Skip to main content

17β-Estradiol promotes cell proliferation in rat osteoarthritis model chondrocytes via PI3K/Akt pathway


Osteoarthritis (OA) is the most common cause of musculoskeletal pain and disability. The importance of chondrocytes in the pathogenesis of OA is unequivocal. 17β-estradiol (E2) has a potential protective effect against OA. However, the mechanism of E2 in OA chondrocytes remains unclear. In this study, we investigated the regulative effect of E2 on cell growth and the relationship between E2 and the PI3K/Akt pathway in rat OA model chondrocytes (pretreated with interleukin-1β). We found that E2 induced chondrocyte proliferation, and increased the expression level of Akt simultaneously, especially the expression level of P-Akt. Furthermore, the inhibition of P-Akt could block chondrocyte proliferation induced by E2. These results suggest that PI3K/Akt activation induced by E2 may be an important factor in the mechanism of E2 in cell proliferation in rat OA model chondrocytes, and help further understanding the role of E2 in OA progression.



protein kinase B








estrogen receptor






Akt phosphorylated


phosphoinositide-3-OH kinase


  1. Richette, P., Dumontier, M.F., François M, Tsagris, L., Korwin-Zmijowska, C., Rannou, F. and Corvol, M.T. Dual effects of 17beta-oestradiol on interleukin 1beta-induced proteoglycan degradation in chondrocytes. Ann. Rheum. Dis. 63 (2004) 191–199. DOI: 10.1136/ard.2003.006510.

    Article  PubMed  CAS  Google Scholar 

  2. Chagin, A.S., Chrysis, D., Takigawa, M., Ritzen, E.M. and Sävendahl, L. Locally produced estrogen promotes fetal rat metatarsal bone growth; an effect mediated through increased chondrocyte proliferation and decreased apoptosis. J. Endocrinol. 188 (2006) 193–203. DOI: 10.1677/joe.1.06364.

    Article  PubMed  CAS  Google Scholar 

  3. Héraud, F., Héraud, A. and Harmand, M.F. Apoptosis in normal and osteoarthritic human articular cartilage. Ann. Rheum. Dis. 59 (2000) 959–965. DOI: 10.1136/ard.59.12.959.

    Article  PubMed  Google Scholar 

  4. Kim, D.Y., Taylor, H.W., Moore, R.M., Paulsen, D.B. and Cho, D.Y. Articular chondrocyte apoptosis in equine osteoarthritis. Vet. J. 166 (2003) 52–57. DOI: 10.1016/S1090-0233(02)00305-2.

    Article  PubMed  CAS  Google Scholar 

  5. Cravero, J.D., Carlson, C.S., Im, H.J., Yammani, R.R., Long, D. and Loeser, R.F. Increased expression of the Akt/PKB inhibitor TRB3 in osteoarthritic chondrocytes inhibits insulin-like growth factor 1-mediated cell survival and proteoglycan synthesis. Arthritis Rheum. 60 (2009) 492–500. DOI: 10.1002/art.24225.

    Article  PubMed  CAS  Google Scholar 

  6. Vasconsuelo, A., Milanesi, L. and Boland, R. 17Beta-estradiol abrogates apoptosis in murine skeletal muscle cells through estrogen receptors: role of the phosphatidylinositol 3-kinase/Akt pathway. J. Endocrinol. 196 (2008) 385–397. DOI: 10.1677/JOE-07-0250.

    Article  PubMed  CAS  Google Scholar 

  7. Boland, R., Vasconsuelo, A., Milanesi, L., Ronda, A.C. and de Boland, A.R. 17beta-estradiol signaling in skeletal muscle cells and its relationship to apoptosis. Steroids 73 (2008) 859–863. DOI:10.1016/j.steroids.2007.12.027.

    Article  PubMed  CAS  Google Scholar 

  8. Uenaka, K., Imai, S., Ando, K. and Matsusue, Y. Relation of low-intensity pulsed ultrasound to the cell density of scaffold-free cartilage in a highdensity static semi-open culture system. J. Orthop. Sci. 15 (2010) 816–824. DOI: 10.1007/s00776-010-1544-3.

    Article  PubMed  Google Scholar 

  9. Zhou, P.H., Liu, S.Q. and Peng, H. The effect of hyaluronic acid on IL-1betainduced chondrocyte apoptosis in a rat model of osteoarthritis. J. Orthop. Res. 26 (2008) 1643–1648. DOI: 10.1002/jor.20683.

    Article  PubMed  CAS  Google Scholar 

  10. Zhang, B. and Xia, C. 12-O-tetradecanoylphorbol-1, 3-acetate induces the negative regulation of protein kinase B by protein kinase Calpha during gastric cancer cell apoptosis. Cell. Mol. Biol. Lett. 15 (2010) 377–394. DOI: 10.2478/s11658-010-0014-4.

    Article  PubMed  CAS  Google Scholar 

  11. Hermann, A., Maisel, M., Wegner, F., Liebau, S., Kim, D.W., Gerlach, M., Schwarz, J., Kim, K.S. and Storch, A. Multipotent neural stem cells from the adult tegmentum with dopaminergic potential develop essential properties of functional neurons. Stem Cells 24 (2006) 949–964. DOI: 10.1634/stemcells.2005-0192.

    Article  PubMed  CAS  Google Scholar 

  12. Maneix, L., Beauchef, G., Servent, A., Wegrowski, Y., Maquart, F.X., Boujrad, N., Flouriot, G. and Pujol, J.P., Boumediene, K., Galera, P. and Moslemi, S. 17Beta-oestradiol up-regulates the expression of a functional UDP-glucose dehydrogenase in articular chondrocytes: comparison with effects of cytokines and growth factors. Rheumatology (Oxford) 47 (2008) 281–288. DOI:10.1093/rheumatology/kem323.

    Article  CAS  Google Scholar 

  13. Luo, H.R., Hattori, H., Hossain, M.A., Hester, L., Huang, Y., Lee-Kwon, W., Donowitz, M., Nagata, E. and Snyder, S.H. Akt as a mediator of cell death. Proc. Natl. Acad. Sci. USA 100 (2003) 11712–11717. DOI:10.1073/pnas.1634990100.

    Article  PubMed  CAS  Google Scholar 

  14. O’Toole, A., Moule, S.K., Lockyer, P.J. and Halestrap, A.P. Tumour necrosis factor-alpha activation of protein kinase B in WEHI-164 cells is accompanied by increased phosphorylation of Ser473, but not Thr308. Biochem. J. 359 (2001) 119–127.

    Article  PubMed  Google Scholar 

  15. Mahajan, K., Coppola, D., Challa, S., Fang, B., Chen, Y.A., Zhu, W., Lopez, A.S., Koomen, J., Engelman, R.W., Rivera, C., Muraoka-Cook, R.S., Cheng, J.Q., Schonbrunn, E., Sebti, S.M., Earp, H.S. and Mahajan, N.P. Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One 19 (2010) e96465. DOI:10.1371/journal.pone.0009646.

    Google Scholar 

  16. Tanamas, S.K., Wijethilake, P., Wluka, A.E., Davies-Tuck, M.L., Urquhart, D.M., Wang, Y. and Cicuttini, F.M. Sex hormones and structural changes in osteoarthritis: A systematic review. Maturitas 69 (2011) 141–156. DOI:10.1016/j.maturitas.2011.03.019.

    Article  PubMed  CAS  Google Scholar 

  17. Song, R.X. and Santen, R.J. Apoptotic action of estrogen. Apoptosis 8 (2003) 55–60. DOI: 10.1023/A:1021649019025.

    Article  PubMed  CAS  Google Scholar 

  18. Zhong, M., Carney, D.H., Boyan, B.D. and Schwartz, Z. 17{beta}-estradiol regulates rat growth plate chondrocyte apoptosis through a mitochondrial pathway not involving nitric oxide or MAPKs. Endocrinology 52 (2011) 82–92. DOI:10.1210/en.2010-0509.

    Article  Google Scholar 

  19. Price, J., Zaidi, A.K., Bohensky, J., Srinivas, V., Shapiro, I.M. and Ali, H. Akt-1 mediates survival of chondrocytes from endoplasmic reticuluminduced stress. J. Cell Physiol. 222 (2010) 502–508. DOI: 10.1002/jcp.22001.

    PubMed  CAS  Google Scholar 

  20. Beier, F. and Loeser, R.F. Biology and pathology of Rho GTPase, PI-3 kinase-Akt, and MAP kinase signaling pathways in chondrocytes. J. Cell Biochem. 110 (2010) 573–580. DOI:10.1002/jcb.22604.

    Article  PubMed  CAS  Google Scholar 

  21. Bredfeldt, T.G., Greathouse, K.L., Safe, S.H., Hung, M.C., Bedford, M.T. and Walker, C.L. Xenoestrogen-induced regulation of EZH2 and histone methylation via estrogen receptor signaling to PI3K/AKT. Mol. Endocrinol. 24 (2010) 993–1006. DOI:10.1210/me.2009-0438.

    Article  PubMed  CAS  Google Scholar 

  22. Björnström, L. and Sjöberg, M. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol. Endocrinol. 19 (2005) 833–842. DOI:10.1210/me.2004-0486.

    Article  PubMed  Google Scholar 

  23. Levin, E.R. Cellular functions of plasma membrane estrogen receptors. Steroids 67 (2002) 471–475. DOI:10.1016/S0039-128X(01)00179-9.

    Article  PubMed  CAS  Google Scholar 

  24. Pietras, R.J., Levin, E.R. and Szego, C.M. Estrogen receptors and cell signaling. Science 310 (2005) 51–53 (author reply). DOI:10.1126/science.310.5745.51.

    Article  PubMed  CAS  Google Scholar 

  25. Le Romancer, M., Treilleux, I., Leconte, N., Robin-Lespinasse, Y., Sentis, S., Bouchekioua-Bouzaghou, K., Goddar, S., Gobert-Gosse, S. and Corbo, L. Regulation of estrogen rapid signaling through arginine methylation by PRMT1. Mol. Cell 31 (2008) 212–221. DOI:10.1016/j.molcel.2008.05.025.

    Article  PubMed  Google Scholar 

  26. Simoncini, T., Hafezi-Moghadam, A., Brazil, D.P., Ley, K., Chin, W.W. and Liao, J.K. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407 (2000) 538–541. DOI:10.1038/35035131.

    Article  PubMed  CAS  Google Scholar 

  27. Li, X., Zhang, S. and Safe, S. Activation of kinase pathways in MCF-7cells by 17{beta}-estradiol and structurally diverse estrogenic compounds. J. Steroid Biochem. Mol. Biol. 98 (2006) 122–132. DOI:10.1016/j.jsbmb.2005.08.018.

    Article  PubMed  CAS  Google Scholar 

  28. Smith, J.A., Zhang, R., Varma, A.K., Das, A., Ray, S.K. and Banik, N.L. Estrogen partially down-regulates PTEN to prevent apoptosis in VSC4.1 motoneurons following exposure to IFN-gamma. Brain Res. 8 (2009) 163–170. DOI:10.1016/j.brainres.2009.09.016.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Chun Xia or Bing Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, J.G., Xia, C., Zheng, X.P. et al. 17β-Estradiol promotes cell proliferation in rat osteoarthritis model chondrocytes via PI3K/Akt pathway. Cell Mol Biol Lett 16, 564 (2011).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:

Key words