Lysophosphatidic Acid Inhibits Nitric Oxide-induced Apoptosis via p70S6kinase Pathway in Rabbit Articular Chondrocytes

  • Yu, Seon-Mi (Department of Biological Sciences, College of Natural Sciences, Kongju National University) ;
  • Kim, Song-Ja (Department of Biological Sciences, College of Natural Sciences, Kongju National University)
  • ;
  • 김송자 (국립공주대학교 자연과학대학 생명과학과)
  • Published : 2009.12.31

Abstract

Lysophosphatidic Acid (LPA) is a bioactive lysophospholipid that is a potent signaling molecule able to provoke a variety of cellular responses in many cell types such as differentiation, inflammation and apoptosis. In this study, we have investigated the effect of LPA on Nitric oxide (NO)-induced apoptosis in rabbit articular chondrocytes. LPA dramatically reduced NO induced apoptosis of chondrocytes determined by phase contrast microscope and MTT assay. When chondrocytes alone treated with LPA, LPA induced phosphorylation of p70S6kinase, a serine/threonine kinase that acts downstream of phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphoinositide-dependent kinase-1 (PDK-1) in the PI3 kinase pathway, dose-dependently detected by Western blot analysis. Phosphorylation of p70S6k with LPA was reduced expression of p53 in NO-induced apoptosis of chondrocytes. Also, inhibition of p70S6kinase with rapamycin was enhanced expression of p53 in chondrocytes. Our findings collectively suggest that LPA regulates NO induced apoptosis through p70S6kinase pathway in rabbit articular chondrocytes.

Keywords

References

  1. Amin AR and Abramson SB. Curr Opin Rheumatol. 1998. 10: 263-268. https://doi.org/10.1097/00002281-199805000-00018
  2. Caverzasio J, Palmer G, Suzuki A, Bonjour JP. Evidence for the involvement of two pathways in activation of extracellular signal-regulated kinase (Erk) and cell proliferation by Gi and Gq protein-coupled receptors in osteoblast-like cells. J Bone Miner Res. 2000. 15: 1697-1706. https://doi.org/10.1359/jbmr.2000.15.9.1697
  3. DeLise AM, Fischer L, Tuan RS. Cellular interactions and signaling in cartilage development. Osteoarthritis Cartilage 2000. 5: 345-351.
  4. Denko CW, Malemud CJ. Frontiers Biosci. 1999. 4: 686-693. https://doi.org/10.2741/A465
  5. Deng W, Balazs L, Wang DA, Van Middlesworth L, Tigyi G, Johnson LR. Lysophosphatidic acid protects and rescues intestinal epithelial cells from radiationand chemotherapyinduced apoptosis. Gastroenterology 2002. 123: 206-216. https://doi.org/10.1053/gast.2002.34209
  6. Eichholz T, Jlink K, Fahrnefort I, Moolenaar WH. The bioactive phospholipid lysophosphatidic acid is released from activated platelets. Biochem J. 1993. 291: 677-680. https://doi.org/10.1042/bj2910677
  7. Fang X, Schummer M, Mao M, Yu S, Tabassam FH, Swaby R, Hasegawa Y, Tanyi JL, LaPushin R, Eder A, Jaffe R, Erickson J, Mills GB. Lysophosphatidic acid is a bioactive mediator in ovarian cancer. Biochem Biophys Acta. 2002. 1582: 257-264. https://doi.org/10.1016/S1388-1981(02)00179-8
  8. Fourcade O, SimonMF, Viode C, Rugani N, Leballe F, Ragab A. Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells. Cell 1995. 80: 919-927. https://doi.org/10.1016/0092-8674(95)90295-3
  9. Hama K, Aoki J, Fukaya M, Kishi Y, Sakai T, Suzuki R, Ohta H, Yamori T, Watanabe M, Chun J, Arai H. Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1. J Biol Chem. 2004. 279: 17634-17639. https://doi.org/10.1074/jbc.M313927200
  10. Kim SJ, Ju JW, Oh CD, Yoon YM, Song WK, Kim JH, Yoo YJ, Bang OS, Kang SS, Chun JS. ERK-1/2 and p38 kinase oppositely regulate nitric oxide-induced apoptosis of chondrocytes in association with p53, caspase-3, and differentiation status. J Biol Chem. 2002a. 277: 1332-1339. https://doi.org/10.1074/jbc.M107231200
  11. Kim SJ, Kim HG, Oh CD, Hwang SG, Song WK, Yoo YJ, Kang SS, Chun JS. p38 kinase-dependent and -independent Inhibition of protein kinase C zeta and -alpha regulates nitric oxide-induced apoptosis and dedifferentiation of articular chondrocytes. J Biol Chem. 2002b. 277: 30375-30381. https://doi.org/10.1074/jbc.M205193200
  12. Martel PJ, Alaaeddine N, Pelletier JP. Frontiers Biosci. 1999. 4: 694-703. https://doi.org/10.2741/Martel
  13. Mills GB, Moolenaar WH. The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer 2003. 3: 582-591. https://doi.org/10.1038/nrc1143
  14. Moolenaar WH. Bioactive lysophospholipids and their G proteincoupled receptors. Exp Cell Res. 1999. 253: 230-238. https://doi.org/10.1006/excr.1999.4702
  15. Moolenaar WH. Development and current understanding of bioactive lysophospholipids. Ann NY Acad Sci. 2000. 905: 1-10.
  16. Panupinthu N, Zhao L, Possmayer F, Ke HZ, Sims SM, Dixon SJ. P2X7 nucleotide receptors mediate blebbing in osteoblasts through a pathway involving lysophosphatidic acid. J Biol Chem. 2007. 282: 3403-3412. https://doi.org/10.1074/jbc.M605620200
  17. Poole S. An introduction to the pathophysiology of osteoarthritis. Front Biosci. 1999. 4: 662-670. https://doi.org/10.2741/Poole
  18. Ren J, Xiao YJ, Singh LS, Zhao X, Zhao Z, Feng L, Rose TM, Prestwich GD, Xu Y. Lysophosphatidic acid is constitutively produced by human peritoneal mesothelial mesothelial cells and enhances adhesion, migration, and invasion of ovarian cancer cells. Cancer Res. 2006. 66: 3006-3014. https://doi.org/10.1158/0008-5472.CAN-05-1292
  19. Sandell LJ, Adler P. Developmental patterns of cartilage. Front Biosci. 1999.15: D731-742.
  20. Stadler J, Stefanovic-Racic M, Billiar TR, Curran RD, McIntyre LA, Georgescu HI, Simmons RL, Evans, CH. J Immunol. 1991. 147: 3915-3920.
  21. Van Corven EJ, Groenink A, Jalink K, Eichholtz T, Moolenaar WH. Lysophosphatidate-induced cell proliferation: identification and dissection of signaling pathways mediated by G proteins. Cell 1989. 59: 45-54. https://doi.org/10.1016/0092-8674(89)90868-4