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)
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 extracellul...
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.
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.
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가설 설정
In this study, we investigated the role of extracellular S100A4 on the inhibition of bone formation by activating the NF-B pathway in osteoblasts. The early differentiation of osteoblast was not affected (Fig.
A number of studies have reported that activation of the NF-kB pathway in osteoblast precursors impairs osteogenic differentiation (10, 11). To investigate the mechanism of mineralization inhibition by S100A4, we tested whether S100A4 activated the NF-kB pathway in calvarial osteoblasts. Stimulating them with recombinant mouse S100A4-increased IKKα/β, IkB, and p65 phosphorylation within 60 minutes (Fig.
제안 방법
We examined the effect of S100A4 on matrix mineralization, a crucial function of osteoblasts during bone formation. Calvarial preosteoblasts were cultured in osteogenic media for ten days and the assessment of mineralization was performed by Alizarin-red staining. The cell proliferation and survival was not affected by the presence of S100A4 at concentrations up to 2 μg/ml until day 6 of the culture and only slightly decreased at 2 μg/ml in 9-day cultures (Fig.
대상 데이터
All experiments, except the mice calvariae organ culture studies, were performed at least three times. All quantitative measurements had 3 or 4 replicates. Two-way ANOVA followed by a Bonferroni test and Student’s t test were performed to define differences between multiple and 2 groups, respectively.
데이터처리
Two-way ANOVA followed by a Bonferroni test and Student’s t test were performed to define differences between multiple and 2 groups, respectively.
성능/효과
In conclusion, our study demonstrates that extracellular S100A4 interrupts the mineralization function of osteoblasts and causes an imbalance in bone homeostasis by inhibiting new bone formation. We demonstrated for the first time that this phenomenon is mediated through NF-B activation.
참고문헌 (28)
1 Heizmann CW Fritz G Schafer BW 2002 S100 proteins: structure, functions and pathology Front Biosci 7 d1356 1368 11991838
2 Roth J Vogl T Sorg C Sunderkotter C 2003 Phagocyte-specific S100 proteins: a novel group of proinflammatory molecules Trends Immunol 24 155 158 10.1016/S1471-4906(03)00062-0 12697438
3 Emberley ED Murphy LC Watson PH 2004 S100 proteins and their influence on pro-survival pathways in cancer Biochem Cell Biol 82 508 515 10.1139/o04-052 15284904
4 Foell D Kane D Bresnihan B 2003 Expression of the pro-inflammatory protein S100A12 (EN-RAGE) in rheumatoid and psoriatic arthritis Rheumatology (Oxford) 42 1383 1389 10.1093/rheumatology/keg385 12832707
5 Grevers LC de Vries TJ Vogl T 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 10.1002/art.30290 21337316
6 Klingelhofer J Senolt L Baslund B 2007 Up-regulation of metastasis-promoting S100A4 (Mts-1) in rheumatoid arthritis: putative involvement in the pathogenesis of rheumatoid arthritis Arthritis Rheum 56 779 789 10.1002/art.22398 17328050
7 Yammani RR Carlson CS Bresnick AR 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 10.1002/art.22042 16948116
8 Sherbet GV 2009 Metastasis promoter S100A4 is a potentially valuable molecular target for cancer therapy Cancer Lett 280 15 30 10.1016/j.canlet.2008.10.037 19059703
9 Boye K Maelandsmo GM 2010 S100A4 and metastasis: a small actor playing many roles Am J Pathol 176 528 535 10.2353/ajpath.2010.090526 2808059 --> 20019188
10 Chang J Wang Z Tang E 2009 Inhibition of osteoblastic bone formation by nuclear factor-kappaB Nat Med 15 682 689 10.1038/nm.1954 2768554 --> 19448637
11 Chang J Liu F Lee M 2013 NF-kappaB inhibits osteogenic differentiation of mesenchymal stem cells by promoting beta-catenin degradation Proc Natl Acad Sci USA 110 9469 9474 10.1073/pnas.1300532110 23690607
12 Yamazaki M Fukushima H Shin M 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 10.1074/jbc.M109.070540 2791026 --> 19854828
13 Hofmann MA Drury S Fu C 1999 RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides Cell 97 889 901 10.1016/S0092-8674(00)80801-6 10399917
14 Ogawa N Yamaguchi T Yano S Yamauchi M Yamamoto M 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 10.1055/s-2007-991157 17960513
16 Ryu J Kim HJ Chang EJ Huang H Banno Y Kim HH 2006 Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling EMBO J 25 5840 5851 10.1038/sj.emboj.7601430 1698879 --> 17124500
17 Lin L Qiu Q Zhou N 2016 Dickkopf-1 is involved in BMP9-induced osteoblast differentiation of C3H10T1/2 mesenchymal stem cells BMB Rep 49 179 184 10.5483/BMBRep.2016.49.3.206 4915233 --> 26674341
18 Gilbert L He X Farmer P 2000 Inhibition of osteoblast differentiation by tumor necrosis factor-alpha Endocrinology 141 3956 3964 11089525
19 Gilbert L He X Farmer P 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 10.1074/jbc.M106339200 11723115
20 Kaneki H Guo R Chen D 2006 Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts J Biol Chem 281 4326 4333 10.1074/jbc.M509430200 16373342
21 Jang WG Jeong BC Kim EJ 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 10.1074/jbc.M114.587923 4505601 --> 25873397
22 Lee ZH Kim HH 2003 Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts Biochem Biophys Res Commun 305 211 214 10.1016/S0006-291X(03)00695-8 12745060
23 Erlandsson MC Svensson MD Jonsson IM 2013 Expression of metastasin S100A4 is essential for bone resorption and regulates osteoclast function Biochim Biophys Acta 1833 2653 2663 10.1016/j.bbamcr.2013.06.020 23830916
24 Mah SJ Lee J Kim H 2015 Induction of S100A4 in periodontal ligament cells enhances osteoclast formation Arch Oral Biol 60 1215 1221 10.1016/j.archoralbio.2015.05.014 26079064
25 Cerezo LA Remakova M Tomcik M 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 10.1093/rheumatology/keu031 24643522
26 Herwig N Belter B Wolf S Haase-Kohn C Pietzsch J 2016 Interaction of extracellular S100A4 with RAGE prompts prometastatic activation of A375 melanoma cells J Cell Mol Med 20 825 835 10.1111/jcmm.12808 4831350 --> 26928771
27 Medapati MR Dahlmann M Ghavami S 2015 RAGE Mediates the Pro-Migratory Response of Extracellular S100A4 in Human Thyroid Cancer Cells Thyroid 25 514 527 10.1089/thy.2014.0257 25744544
28 Siddique HR Adhami VM Parray A 2013 The S100A4 Oncoprotein Promotes Prostate Tumorigenesis in a Transgenic Mouse Model: Regulating NFkappaB through the RAGE Receptor Genes Cancer 4 224 234 10.1177/1947601913492420 3782007 --> 24069509
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