DOI QR코드

DOI QR Code

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)
  • Received : 2014.08.04
  • Accepted : 2014.09.11
  • Published : 2014.11.30

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

References

  1. Boyle, W.J., Simonet, W.S., and Lacey, D.L. (2003). Osteoclast differentiation and activation. Nature 423, 337-342. https://doi.org/10.1038/nature01658
  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. https://doi.org/10.1210/me.2003-0051
  3. 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. https://doi.org/10.1016/j.cellsig.2013.02.015
  4. 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. https://doi.org/10.1002/(SICI)1098-2264(200003)27:3<332::AID-GCC15>3.0.CO;2-K
  5. 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.
  6. 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. https://doi.org/10.1016/j.cell.2010.06.003
  7. 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. https://doi.org/10.1016/j.cell.2010.06.002
  8. 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. https://doi.org/10.1074/jbc.M105757200
  9. 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. https://doi.org/10.1073/pnas.1321071111
  10. 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. https://doi.org/10.1002/jcb.22879
  11. Harada, S., and Rodan, G.A. (2003). Control of osteoblast function and regulation of bone mass. Nature 423, 349-355. https://doi.org/10.1038/nature01660
  12. Karsenty, G., and Wagner, E.F. (2002). Reaching a genetic and molecular understanding of skeletal development. Dev. Cell 2, 389-406. https://doi.org/10.1016/S1534-5807(02)00157-0
  13. 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. https://doi.org/10.1007/BF03343726
  14. 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. https://doi.org/10.1016/j.cellsig.2010.05.001
  15. 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. https://doi.org/10.1371/journal.pone.0003174
  16. Krebs, D.L., and Hilton, D.J. (2001). SOCS proteins: negative regulators of cytokine signaling. Stem Cells 19, 378-387. https://doi.org/10.1634/stemcells.19-5-378
  17. 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. https://doi.org/10.1016/j.lfs.2014.07.006
  18. 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. https://doi.org/10.1007/978-1-4419-0298-6_7
  19. 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. https://doi.org/10.1210/en.2008-0922
  20. 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. https://doi.org/10.1203/01.PDR.0000148735.21084.D3
  21. 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. https://doi.org/10.1038/35016611
  22. 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.
  23. 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. https://doi.org/10.1002/eji.200425141
  24. 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. https://doi.org/10.1074/jbc.M003622200
  25. 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. https://doi.org/10.1038/35023629
  26. Takai, N., Hamanaka, R., Yoshimatsu, J., and Miyakawa, I. (2005) Polo-like kinases (Plks) and cancer. Oncogene 24, 287-291. https://doi.org/10.1038/sj.onc.1208272
  27. Teitelbaum, S.L. (2000). Bone resorption by osteoclasts. Science 289, 1504-1508. https://doi.org/10.1126/science.289.5484.1504
  28. Teitelbaum, S.L. (2007). Osteoclasts: what do they do and how do they do it? Am. J. Pathol. 170, 427-435. https://doi.org/10.2353/ajpath.2007.060834
  29. 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. https://doi.org/10.1016/S8756-3282(98)00095-7
  30. 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. https://doi.org/10.1152/ajpendo.00159.2005
  31. 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. https://doi.org/10.1074/jbc.M101831200
  32. Wang, Y., Inger, M., Jiang, H., Tenenbaum, H., and Glogauer, M. (2013). CD109 plays a role in osteoclastogenesis. PLoS One 8, e61213. https://doi.org/10.1371/journal.pone.0061213
  33. 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. https://doi.org/10.1002/cbf.1668

Cited by

  1. Selective control of up-regulated and down-regulated genes by temporal patterns and doses of insulin vol.9, pp.455, 2016, https://doi.org/10.1126/scisignal.aaf3739
  2. Insulin enhances RANKL-induced osteoclastogenesis via ERK1/2 activation and induction of NFATc1 and Atp6v0d2 vol.27, pp.12, 2015, https://doi.org/10.1016/j.cellsig.2015.09.002
  3. Up-Regulation of RANK Expression via ERK1/2 by Insulin Contributes to the Enhancement of Osteoclast Differentiation vol.40, pp.5, 2014, https://doi.org/10.14348/molcells.2017.0025
  4. A2B Adenosine Receptor Stimulation Down-regulates M-CSF-mediated Osteoclast Proliferation vol.23, pp.3, 2014, https://doi.org/10.15616/bsl.2017.23.3.194
  5. Trans-omic Analysis Reveals Selective Responses to Induced and Basal Insulin across Signaling, Transcriptional, and Metabolic Networks vol.7, pp.None, 2014, https://doi.org/10.1016/j.isci.2018.07.022
  6. Integration of TGF-β-induced Smad signaling in the insulin-induced transcriptional response in endothelial cells vol.9, pp.None, 2014, https://doi.org/10.1038/s41598-019-53490-x
  7. Searching for valuable differentially expressed miRNAs in postmenopausal osteoporosis by RNA sequencing vol.46, pp.7, 2014, https://doi.org/10.1111/jog.14307
  8. Comprehensive Transcriptomic Profiling of Murine Osteoclast Differentiation Reveals Novel Differentially Expressed Genes and LncRNAs vol.12, pp.None, 2021, https://doi.org/10.3389/fgene.2021.781272