Erythropoietin reduces the degree of arthritis caused by type II collagen in the mouse
Corresponding Author
Salvatore Cuzzocrea
University of Messina, Messina, Italy
Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario Via C. Valeria, Gazzi, 98100 Messina, ItalySearch for more papers by this authorNimesh S. A. Patel
The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, London UK
Search for more papers by this authorChristoph Thiemermann
The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, London UK
Search for more papers by this authorCorresponding Author
Salvatore Cuzzocrea
University of Messina, Messina, Italy
Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario Via C. Valeria, Gazzi, 98100 Messina, ItalySearch for more papers by this authorNimesh S. A. Patel
The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, London UK
Search for more papers by this authorChristoph Thiemermann
The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, London UK
Search for more papers by this authorAbstract
Objective
Erythropoietin (EPO) is a potent stimulator of erythroid progenitor cells, and its expression is enhanced by hypoxia. The aim of this study was to investigate the effect of EPO on collagen-induced arthritis (CIA) in the mouse.
Methods
CIA was induced by intradermal injection of bovine type II collagen (CII) and Freund's complete adjuvant. Starting on day 25, some of the mice with CIA received daily subcutaneous injections of EPO (1,000 units/kg). Two other groups of mice received sham treatment alone or sham treatment followed by EPO treatment, respectively. Arthritis was assessed clinically, radiologically, and histologically. Cytokine and chemokine levels were measured, and neutrophil infiltration into inflamed joints was quantitated. Immunohistochemistry studies were performed to measure protein nitrosylation. Chondrocyte apoptosis was assessed by TUNEL assay.
Results
Macroscopic clinical evidence of CIA first appeared as periarticular erythema and edema in the hind paws. The incidence of CIA was 100% by day 27 in the CII-challenged mice, and the severity of CIA progressed over a 35-day period, with radiographic evaluation revealing focal resorption of bone. Histopathologic features of CIA included erosion of the cartilage at the joint margins. Treatment with EPO starting at the onset of arthritis (day 25) ameliorated the clinical signs on days 26–35 and improved histologic status in the joints and paws. The degree of oxidative and nitrosative damage was significantly reduced in EPO-treated mice as indicated by decreased nitrotyrosine formation and poly(ADP-ribose) polymerase activation. Plasma levels of the proinflammatory cytokine tumor necrosis factor α were also significantly reduced by EPO treatment. In addition, EPO reduced the levels of apoptosis in chondrocytes in articular cartilage, as indicated by decreased TUNEL staining.
Conclusion
These findings demonstrate that EPO exerts an antiinflammatory effect during chronic inflammation and is able to ameliorate the tissue damage associated with CIA.
REFERENCES
- 1 Harris ED Jr. Rheumatoid arthritis: pathophysiology and implications for therapy [review] [published erratum appears in N Engl J Med 1990;323:996]. N Engl J Med 1990; 322: 1277–89.
- 2 Stuart JM, Townes AS, Kang AH. Collagen autoimmune arthritis. Annu Rev Immunol 1984; 2: 199–218.
- 3 Holmdahl RM, Andersson TJ, Goldschmidt K, Gustafsson L, Jansson L, Mo JA. Type II collagen autoimmunity in animals and provocations leading to arthritis. Immunol Rev 1990; 118: 193–232.
- 4 Larsen CG, Anderson AO, Appella A, Oppenheim JJ, Matsushima K. Identity of the chemotactic cytokine for T-lymphocyte with neutrophil activating protein (NAP-1): a candidate interleukin-8. Science 1989; 243: 1464–6.
- 5 Schall TJ, Bacon K, Toy KJ, Goeddel DV. Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Nature 1990; 347: 669–71.
- 6 Tanaka Y, Adams DH, Hubscher S, Hirano H, Siebenlist U, Shaw S. T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-1β. Nature 1993; 361: 79–82.
- 7 Taub DD, Conlon K, Lloyd AR, Oppenheim JJ, Kelvin DJ. Preferential migration of activated CD4+ and CD8+ T cells in response to MIP-1α and MIP-1β. Science 1993; 260: 355–8.
- 8 Sasaki R, Masuda S, Nagao M. Erythropoietin: multiple physiological functions and regulation of biosynthesis. Biosci Biotechnol Biochem 2000; 64: 1775–93.
- 9 Sadamoto Y, Igase K, Sakanaka M, Sato K, Otsuka H, Sakaki S, et al. Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochem Biophys Res Commun 1998; 253: 26–32.
- 10 Sakanaka M, Wen TC, Matsuda S, Masuda S, Morishita E, Nagao M, et al. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci U S A 1998; 95: 4635–40.
- 11 Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R. Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 1997; 76: 105–16.
- 12 Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 2000; 97: 10526–31.
- 13 Shingo T, Sorokan ST, Shimazaki T, Weiss S. Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J Neurosci 2001; 21: 9733–43.
- 14 Bernaudin M, Nedelec AS, Divoux D, MacKenzie ET, Petit E, Schumann-Bard P. Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. J Cereb Blood Flow Metab 2002; 22: 393–403.
- 15 Prass K, Scharff A, Ruscher K, Lowl D, Muselmann C, Victorov I, et al. Hypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin. Stroke 2003; 34: 1981–6.
- 16 Parsa CJ, Matsumoto A, Kim J, Riel RU, Pascal LS, Walton GB, et al. A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest 2003; 112: 999–1007.
- 17 Cartwright GE. The anemia of chronic disorders. Semin Hematol 1966; 3: 351–75.
- 18 Bush JA, Ashenbrucker H, Cartwright GE, Wintrobe MM. The anemia of infection. XX. The kinetics of iron metabolism in the anemia associated with chronic infection. J Clin Invest 1956; 35: 89–97.
- 19 Chodos RB, Emerson CP, Miller A, Ross JF. Studies of the anemia and iron metabolism in cancer. J Clin Invest 1956; 35: 1248–62.
- 20 Freireich EJ, Ross JF, Bayles TB, Emerson CP, Finch SC. Radioactive iron metabolism and erythrocyte survival studies of the mechanism of the anemia associated with rheumatoid arthritis. J Clin Invest 1957; 36: 1043–58.
- 21
Campbell IK,
Hamilton JA,
Wicks IP.
Collagen-induced arthritis in C57BL/6 (H-2b) mice: new insights into an important disease model of rheumatoid arthritis.
Eur J Immunol
2000;
30:
1568–75.
10.1002/1521-4141(200006)30:6<1568::AID-IMMU1568>3.0.CO;2-R CAS PubMed Web of Science® Google Scholar
- 22 Szabo C, Virag L, Cuzzocrea S, Scott GS, Hake P, O'Connor M, et al. Protection against peroxynitrite-induced fibroblast injury and arthritis development by inhibition of poly (ADP-ribose) synthetase. Proc Natl Acad Sci U S A 1998; 9: 3867–72.
- 23 Cuzzocrea S, Zingarelli B, Costantino G, Caputi AP. Beneficial effects of Mn(III) tetrakis (4-benzoic acid) porphyrin (MnTBAP), a superoxide dismutase mimetic, in carrageenan-induced pleurisy. Free Radic Biol Med 1999; 26: 25–33.
- 24 Kasama T, Strieter RM, Lukacs NW, Burdick MD, Kunke SL. Regulation of neutrophil-derived chemokine expression by IL-10. J Immunol 1994; 152: 3559–69.
- 25 Goldblum SE, Wu KM, Jay M. Lung myeloperoxidase as a measure of pulmonary leukostasis in rabbits. J Appl Physiol 1985; 59: 1978–85.
- 26 Cuzzocrea S, Riley DP, Caputi AP, Salvemini D. Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacol Rev 2001; 53: 135–59.
- 27 Tiku ML, Shah R, Allison GT. Evidence linking chondrocyte lipid peroxidation to cartilage matrix protein degradation: possible role in cartilage aging and the pathogenesis of osteoarthritis. J Biol Chem 2000; 275: 20069–76.
- 28 Sorsa T, Saari H, Konttinen YT, Suomalainen K, Lindy S, Uitto VJ. Non-proteolytic activation of latent human neutrohil collagenase and its role in matrix destruction in periodontal diseases. Int J Tissue React 1989; 11: 153–9.
- 29 Monboisse JC, Bellon G, Randoux A, Dufer J, Borel JP. Activation of human neutrophils by type I collagen: requirement of two different sequences. Biochem J 1990; 270: 459–62.
- 30 Monboisse JC, Bellon G, Dufer J, Randoux A, Borel JP. Collagen activates superoxide anion production by human polymorphonuclear neutrophils. Biochem J 1987; 246: 599–603.
- 31 Volk T, Gerst J, Faust-Belbe G, Stroehmann A, Kox WJ. Monocyte stimulation by reactive oxygen species: role of superoxide and intracellular Ca2+. Inflamm Res 1999; 48: 544–9.
- 32 Carteron NL. Cytokines in rheumatoid arthritis: trials and tribulations. Mol Med Today 2000; 6: 315–23.
- 33 Maini RN. A perspective on anti-cytokine and anti-T cell-directed therapies in rheumatoid arthritis. Clin Exp Rheumatol 1995; 12: S35–40.
- 34 Moreland LW, McCabe DP, Caldwell JR, Sack M, Weisman M, Henry G, et al. Phase I/II trial of recombinant methionyl human tumor necrosis factor binding protein PEGylated dimer in patients with active refractory rheumatoid arthritis. J Rheumatol 2000; 27: 601–9.
- 35 Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan Z, Emery P, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 1998; 41: 2196–204.
- 36 Eiserich JP, Hristova M, Cross CE. Formation of nitric oxide derivatives catalysed by myeloperoxidase in neutrophils. Nature 1998; 391: 393–7.
- 37 Halliwell B. What nitrates tyrosine? Is nitrotyrosine specific as a biomarker of peroxinitrite formation in vivo? FEBS Lett 1997; 411: 157–60.
- 38 Cuzzocrea S, Zingarelli B, Gilard E, Hake P, Salzman AL, Szabo C. Anti-inflammatory effects of mercaptoethylguanidine, a combined inhibitor of nitric oxide synthase and peroxynitrite scavenger, in carrageenan-induced models of inflammation. Free Radic Biol Med 1998; 24: 450–9.
- 39 Cuzzocrea S, Costantino G, Mazzon E, Caputi AP. Beneficial effects of raxofelast (IRFI 016), a new hydrophilic vitamin E-like antioxidant, in carrageenan-induced pleurisy. Br J Pharmacol 1999; 126: 407–14.
- 40 Salvemini D, Wang ZQ, Stern MK, Currie MG, Misko TP. Peroxynitrite decomposition catalysts: therapeutics for peroxynitrite-mediated pathology. Proc Natl Acad Sci U S A 1998; 95: 2659–63.
- 41 Ialenti A, Moncada S, di Rosa M. Modulation of adjuvant arthritis by endogenous nitric oxide. Br J Pharmacol 1993; 110: 701–6.
- 42 Squadrito F, Altavilla D, Squadrito G, Campo GM, Arlotta M, Quartarone C, et al. Recombinant human erythropoietin inhibits iNOS activity and reverts vascular dysfunction in splanchnic artery occlusion shock. Br J Pharmacol 1999; 127: 482–8.
- 43 Hirayama A, Nagase S, Gotoh M, Ueda A, Ishizu T, Yoh K, et al. Reduced serum hydroxyl radical scavenging activity in erythropoietin therapy resistant renal anemia. Free Radic Res 2002; 36: 1155–61.
- 44 Akisu M, Tuzun S, Arslanoglu S, Yalaz M, Kultursay N. Effect of recombinant human erythropoietin administration on lipid peroxidation and antioxidant enzyme(s) activities in preterm infants. Acta Med Okayama 2001; 55: 357–62.
- 45 Szabo C, Dawson VL. Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci 1998; 19: 287–98.
- 46 Lautier D, Lagueux J, Thibodeau J, Menard L, Poirier GG. Molecular and biochemical features of poly (ADP-ribose) metabolism. Mol Cell Biochem 1993; 122: 171–93.
- 47 Cuzzocrea S, Zingarelli B, Gilad E, Hake P, Salzman AL, Szabo C. Protective effects of 3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthase in a carrageenan-induced model of local inflammation. Eur J Pharmacol 1998; 342: 67–76.
- 48 Chong ZZ, Kang JQ, Maiese K. Erythropoietin is a novel vascular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases. Circulation 2002; 106: 2973–9.
- 49 Patel NS, Sharples EJ, Cuzzocrea S, Chatterjee PK, Britti D, Yaqoob MM, et al. Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo. Kidney Int 2004; 66: 983–9.
- 50 Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296: 1655–7.
- 51 Abdelrahman M, Sharples EJ, McDonald MC, Collin M, Patel NS, Yaqoob MM, et al. Erythropoietin attenuates the tissue injury associated with hemorrhagic shock and myocardial ischemia. Shock 2004; 22: 63–9.
