35. Nanki T, Hayashida K, El-Gabalawy HS, Suson S, Shi K, Girschick HJ, Yavuz S, Lipsky PE (2000) Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4 + T cell accumulation in rheumatoid arthritis synovium. J Immunol 165(11):6590–6598

    Article  PubMed  CAS  Google Scholar 

  36. Pablos JL, Santiago B, Galindo M, Torres C, Brehmer MT, Blanco FJ, Garcia-Lazaro FJ (2003) Synoviocyte-derived CXCL12 is displayed on endothelium and induces angiogenesis in rheumatoid arthritis. J Immunol 170(4):2147–2152

    Article  PubMed  CAS  Google Scholar 

  37. De Klerck B, Geboes L, Hatse S, Kelchtermans H, Meyvis Y, Vermeire K, Bridger G, Billiau A, Schols D, Matthys P (2005) Pro-inflammatory properties of stromal cell-derived factor-1 (CXCL12) in collagen-induced arthritis. Arthritis Res Ther 7(6):R1208–R1220. https://doi.org/10.1186/ar1806

    Article  CAS  Google Scholar 

  38. Yang L, Wang M, Guo YY, Sun T, Li YJ, Yang Q, Zhang K, Liu SB, Zhao MG, Wu YM (2016) Systemic inflammation induces anxiety disorder through CXCL12/CXCR4 pathway. Brain Behav Immun 56:352–362. https://doi.org/10.1016/j.bbi.2016.03.001

    Article  PubMed  CAS  Google Scholar 

  39. Konrad FM, Meichssner N, Bury A, Ngamsri KC, Reutershan J (2017) Inhibition of SDF-1 receptors CXCR4 and CXCR7 attenuates acute pulmonary inflammation via the adenosine A2B-receptor on blood cells. Cell Death Dis 8(5):e2832. https://doi.org/10.1038/cddis.2016.482

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Xing Q, de Vos P, Faas MM, Ye Q, Ren Y (2011) LPS promotes pre-osteoclast activity by up-regulating CXCR4 via TLR-4. J Dent Res 90(2):157–162. https://doi.org/10.1177/0022034510379019

    Article  PubMed  CAS  Google Scholar 

  41. Yu L, Yu L, Pham Q, Wang TTY (2018) Transcriptional and translational-uncoupling in regulation of the CXCL12 and its receptors CXCR4, 7 in THP-1 monocytes and macrophages. Immun Inflamm Dis 6(1):106–116. https://doi.org/10.1002/iid3.199

    Article  PubMed  CAS  Google Scholar 

  42. Souza JAC, Nogueira AVB, Souza PPC, Oliveira G, Medeiros MC, Garlet GP, Cirelli JA, Rossa CJ (2017) Suppressor of cytokine signaling 1 expression during LPS-induced inflammation and bone loss in rats. Braz Oral Res 31:e75

    PubMed  Google Scholar 

  43. Kong L, Ma R, Yang X, Zhu Z, Guo H, He B, Wang B, Hao D (2017) Psoralidin suppresses osteoclastogenesis in BMMs and attenuates LPS-mediated osteolysis by inhibiting inflammatory cytokines. Int Immunopharmacol 51:31–39. https://doi.org/10.1016/j.intimp.2017.07.003

    Article  PubMed  CAS  Google Scholar 

  44. Leite FR, de Aquino SG, Guimaraes MR, Cirelli JA, Zamboni DS, Silva JS, Junior CR (2015) Relevance of the myeloid differentiation factor 88 (MyD88) on RANKL, OPG, and nod expressions induced by TLR and IL-1R signaling in bone marrow stromal cells. Inflammation 38(1):1–8. https://doi.org/10.1007/s10753-014-0001-4

    Article  PubMed  CAS  Google Scholar 

  45. Wada N, Maeda H, Yoshimine Y, Akamine A (2004) Lipopolysaccharide stimulates expression of osteoprotegerin and receptor activator of NF-kappa B ligand in periodontal ligament fibroblasts through the induction of interleukin-1 beta and tumor necrosis factor-alpha. Bone 35(3):629–635. https://doi.org/10.1016/j.bone.2004.04.023

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by a JSPS KAKENHI grant from the Japan Society for the Promotion of Science (No. 16K11776 to H. K., No. 17K17306 to K. S., No. 16K20637 to K. K., No. 16K20636 to M. I.).

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  1. Division of Orthodontics and Dentofacial Orthopedics, Department of Translational Medicine, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan

    Kazuhiro Shima, Keisuke Kimura, Masahiko Ishida, Akiko Kishikawa, Saika Ogawa, Jiawei Qi, Wei-Ren Shen, Fumitoshi Ohori, Takahiro Noguchi, Aseel Marahleh & Hideki Kitaura

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  1. Kazuhiro Shima
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Contributions

KS contributed to the conception, design, data acquisition, data analysis, data interpretation, and drafting of the manuscript. HK contributed to conception, design, data acquisition, data analysis, data interpretation, and drafting and critical revision of the manuscript. KK, MI, AK, SO, JQ, W-RS, FO, TN, and AM contributed to data acquisition and analysis and drafting of the manuscript. All authors provided final approval and agree to be accountable for all aspects of the work.

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Correspondence to Hideki Kitaura.

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Kazuhiro Shima, Keisuke Kimura, Masahiko Ishida, Akiko Kishikawa, Saika Ogawa, Jiawei Qi, Wei-Ren Shen, Fumitoshi Ohori, Takahiro Noguchi, Aseel Marahleh, and Hideki Kitaura have declare that they have no conflicts of interest.

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All animal procedures and animal care were performed according to Tohoku University rules and regulations.

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Shima, K., Kimura, K., Ishida, M. et al. C-X-C Motif Chemokine 12 Enhances Lipopolysaccharide-Induced Osteoclastogenesis and Bone Resorption In Vivo. Calcif Tissue Int 103, 431–442 (2018). https://doi.org/10.1007/s00223-018-0435-z

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