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Localization of erythropoietin in and around growing cartilage

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Abstract

Erythropoietin (EPO) is known to be a hematopoietic growth factor and a regulator of red blood cell production. Recently, EPO has also been reported to function as a tissue-protective cytokine and as an angiogenesis promoting factor. EPO is mainly regulated by hypoxia through the action of hypoxia inducible factors (HIF-1α and HIF-2α). The localization of the EPO protein and the HIF-2α protein were immunohistochemically analyzed in developing porcine embryos. Both proteins were localized in developing cartilage tissue. HIF-2α and EPO protein were expressed in the peripheral chondrocytes of cartilage anlagen, in the perichondrium and in the cell condensations that will eventually differentiate into cartilage tissue. The results of this study reveal that EPO might play a role as a survival factor or as a mitogen in developing cartilage tissue. Moreover, the presence of both proteins at the same locations supports the hypothesis that EPO expression is regulated by HIF-2α.

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References

  1. Shum L, Nuckolls G (2002) The life cycle of chondrocytes in the developing skeleton. Arthritis Res 4:94–106. doi:10.1186/ar396

    Article  CAS  PubMed  Google Scholar 

  2. Pfander D, Gelse K (2007) Hypoxia and osteoarthritis: how chondrocytes survive hypoxic environments. Curr Opin Rheumatol 19:457–462. doi:10.1097/BOR.0b013e3282ba5693

    Article  CAS  PubMed  Google Scholar 

  3. Ratcliffe PJ (2007) HIF-1 and HIF-2: working alone or together in hypoxia? J Clin Invest 117:862–865. doi:10.1172/JCI31750

    Article  CAS  PubMed  Google Scholar 

  4. Wang Y, Wan C, Gilbert SR, Clemens TL (2007) Oxygen sensing and osteogenesis. Ann N Y Acad Sci 1117:1–11. doi:10.1196/annals.1402.049

    Article  CAS  PubMed  Google Scholar 

  5. Schipani E (2006) Hypoxia and HIF-1 alpha in chondrogenesis. Ann N Y Acad Sci 1068:66–73. doi:10.1196/annals.1346.009

    Article  CAS  PubMed  Google Scholar 

  6. Schipani E, Ryan HE, Didrickson S, Kobayashi T, Knight M, Johnson RS (2001) Hypoxia in cartilage: HIF-1 alpha is essential for chondrocyte growth arrest and survival. Genes Dev 15:2865–2876. doi:10.1101/gad.934301

    CAS  PubMed  Google Scholar 

  7. Krantz SB (1991) Erythropoietin. Blood 77:419–434

    CAS  PubMed  Google Scholar 

  8. Arcasoy MO (2008) The non-haematopoietic biological effects of erythropoietin. Br J Haematol 141:14–31. doi:10.1111/j.1365-2141.2008.07014.x

    Article  CAS  PubMed  Google Scholar 

  9. Ogilvie M, Yu XB, Nicolas-Metral V, Pulido SM, Liu C, Ruegg UT, Noguchi CT (2000) Erythropoietin stimulates proliferation and interferes with differentiation of myoblasts. J Biol Chem 275:39754–39761. doi:10.1074/jbc.M004999200

    Article  CAS  PubMed  Google Scholar 

  10. Juul SE, Ledbetter DJ, Joyce AE, Dame C, Christensen RD, Zhao Y, DeMarco V (2001) Erythropoietin acts as a trophic factor in neonatal rat intestine. Gut 49:182–189. doi:10.1136/gut.49.2.182

    Article  CAS  PubMed  Google Scholar 

  11. Knabe W, Siren AL, Ehrenreich H, Kuhn HJ (2005) Expression patterns of erythropoietin and its receptor in the developing spinal cord and dorsal root ganglia. Anat Embryol 210:209–219. doi:10.1007/s00429-005-0019-3

    Article  CAS  PubMed  Google Scholar 

  12. Eckardt KU, Bernhardt W, Willam C, Wiesener M (2007) Hypoxia-inducible transcription factors and their role in renal disease. Semin Nephrol 27:363–372. doi:10.1016/j.semnephrol.2007.02.007

    Article  CAS  PubMed  Google Scholar 

  13. Kertesz N, Wu J, Chen THP, Sucov HM, Wu H (2004) The role of erythropoietin in regulating angiogenesis. Dev Biol 276:101–110. doi:10.1016/j.ydbio.2004.08.025

    Article  CAS  PubMed  Google Scholar 

  14. Fliser D, Bahlmann FH (2008) Erythropoietin and the endothelium—a promising link? Eur J Clin Invest 38:457–461. doi:10.1111/j.1365-2362.2008.01968.x

    Article  CAS  PubMed  Google Scholar 

  15. Holstein JH, Menger MD, Scheuer C, Meier C, Culemann U, Wirbel RJ, Garcia P, Pohlemann T (2007) Erythropoietin (EPO)—EPO-receptor signaling improves early endochondral ossification and mechanical strength in fracture healing. Life Sci 80:893–900. doi:10.1016/j.lfs.2006.11.023

    Article  CAS  PubMed  Google Scholar 

  16. Hayes AJ, MacPherson S, Morrison H, Dowthwaite G, Archer CW (2001) The development of articular cartilage: evidence for an appositional growth mechanism. Anat Embryol 203:469–479. doi:10.1007/s004290100178

    Article  CAS  PubMed  Google Scholar 

  17. Asanbaeva A, Masuda K, Thonar E, Klisch SM, Sah RL (2008) Regulation of immature cartilage growth by IGF-I, TGF-beta 1, BMP-7, and PDGF-AB: role of metabolic balance between fixed charge and collagen network. Biomech Model Mechanobiol 7:263–276. doi:10.1007/s10237-007-0096-8

    Article  PubMed  Google Scholar 

  18. Gonzalez L, Anderson I, Deane D, Summers C, Buxton D (2001) Detection of immune system cells in paraffin wax-embedded ovine tissues. J Comp Pathol 125:41–47. doi:10.1053/jcpa.2001.0475

    Article  CAS  PubMed  Google Scholar 

  19. Hicks DJ, Johnson L, Mitchell SM, Gough J, Cooley WA, La Ragione RM, Spencer YI, Wangoo A (2006) Evaluation of zinc salt based fixatives for preserving antigenic determinants for immunohistochemical demonstration of murine immune system cell markers. Biotech Histochem 81:23–30. doi:10.1080/10520290600725375

    Article  CAS  PubMed  Google Scholar 

  20. Casteleyn CR, Breugelmans S, Simoens P, Van den Broeck W (2008) Morphological and immunological characteristics of the bovine temporal lymph node and hemal node. Vet Immunol Immunopathol 126:339–350. doi:10.1016/j.vetimm.2008.09.010

    Article  PubMed  Google Scholar 

  21. Giaccia AJ, Simon MC, Johnson R (2004) The biology of hypoxia: the role of oxygen sensing in development, normal function, and disease. Genes Dev 18:2183–2194. doi:10.1101/gad.1243304

    Article  CAS  PubMed  Google Scholar 

  22. Rankin EB, Biju MP, Liu QD, Unger TL, Rha J, Johnson RS, Simon MC, Keith B, Haase VH (2007) Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest 117:1068–1077. doi:10.1172/JCI30117

    Article  CAS  PubMed  Google Scholar 

  23. Dealy CN, Beyer EC, Kosher RA (1994) Expression patterns of messenger-RNAs for the gap junction proteins connexin43 and connexin42 suggest their involvement in chick limb morphogenesis and specification of the arterial vasculature. Dev Dyn 199:156–167. doi:10.1002/aja.1001990208

    CAS  PubMed  Google Scholar 

  24. Kang SS (2008) Regulation of early steps of chondrogenesis in the developing limb. Anim Cells Syst 12:1–9. doi:10.1002/0470846658.ch3

    CAS  Google Scholar 

  25. Krysko DV, Leybaert L, Vandenabeele P, D’Herde K (2005) Gap junctions and the propagation of cell survival and cell death signals. Apoptosis 10:459–469. doi:10.1007/s10495-005-1875-2

    Article  CAS  PubMed  Google Scholar 

  26. Rodriguez-Sinovas A, Cabestrero A, Lopez D, Torre I, Morente M, Abellan A, Miro E, Ruiz-Meana M, Garcia-Dorado D (2007) The modulatory effects of connexin 43 on cell death/survival beyond cell coupling. Prog Biophys Mol Biol 94:219–232. doi:10.1016/j.pbiomolbio.2007.03.003

    Article  CAS  PubMed  Google Scholar 

  27. Lin JHC, Weigel H, Cotrina ML, Liu SJ, Bueno E, Hansen AJ, Hansen TW, Goldman S, Nedergaard M (1998) Gap-junction-mediated propagation and amplification of cell injury. Nat Neurosci 1:494–500. doi:10.1038/2210

    Article  CAS  PubMed  Google Scholar 

  28. Goldman SA, Nedergaard M (2002) Erythropoietin strikes a new cord. Nat Med 8:785–787. doi:10.1038/nm0802-785

    Article  CAS  PubMed  Google Scholar 

  29. Gorio A, Gokmen N, Erbayraktar S, Yilmaz O, Madaschi L, Cichetti C, Di Giulio AM, Vardar E, Cerami A, Brines M (2002) Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci USA 99:9450–9455. doi:10.1073/pnas.142287899

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors wish to thank Jurgen De Craene and Lobke De Bels for their excellent technical assistance. This project was financially supported by the Special Research Fund (BOF) project (05B01906) of Ghent University.

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Correspondence to Ward De Spiegelaere.

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De Spiegelaere, W., Cornillie, P. & Van den Broeck, W. Localization of erythropoietin in and around growing cartilage. Mol Cell Biochem 337, 287–291 (2010). https://doi.org/10.1007/s11010-009-0310-3

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  • DOI: https://doi.org/10.1007/s11010-009-0310-3

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