The Regulatory Role of 5-Lipoxygenase in Mature Osteoclasts

5-Lipoxygenase에 의한 성숙 파골세포의 조절

  • Noh, A Long Sae Mi (College of Pharmacy, Sookmyung Women's University) ;
  • Moon, Miran (College of Pharmacy, Sookmyung Women's University) ;
  • Jeong, Ji-Eun (College of Pharmacy, Sookmyung Women's University) ;
  • Yim, Mijung (College of Pharmacy, Sookmyung Women's University)
  • Received : 2012.09.01
  • Accepted : 2012.09.10
  • Published : 2012.12.31

Abstract

5-Lipoxygenase (5-LO) catalyzes the formation of two major groups of leukotrienes, LTB4 and cysteinyl leukotrienes (CysLT), and it has been implicated as a promising drug target to treat various inflammatory diseases. Since its role in mature osteoclasts (mOCs) had not been reported, we investigated the effect of 5-LO inhibitors on mOCs. We showed that 5-LO inhibitors dose-dependently decreases the number of mOCs. The effects of 5-LO inhibitors were reversible, suggesting that they did not cause any cellular damages in mOCs. We further demonstrated that the suppression of mOCs by 5-LO inhibitors was caused mainly by disruption of the actin ring formation. Similar effects were shown with CysLT receptor (CysLTR)1 antagonist in mOCs. The mRNA expression of CysLTR1 and the production of CysLT were increased in mOCs. These results indicate that CysLTR1 mediates the suppression of mOCs by 5-LO inhibitors. Taken together, this study demonstrated that 5-LO plays important role in mOCs and possibly a novel therapeutic target for bone resorption diseases.

Keywords

References

  1. Takahashi, N., Akatsu, T., Udagawa, N., Sasaki, T., Yamaguchi, A., Moseley, J. M., Martin, T. J. and Suda, T. : Osteoblastic cells are involved in osteoclast formation. Endocrinology 123, 2600 (1988). https://doi.org/10.1210/endo-123-5-2600
  2. Suda, T., Takahashi, N., Udagawa, N., Jimi, E., Gillespie, M. T. and Martin, T. J. : Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr. Rev. 20, 345 (1999). https://doi.org/10.1210/edrv.20.3.0367
  3. Wong, B. R., Rho, J., Arron, J., Robinson, E., Orlinick, J., Chao, M., Kalachikov, S., Cayani, E., Bartlett, F. S. 3rd, Frankel, W. N., Lee, S. Y. and Choi, Y. : TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun Nterminal kinase in T cells. J. Biol. Chem. 272, 25190 (1997). https://doi.org/10.1074/jbc.272.40.25190
  4. Yasuda, H., Shima, N., Nakagawa, N., Yamaguchi, K., Kinosaki, M., Mochizuki, S., Tomoyasu, A., Yano, K., Goto, M., Murakami, A., Tsuda, E., Morinaga, T., Higashio, K., Udagawa, N., Takahashi, N. and Suda, T. : Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesisinhibitory factor and is identical to TRANCE/RANKL. Proc. Natl. Acad. Sci. U.S.A. 95, 3597 (1998). https://doi.org/10.1073/pnas.95.7.3597
  5. Lacey, D. L., Timms, E., Tan, H. L., Kelley, M. J., Dunstan, C. R., Burgess, T., Elliott, R., Colombero, A., Elliott, G., Scully, S., Hsu, H., Sullivan, J., Hawkins, N., Davy, E., Capparelli, C., Eli, A., Qian, Y. X., Kaufman, S., Sarosi, I., Shalhoub, V., Senaldi, G., Guo, J., Delaney, J. and Boyle, W. J. : Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165 (1998). https://doi.org/10.1016/S0092-8674(00)81569-X
  6. Murphy, R. C., Gijon, M. A. : Biosynthesis and metabolism of leukotrienes. Biochem. J. 405, 379 (2007). https://doi.org/10.1042/BJ20070289
  7. Rådmark, O., Werz, O., Steinhilber, D. and Samuelsson, B. : 5- Lipoxygenase: Regulation of expression and enzyme activity. Trends Biochem. Sci. 32, 332 (2007). https://doi.org/10.1016/j.tibs.2007.06.002
  8. Yokomizo, T., Izumi, T., Chang, K., Takuwa, Y. and Shimizu, T. : A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 387, 620 (1997). https://doi.org/10.1038/42506
  9. Yokomizo, T., Kato, K., Terawaki, K., Izumi, T. and Shimizu, T. : A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders. J. Exp. Med. 192, 421 (2000). https://doi.org/10.1084/jem.192.3.421
  10. Lynch, K. R., O'Neill, G. P., Liu, Q., Im, D. S., Sawyer, N., Metters, K. M., Coulombe, N., Abramovitz, M., Figueroa, D. J., Zeng, Z., Connolly, B. M., Bai, C., Austin, C. P., Chateauneuf, A., Stocco, R., Greig, G. M., Kargman, S., Hooks, S. B., Hosfield, E., Williams, D. L. Jr., Ford-Hutchinson, A. W., Caskey, C. T. and Evans, J. F. : Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 399, 789 (1999). https://doi.org/10.1038/21658
  11. Heise, C. E., O'Dowd, B. F., Figueroa, D. J., Sawyer, N., Nguyen. T., Im, D. S., Stocco, R., Bellefeuille, J. N., Abramovitz, M., Cheng, R., Williams, D. L. Jr., Zeng, Z., Liu, Q., Ma, L., Clements, M. K., Coulombe, N., Liu, Y., Austin, C. P., George, S. R., O'Neill, G. P., Metters, K. M., Lynch, K. R. and Evans, J. F. : Characterization of the human cysteinyl leukotriene 2 receptor. J. Biol. Chem. 275, 30531 (2000). https://doi.org/10.1074/jbc.M003490200
  12. Takasaki, J., Kamohara, M., Matsumoto, M., Saito, T., Sugimoto, T., Ohishi, T., Ishii, H., Ota, T., Nishikawa, T., Kawai, Y., Masuho, Y., Isogai, T., Suzuki, Y., Sugano, S. and Furuichi, K. : The molecular characterization and tissue distribution of the human cysteinyl leukotriene CysLT(2) receptor. Biochem. Biophys. Res. Commun. 274, 316 (2000). https://doi.org/10.1006/bbrc.2000.3140
  13. Rådmark O. and Samuelsson B. : Regulation of the activity of 5-lipoxygenase, a key enzyme in leukotriene biosynthesis. Biochem Biophys Res Commun. 396, 105 (2010). https://doi.org/10.1016/j.bbrc.2010.02.173
  14. Bonewald, L. F., Flynn, M., Qiao, M., Dallas, M. R., Mundy, G. R. and Boyce, B. F. : Mice lacking 5-lipoxygenase have increased cortical bone thickness. Adv. Exp. Med. Biol. 433, 299 (1997).
  15. Cottrell, J. A. and O'Connor, J. P. : Pharmacological inhibition of 5-lipoxygenase accelerates and enhances fracture-healing. J. Bone. Joint. Surg. Am. 91, 2653 (2009). https://doi.org/10.2106/JBJS.H.01844
  16. Manigrasso, M. B. and O'Connor, J. P. : Accelerated fracture healing in mice lacking the 5-lipoxygenase gene. Acta. Orthop. 81, 748 (2010). https://doi.org/10.3109/17453674.2010.533931
  17. Paredes, Y., Massicotte, F., Pelletier, J. P., Martel-Pelletier, J., Laufer, S. and Lajeunesse, D. : Study of the role of leukotriene B4 in abnormal function of human subchondral osteoarthritis osteoblasts: effects of cyclooxygenase and/or 5-lipoxygenase inhibition. Arthritis Rheum. 46, 1804 (2002). https://doi.org/10.1002/art.10357