Molecules and Cells

  • 제37권9호
  • /
  • Pages.685-690
  • /
  • 2014
  • /
  • 1016-8478(pISSN)
  • /
  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
권호 표지
DOI QR코드

DOI QR Code

Carboxypeptidase E Is a Novel Modulator of RANKL-Induced Osteoclast Differentiation

  • Kim, Hyun-Ju (Department of Molecular Medicine, Cell and Matrix Research Institute, Clinical Trial Center, School of Medicine,Kyungpook National University) ;
  • Hong, JungMin (Skeletal Diseases Genome Research Center, Kyungpook National University Hospital) ;
  • Yoon, Hye-Jin (Skeletal Diseases Genome Research Center, Kyungpook National University Hospital) ;
  • Yoon, Young-Ran (Department of Molecular Medicine, Cell and Matrix Research Institute, Clinical Trial Center, School of Medicine,Kyungpook National University) ;
  • Kim, Shin-Yoon (Skeletal Diseases Genome Research Center, Kyungpook National University Hospital)
  • 투고 : 2014.06.26
  • 심사 : 2014.07.30
  • 발행 : 2014.09.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Osteoclasts are large polykaryons that have the unique capacity to degrade bone and are generated by the differentiation of myeloid lineage progenitors. To identify the genes involved in osteoclast development, we performed microarray analysis, and we found that carboxypeptidase E (CPE), a prohormone processing enzyme, was highly upregulated in osteoclasts compared with their precursors, bone marrow-derived macrophages (BMMs). Here, we demonstrate a novel role for CPE in receptor activator of NF-${\kappa}B$ ligand (RANKL)-induced osteoclast differentiation. The overexpression of CPE in BMMs increases the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts and the expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are key regulators in osteoclastogenesis. Furthermore, employing CPE knockout mice, we show that CPE deficiency attenuates osteoclast formation. Together, our data suggest that CPE might be an important modulator of RANKL-induced osteoclast differentiation.

키워드

참고문헌

  1. Anderson, D.M., Maraskovsky, E., Billingsley, W.L., Dougall, W.C., Tometsko, M.E., Roux, E.R., Teepe, M.C., DuBose, R.F., Cosman, D., and Galibert, L. (1997). A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390, 175-179. https://doi.org/10.1038/36593
  2. Baron, R., and Hesse, E. (2012). Update on bone anabolics in osteoporosis treatment: rationale, current status, and perspectives. J. Clin. Endocrinol. Metabol. 97, 311-325. https://doi.org/10.1210/jc.2011-2332
  3. 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
  4. Cawley, N.X., Zhou, J., Hill, J.M., Abebe, D., Romboz, S., Yanik, T., Rodriguiz, R.M., Wetsel, W.C., and Loh, Y.P. (2004). The carboxypetidase E Knockout mouse exhibits endocrinological and behavioral deficits. Endocrinology 145, 5807-5819. https://doi.org/10.1210/en.2004-0847
  5. Cawley, N.X., Yanik, T., Woronowicz, A., Chang, W., Marini, J.C., and Loh, Y.P. (2010). Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density. Am. J. Physiol. Endocrinol. Metab. 299, E189-197. https://doi.org/10.1152/ajpendo.00516.2009
  6. Cawley, N.X., Wetsel, W.C., Murthy, S.R., Park, J.J., Pacak, K., and Loh, Y.P. (2012). New roles of carboxypeptidase E in endocrine and neural function and cancer. Endocrine Rev. 33, 216-253. https://doi.org/10.1210/er.2011-1039
  7. Cool, D.R., Normant, E., Shen, F., Chen, H.C., Pannell, L., Zhang, Y., and Loh, Y.P. (1997). Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice. Cell 88, 73-83. https://doi.org/10.1016/S0092-8674(00)81860-7
  8. Cornish, J., Callon, K.E., Mountjoy, K.G., Bava, U., Lin, J.M., Myers, D.E., Naot, D., and Reid, I.R. (2003). alpha -melanocytestimulating hormone is a novel regulator of bone. American journal of physiology. Endocrinol. Metabol. 284, E1181-1190.
  9. D'Agostino, G., and Diano, S. (2010). Alpha-melanocyte stimulating hormone: production and degradation. J. Mol. Med. 88, 1195-1201. https://doi.org/10.1007/s00109-010-0651-0
  10. Du, J., Keegan, B.P., and North, W.G. (2001). Key peptide processing enzymes are expressed by breast cancer cells. Cancer Lett. 165, 211-218. https://doi.org/10.1016/S0304-3835(01)00409-8
  11. Fricker, L.D., and Snyder, S.H. (1982). Enkephalin convertase: purification and characterization of a specific enkephalin-synthesizing carboxypeptidase localized to adrenal chromaffin granules. Proc. Natl. Acad. Sci. USA 79, 3886-3890. https://doi.org/10.1073/pnas.79.12.3886
  12. He, P., Varticovski, L., Bowman, E.D., Fukuoka, J., Welsh, J.A., Miura, K., Jen, J., Gabrielson, E., Brambilla, E., Travis, W.D., et al. (2004). Identification of carboxypeptidase E and gamma-glutamyl hydrolase as biomarkers for pulmonary neuroendocrine tumors by cDNA microarray. Hum. Pathol. 35, 1196-1209. https://doi.org/10.1016/j.humpath.2004.06.014
  13. Hirotani, H., Tuohy, N.A., Woo, J.T., Stern, P.H., and Clipstone, N.A. (2004). The calcineurin/nuclear factor of activated T cells signaling pathway regulates osteoclastogenesis in RAW264.7 cells. J. Biol. Chem. 279, 13984-13992. https://doi.org/10.1074/jbc.M213067200
  14. Hook, V.Y., and Loh, Y.P. (1984). Carboxypeptidase B-like converting enzyme activity in secretory granules of rat pituitary. Proc. Natl. Acad. Sci. USA 81, 2776-2780. https://doi.org/10.1073/pnas.81.9.2776
  15. Ikeda, F., Nishimura, R., Matsubara, T., Hata, K., Reddy, S.V., and Yoneda, T. (2006). Activation of NFAT signal in vivo leads to osteopenia associated with increased osteoclastogenesis and boneresorbing activity. J. Immunol. 177, 2384-2390. https://doi.org/10.4049/jimmunol.177.4.2384
  16. Johnson, R.S., Spiegelman, B.M., and Papaioannou, V. (1992). Pleiotropic effects of a null mutation in the c-fos proto-oncogene. Cell 71, 577-586. https://doi.org/10.1016/0092-8674(92)90592-Z
  17. Kim, H.J., Hong, J.M., Yoon, K.A., Kim, N., Cho, D.W., Choi, J.Y., Lee, I.K., and Kim, S.Y. (2012). Early growth response 2 negatively modulates osteoclast differentiation through upregulation of Id helix-loop-helix proteins. Bone 51, 643-650. https://doi.org/10.1016/j.bone.2012.07.015
  18. Lacey, D.L., Timms, E., Tan, H.L., Kelley, M.J., Dunstan, C.R., Burgess, T., Elliott, R., Colombero, A., Elliott, G., Scully, S., et al. (1998). Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165-176. https://doi.org/10.1016/S0092-8674(00)81569-X
  19. Lee, T.K., Murthy, S.R., Cawley, N.X., Dhanvantari, S., Hewitt, S.M., Lou, H., Lau, T., Ma, S., Huynh, T., Wesley, R.A., et al. (2011). An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers. J. Clin. Invest. 121, 880-892. https://doi.org/10.1172/JCI40433
  20. Leiter, E.H., Kintner, J., Flurkey, K., Beamer, W.G., and Naggert, J.K. (1999). Physiologic and endocrinologic characterization of male sex-biased diabetes in C57BLKS/J mice congenic for the fat mutation at the carboxypeptidease E locus. Endocrine 10, 57-66. https://doi.org/10.1385/ENDO:10:1:57
  21. Morita, S., Kojima, T., and Kitamura, T. (2000). Plat-E: an efficient and stable system for transient packaging of retroviruses. Gene Ther. 7, 1063-1066. https://doi.org/10.1038/sj.gt.3301206
  22. Murthy, S.R., Pacak, K., and Loh, Y.P. (2010). Carboxypeptidase E:elevated expression correlated with tumor growth and metastasis in pheochromocytomas and other cancers. Cell. Mol. Neurobiol. 30, 1377-1381. https://doi.org/10.1007/s10571-010-9592-y
  23. Naggert, J.K., Fricker, L.D., Varlamov, O., Nishina, P.M., Rouille, Y., Steiner, D.F., Carroll, R.J., Paigen, B.J., and Leiter, E.H. (1995). Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nat. Genet. 10, 135-142. https://doi.org/10.1038/ng0695-135
  24. Novack, D.V., and Teitelbaum, S.L. (2008). The osteoclast: friend or foe? Ann. Rev. Pathol. 3, 457-484. https://doi.org/10.1146/annurev.pathmechdis.3.121806.151431
  25. Takayanagi, H., Kim, S., Koga, T., Nishina, H., Isshiki, M., Yoshida, H., Saiura, A., Isobe, M., Yokochi, T., Inoue, J., et al. (2002). Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell 3, 889-901. https://doi.org/10.1016/S1534-5807(02)00369-6
  26. Tang, S.S., Zhang, J.H., Liu, H.X., and Li, H.Z. (2009). PC2/CPEmediated pro-protein processing in tumor cells and its differentiated cells or tissues. Mol. Cell. Endocrinol. 303, 43-49. https://doi.org/10.1016/j.mce.2009.01.020
  27. 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
  28. Teitelbaum, S.L., and Ross, F.P. (2003). Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 4, 638-649. https://doi.org/10.1038/nrg1122
  29. Wang, Z.Q., Ovitt, C., Grigoriadis, A.E., Mohle-Steinlein, U., Ruther,U., and Wagner, E.F. (1992). Bone and haematopoietic defects in mice lacking c-fos. Nature 360, 741-745. https://doi.org/10.1038/360741a0
  30. Zhang, M., Pritchard, M.R., Middleton, F.A., Horton, J.A., and Damron, T.A. (2008). Microarray analysis of perichondral and reserve growth plate zones identifies differential gene expressions and signal pathways. Bone 43, 511-520. https://doi.org/10.1016/j.bone.2008.04.021
  31. Zheng, M., Streck, R.D., Scott, R.E., Seidah, N.G., and Pintar, J.E. (1994). The developmental expression in rat of proteases furin, PC1, PC2, and carboxypeptidase E: implications for early maturation of proteolytic processing capacity. J. Neurosci. 14, 4656-4673.
  32. Zhong, Q., Sridhar, S., Ruan, L., Ding, K.H., Xie, D., Insogna, K., Kang, B., Xu, J., Bollag, R.J., and Isales, C.M. (2005). Multiple melanocortin receptors are expressed in bone cells. Bone 36, 820-831. https://doi.org/10.1016/j.bone.2005.01.020

피인용 문헌

  1. Carboxypeptidase E (CPE) inhibits the secretion and activity of Wnt3a vol.35, pp.50, 2016, https://doi.org/10.1038/onc.2016.173
  2. 筛选高表达CPEΔN的H1299肺癌细胞株 vol.18, pp.6, 2014, https://doi.org/10.3779/j.issn.1009-3419.2015.06.03
  3. Dissecting carboxypeptidase E: properties, functions and pathophysiological roles in disease vol.6, pp.4, 2014, https://doi.org/10.1530/ec-17-0020