DOI QR코드

DOI QR Code

Extracellular S100A4 negatively regulates osteoblast function by activating the NF-κB pathway

  • Kim, Haemin (Department of Cell and Developmental Biology, BK21 Program and DRI, School of Dentistry, Seoul National University) ;
  • Lee, Yong Deok (Department of Cell and Developmental Biology, BK21 Program and DRI, School of Dentistry, Seoul National University) ;
  • Kim, Min Kyung (Department of Cell and Developmental Biology, BK21 Program and DRI, School of Dentistry, Seoul National University) ;
  • Kwon, Jun-Oh (Department of Cell and Developmental Biology, BK21 Program and DRI, School of Dentistry, Seoul National University) ;
  • Song, Min-Kyoung (Department of Cell and Developmental Biology, BK21 Program and DRI, School of Dentistry, Seoul National University) ;
  • Lee, Zang Hee (Department of Cell and Developmental Biology, BK21 Program and DRI, School of Dentistry, Seoul National University) ;
  • Kim, Hong-Hee (Department of Cell and Developmental Biology, BK21 Program and DRI, School of Dentistry, Seoul National University)
  • Received : 2016.10.07
  • Accepted : 2016.12.20
  • Published : 2017.02.28

Abstract

Patients with inflammatory bone disease or cancer exhibit an increased risk of fractures and delayed bone healing. The S100A4 protein is a member of the calcium-binding S100 protein family, which is abundantly expressed in inflammatory diseases and cancers. We investigated the effects of extracellular S100A4 on osteoblasts, which are cells responsible for bone formation. Treating primary calvarial osteoblasts with recombinant S100A4 resulted in matrix mineralization reductions. The expression of osteoblast marker genes including osteocalcin and osterix was also suppressed. Interestingly, S100A4 stimulated the nuclear factor-kappaB (NF-${\kappa}B$) signaling pathway in osteoblasts. More importantly, the ex vivo organ culture of mouse calvariae with recombinant S100A4 decreased the expression levels of osteocalcin, supporting the results of our in vitro experiments. This suggests that extracellular S100A4 is important for the regulation of bone formation by activating the NF-${\kappa}B$ signaling pathway in osteoblasts.

Keywords

References

  1. Heizmann CW, Fritz G and Schafer BW (2002) S100 proteins: structure, functions and pathology. Front Biosci 7, d1356-1368
  2. Roth J, Vogl T, Sorg C and Sunderkotter C (2003) Phagocyte-specific S100 proteins: a novel group of proinflammatory molecules. Trends Immunol 24, 155-158 https://doi.org/10.1016/S1471-4906(03)00062-0
  3. Emberley ED, Murphy LC and Watson PH (2004) S100 proteins and their influence on pro-survival pathways in cancer. Biochem Cell Biol 82, 508-515 https://doi.org/10.1139/o04-052
  4. Foell D, Kane D, Bresnihan B et al (2003) Expression of the pro-inflammatory protein S100A12 (EN-RAGE) in rheumatoid and psoriatic arthritis. Rheumatology (Oxford) 42, 1383-1389 https://doi.org/10.1093/rheumatology/keg385
  5. Grevers LC, de Vries TJ, Vogl T et al (2011) S100A8 enhances osteoclastic bone resorption in vitro through activation of Toll-like receptor 4: implications for bone destruction in murine antigen-induced arthritis. Arthritis Rheum 63, 1365-1375
  6. Klingelhofer J, Senolt L, Baslund B et al (2007) Upregulation of metastasis-promoting S100A4 (Mts-1) in rheumatoid arthritis: putative involvement in the pathogenesis of rheumatoid arthritis. Arthritis Rheum 56, 779-789 https://doi.org/10.1002/art.22398
  7. Yammani RR, Carlson CS, Bresnick AR and Loeser RF (2006) Increase in production of matrix metalloproteinase 13 by human articular chondrocytes due to stimulation with S100A4: Role of the receptor for advanced glycation end products. Arthritis Rheum 54, 2901-2911 https://doi.org/10.1002/art.22042
  8. Sherbet GV (2009) Metastasis promoter S100A4 is a potentially valuable molecular target for cancer therapy. Cancer Lett 280, 15-30 https://doi.org/10.1016/j.canlet.2008.10.037
  9. Boye K and Maelandsmo GM (2010) S100A4 and metastasis: a small actor playing many roles. Am J Pathol 176, 528-535 https://doi.org/10.2353/ajpath.2010.090526
  10. Chang J, Wang Z, Tang E et al (2009) Inhibition of osteoblastic bone formation by nuclear factor-kappaB. Nat Med 15, 682-689 https://doi.org/10.1038/nm.1954
  11. Chang J, Liu F, Lee M et al (2013) NF-kappaB inhibits osteogenic differentiation of mesenchymal stem cells by promoting beta-catenin degradation. Proc Natl Acad Sci U S A 110, 9469-9474 https://doi.org/10.1073/pnas.1300532110
  12. Yamazaki M, Fukushima H, Shin M et al (2009) Tumor necrosis factor alpha represses bone morphogenetic protein (BMP) signaling by interfering with the DNA binding of Smads through the activation of NF-kappaB. J Biol Chem 284, 35987-35995 https://doi.org/10.1074/jbc.M109.070540
  13. Hofmann MA, Drury S, Fu C et al (1999) RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97, 889-901 https://doi.org/10.1016/S0092-8674(00)80801-6
  14. Ogawa N, Yamaguchi T, Yano S, Yamauchi M, Yamamoto M and Sugimoto M (2007) The combination of high glucose and advanced glycation end-products (AGEs) inhibits the mineralization of osteoblastic MC3T3-E1 cells through glucose-induced increase in the receptor for AGEs. Horm Metab Res 39, 871-875 https://doi.org/10.1055/s-2007-991157
  15. Choi SW, Lee KS, Lee JH et al (2016) Suppression of Akt-HIF-$1{\alpha}$ signaling axis by diacetyl atractylodiol inhibits hypoxia-induced angiogenesis. BMB Rep 49, 508-513 https://doi.org/10.5483/BMBRep.2016.49.9.069
  16. Ryu J, Kim HJ, Chang EJ, Huang H, Banno Y and Kim HH (2006) Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling. EMBO J 25, 5840-5851 https://doi.org/10.1038/sj.emboj.7601430
  17. Lin L, Qiu Q, Zhou N et al (2016) Dickkopf-1 is involved in BMP9-induced osteoblast differentiation of C3H10T1/2 mesenchymal stem cells. BMB Rep 49, 179-184 https://doi.org/10.5483/BMBRep.2016.49.3.206
  18. Gilbert L, He X, Farmer P et al (2000) Inhibition of osteoblast differentiation by tumor necrosis factor-alpha. Endocrinology 141, 3956-3964 https://doi.org/10.1210/endo.141.11.7739
  19. Gilbert L, He X, Farmer P et al (2002) Expression of the osteoblast differentiation factor RUNX2 (Cbfa1/AML3/Pebp2alpha A) is inhibited by tumor necrosis factor-alpha. J Biol Chem 277, 2695-2701 https://doi.org/10.1074/jbc.M106339200
  20. Kaneki H, Guo R, Chen D et al (2006) Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts. J Biol Chem 281, 4326-4333 https://doi.org/10.1074/jbc.M509430200
  21. Jang WG, Jeong BC, Kim EJ et al (2015) Cyclic AMP Response Element-binding Protein H (CREBH) Mediates the Inhibitory Actions of Tumor Necrosis Factor alpha in Osteoblast Differentiation by Stimulating Smad1 Degradation. J Biol Chem 290, 13556-13566 https://doi.org/10.1074/jbc.M114.587923
  22. Lee ZH and Kim HH (2003) Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts. Biochem Biophys Res Commun 305, 211-214 https://doi.org/10.1016/S0006-291X(03)00695-8
  23. Erlandsson MC, Svensson MD, Jonsson IM et al (2013) Expression of metastasin S100A4 is essential for bone resorption and regulates osteoclast function. Biochim Biophys Acta 1833, 2653-2663 https://doi.org/10.1016/j.bbamcr.2013.06.020
  24. Mah SJ, Lee J, Kim H et al (2015) Induction of S100A4 in periodontal ligament cells enhances osteoclast formation. Arch Oral Biol 60, 1215-1221 https://doi.org/10.1016/j.archoralbio.2015.05.014
  25. Cerezo LA, Remakova M, Tomcik M et al (2014) The metastasis-associated protein S100A4 promotes the inflammatory response of mononuclear cells via the TLR4 signalling pathway in rheumatoid arthritis. Rheumatology (Oxford) 53, 1520-1526 https://doi.org/10.1093/rheumatology/keu031
  26. Herwig N, Belter B, Wolf S, Haase-Kohn C and Pietzsch J (2016) Interaction of extracellular S100A4 with RAGE prompts prometastatic activation of A375 melanoma cells. J Cell Mol Med 20, 825-835 https://doi.org/10.1111/jcmm.12808
  27. Medapati MR, Dahlmann M, Ghavami S et al (2015) RAGE Mediates the Pro-Migratory Response of Extracellular S100A4 in Human Thyroid Cancer Cells. Thyroid 25, 514-527 https://doi.org/10.1089/thy.2014.0257
  28. Siddique HR, Adhami VM, Parray A et al (2013) The S100A4 Oncoprotein Promotes Prostate Tumorigenesis in a Transgenic Mouse Model: Regulating NFkappaB through the RAGE Receptor. Genes Cancer 4, 224-234 https://doi.org/10.1177/1947601913492420

Cited by

  1. Role of metastasis-induced protein S100A4 in human non-tumor pathophysiologies vol.7, pp.1, 2017, https://doi.org/10.1186/s13578-017-0191-1
  2. RAGE Signaling in Skeletal Biology vol.17, pp.1, 2019, https://doi.org/10.1007/s11914-019-00499-w