Browse > Article
http://dx.doi.org/10.14348/molcells.2014.0223

Gene Expression Profiling in Osteoclast Precursors by Insulin Using Microarray Analysis  

Kim, Hong Sung (Department of Biomedical Laboratory Science, Korea Nazarene University)
Lee, Na Kyung (Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University)
Abstract
The balance between bone formation by osteoblasts and destruction of mineralized bone matrix by osteoclasts is important for bone homeostasis. The increase of osteoclast differentiation by RANKL induces bone diseases such as osteoporosis. Recent studies have shown that insulin is one of main factors mediating the cross-talk between bone remodeling and energy metabolism. However, the systemic examination of insulin-induced differential gene expression profiles in osteoclasts has not been extensively studied. Here, we investigated the global effects of insulin on osteoclast precursors at the level of gene transcription by microarray analysis. The number of genes that were up-regulated by ${\geq}1.5$ fold after insulin treatment for 6 h, 12 h, or 24 h was 76, 73, and 39; and 96, 83, and 54 genes were down-regulated, respectively. The genes were classified by 20 biological processes or 24 molecular functions and the number of genes involved in 'development processes' and 'cell proliferation and differentiation' was 25 and 18, respectively, including Inhba, Socs, Plk3, Tnfsf4, and Plk1. The microarray results of these genes were verified by real-time RT-PCR analysis. We also compared the effects of insulin and RANKL on the expression of these genes. Most genes had a very similar pattern of expressions in insulin- and RANKL-treated cells. Interestingly, Tnfsf4 and Inhba genes were affected by insulin but not by RANKL. Taken together, these results suggest a potential role for insulin in osteoclast biology, thus contributing to the understanding of the pathogenesis and development of therapeutics for numerous bone and metabolic diseases.
Keywords
insulin; microarray; osteoclasts;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Boyle, W.J., Simonet, W.S., and Lacey, D.L. (2003). Osteoclast differentiation and activation. Nature 423, 337-342.   DOI   ScienceOn
2 Brown, C.W., Li, L., Houston-Hawkins, D.E., and Matzuk, M.M. (2003). Activins are critical modulators of growth and survival. Mol. Endocrinol. 17, 2404-2417.   DOI   ScienceOn
3 Gori, F., Divieti, P., and Demay, M.B. (2001). Cloning and characterization of a novel WD-40 repeat protein that dramatically accelerates osteoblastic differentiation. J. Biol. Chem. 276, 46515-46522.   DOI   ScienceOn
4 Teitelbaum, S.L. (2000). Bone resorption by osteoclasts. Science 289, 1504-1508.   DOI   ScienceOn
5 Choi, J., Choi, S.Y., Lee, S.Y., Lee, J.Y., Kim, H.S., Lee, S.Y., and Lee, N.K. (2013). Caffeine enhances osteoclast differentiation and maturation through p38 MAP kinase/Mitf and DCSTAMP/CtsK and TRAP pathway. Cell. Signal. 25, 1222-1227.   DOI   ScienceOn
6 Dai, W., Li, Y., Ouyang, B., Pan, H., Reissmann, P., Li, J., Wiest, J., Stambrook, P., Gluckman, J.L., Noffsinger, A., and Bejarano, P. (2000). PRK, a cell cycle gene localized to 8p21, is downregulated in head and neck cancer. Genes Chromosomes Cancer 27, 332-336.   DOI
7 Dai, W., Liu, T., Wang, Q., Rao, C.V., and Reddy, B.S. (2002). Down-regulation of PLK3 gene expression by types and amount of dietary fat in rat colon tumors. Int. J. Oncol. 20, 121-126.
8 Ferron, M., Wei, J., Yoshizawa, T., Del Fattore, A., DePinho, R.A., Teti, A., Ducy, P., and Karsenty, G. (2010). Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 142, 296-308.   DOI   ScienceOn
9 Fulzele, K., Riddle, R.C., DiGirolamo, D.J., Cao, X., Wan, C., Chen, D,, Faugere, M.C., Aja, S., Hussain, M.A., Brüning, J.C., and Clemens, T.L. (2010). Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell 142, 309-319.   DOI   ScienceOn
10 Gwyer Findlay, E., Danks, L., Madden, J., Cavanagh, M.M., McNamee, K., McCann, F., Snelgrove, R.J., Shaw, S., Feldmann, M., Taylor, P.C., Horwood, N.J., and Hussell, T. (2014). OX40L blockade is therapeutic in arthritis, despite promoting osteoclastogenesis. Proc. Natl. Acad. Sci. USA 111, 2289-2294.   DOI   ScienceOn
11 Han, S.H., Odathurai Saminathan, S., and Kim, S.J. (2010). Insulin stimulates gene expression of ferritin light chain in osteoblast cells. J. Cell. Biochem. 111, 1493-1500.   DOI   ScienceOn
12 Kim, J.H., Kim, K., Youn, B.U., Jin, H.M., and Kim, N. (2010). MHC class II transactivator negatively regulates RANKL-mediated osteoclast differentiation by downregulating NFATc1 and OSCAR. Cell. Signal. 22, 1341-1349.   DOI   ScienceOn
13 Harada, S., and Rodan, G.A. (2003). Control of osteoblast function and regulation of bone mass. Nature 423, 349-355.   DOI   ScienceOn
14 Karsenty, G., and Wagner, E.F. (2002). Reaching a genetic and molecular understanding of skeletal development. Dev. Cell 2, 389-406.   DOI   ScienceOn
15 Kemink, S.A., Hermus, A.R., Swinkels, L.M., Lutterman, J.A., and Smals, A.G. (2000). Osteopenia in insulin-dependent diabetes mellitus; prevalence and aspects of pathophysiology. J. Endocrinol. Invest. 23, 295-303.   DOI
16 Kimura, H., Kwan, K.M., Zhang, Z., Deng, J.M., Darnay, B.G., Behringer, R.R., Nakamura, T., de Crombrugghe, B., and Akiyama, H. (2008). Cthrc1 is a positive regulator of osteoblastic bone formation. PLoS One 3, e3174.   DOI   ScienceOn
17 Li, L., Shen, J.J., Bournat, J.C., Huang, L., Chattopadhyay, A., Li, Z., Shaw, C., Graham, B.H., and Brown, C.W. (2009). Activin signaling: effects on body composition and mitochondrial energy metabolism. Endocrinology 150, 3521-3529.   DOI   ScienceOn
18 Krebs, D.L., and Hilton, D.J. (2001). SOCS proteins: negative regulators of cytokine signaling. Stem Cells 19, 378-387.   DOI   ScienceOn
19 Lee, J.Y., and Lee, N.K. (2014). Up-regulation of cyclinD1 and Bcl2A1 by insulin is involved in osteoclasts proliferation. Life Sci. 114, 57-61.   DOI   ScienceOn
20 Leibbrandt, A., and Penninger, J.M. (2009). RANKL/RANK as key factors for osteoclast development and bone loss in arthropathies. Adv. Exp. Med. Biol. 649, 100-113.   DOI
21 Lorentzon, M., Greenhalgh, C.J., Mohan, S., Alexander, W.S., and Ohlsson, C. (2005). Reduced bone mineral density in SOCS-2-deficient mice. Pediatr. Res, 57, 223-226.   DOI   ScienceOn
22 Petersen, D.N., Tkalcevic, G.T., Mansolf, A.L., Rivera-Gonzalez, R., and Brown, T.A. (2000). Identification of osteoblast/osteocyte factor 45 (OF45), a bone-specific cDNA encoding an RGDcontaining protein that is highly expressed in osteoblasts and osteocytes. J. Biol. Chem. 275, 36172-36180.   DOI   ScienceOn
23 Ohshima, Y., Tanaka, Y., Tozawa, H., Takahashi, Y., Maliszewski, C., and Delespesse, G., (1997). Expression and function of OX40 ligand on human dendritic cells. J. Immunol. 159, 3838-3848.
24 Pakala, S.V., Bansal-Pakala, P., Halteman, B.S., and Croft, M. (2004). Prevention of diabetes in NOD mice at a late stage by targeting OX40/OX40 ligand interactions. Eur. J. Immunol. 34, 3039-3046.   DOI   ScienceOn
25 Thomas, D.M., Udagawa, N., Hards, D.K., Quinn, J.M., Moseley, J.M., Findlay, D.M., and Best, J.D. (1998). Insulin receptor ex832 Mol. Cells http://molcells.org pression in primary and cultured osteoclast-like cells. Bone 23, 181-186.   DOI   ScienceOn
26 Smits, V.A., Klompmaker, R., Arnaud, L., Rijksen, G., Nigg, E.A., and Medema, R.H. (2000). Polo-like kinase-1 is a target of the DNA damage checkpoint. Nat. Cell Biol. 2, 672-676.   DOI   ScienceOn
27 Takai, N., Hamanaka, R., Yoshimatsu, J., and Miyakawa, I. (2005) Polo-like kinases (Plks) and cancer. Oncogene 24, 287-291.   DOI   ScienceOn
28 Teitelbaum, S.L. (2007). Osteoclasts: what do they do and how do they do it? Am. J. Pathol. 170, 427-435.   DOI   ScienceOn
29 Van Vugt, M.A., Smits, V.A., Klompmaker, R., and Medema, R.H. (2001). Inhibition of Polo-like kinase-1 by DNA damage occurs in an ATM-or ATR-dependent fashion. J. Biol. Chem. 276, 41656-41660.   DOI   ScienceOn
30 Wang, Y., Inger, M., Jiang, H., Tenenbaum, H., and Glogauer, M. (2013). CD109 plays a role in osteoclastogenesis. PLoS One 8, e61213.   DOI
31 Yang, J., Zhang, X., Wang, W., and Liu, J. (2010). Insulin stimulates osteoblast proliferation and differentiation through ERK and PI3K in MG-63 cells. Cell. Biochem. Funct. 28, 334-341.   DOI   ScienceOn
32 Thrailkill, K.M., Lumpkin, Jr. C.K., Bunn, R.C., Kemp, S.F., and Fowlkes, J.L. (2005). Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues. Am. J. Physiol. Endocrinol. Metab. 289, E735-745.   DOI   ScienceOn
33 Metcalf, D., Greenhalgh, C.J., Viney, E., Willson, T.A., Starr, R., Nicola, N.A., Hilton, D.J., and Alexander, W.S. (2000). Gigantism in mice lacking suppressor of cytokine signalling-2. Nature 405, 1069-1073.   DOI   ScienceOn