The Role of Bone Marrow Edema and Lymphangiogenesis in Inflammatory-Erosive Arthritis

  • Edward M. Schwarz
  • Steven T. Proulx
  • Christopher T. Ritchlin
  • Brendan F. Boyce
  • Lianping Xing
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 658)

Abstract

A common feature of autoimmune diseases is the perpetual production of macrophage, dendritic and/or osteoclast effector cells, which mediate parenchymal tissue destruction in end organs. In support of this, we have demonstrated previously that patients and mice with inflammatory-erosive arthritis have a marked increase in circulating CD11b+ precursor cells, which are primed for osteoclastogenesis, and that this increase in osteoclast precursors (OCPs) is due to systemically increased TNF production. From these data, we proposed a unifying hypothesis to explain these osteoimmunologic findings during the pathogenesis of inflammatory-erosive arthritis, which has three postulates: (1) myelopoiesis chronically induced by TNF has profound effects on the bone marrow and joint tissues that should be evident from a longitudinal MRI; (2) TNF alters the chemokine/chemokine receptor axis in the bone marrow to stimulate OCP release into the blood, and (3) OCP-mediated lymphangiogenesis occurs in the end organ as a compensatory mechanism to drain the inflammation and remove by-products of joint catabolism. Here, we describe our recent experimental findings that support these hypotheses and speculate on how this information can be used as diagnostic biomarkers and tools to discover novel therapies to treat patients with inflammatory-erosive arthritis.

Keywords

Inflammatory arthritis Lymphangiogenesis In vivo imaging 3D-MRI 

References

  1. 1.
    Appel, H., Kuhne, M., Spiekermann, S., Kohler, D., Zacher, J., Stein, H. et al. (2006). Immunohistochemical analysis of hip arthritis in ankylosing spondylitis: evaluation of the bone-cartilage interface and subchondral bone marrow. Arthritis Rheum, 54(6):1805–1813.CrossRefPubMedGoogle Scholar
  2. 2.
    Appel, H., Loddenkemper, C., Grozdanovic, Z., Ebhardt, H., Dreimann, M., Hempfing, A. et al. (2006). Correlation of histopathological findings and magnetic resonance imaging in the spine of patients with ankylosing spondylitis. Arthritis Res Ther, 8(5):R143CrossRefPubMedGoogle Scholar
  3. 3.
    Anandarajah, A.P., Schwarz, E.M., Totterman, S., Monu, J., Feng, C.Y., Shao, T. et al. (2008). The effect of etanercept on osteoclast precursor frequency and enhancing bone marrow oedema in patients with psoriatic arthritis. Ann Rheum Dis, 67(3):296–301.CrossRefPubMedGoogle Scholar
  4. 4.
    Benton, N., Stewart, N., Crabbe, J., Robinson, E., Yeoman, S., & McQueen, F.M. (2004). MRI of the wrist in early rheumatoid arthritis can be used to predict functional outcome at 6 years. Ann Rheum Dis, 63(5):555–561.CrossRefPubMedGoogle Scholar
  5. 5.
    Boyce, B.F., Schwarz, E.M., & Xing, L. (2006). Osteoclast precursors: cytokine-stimulated immunomodulators of inflammatory bone disease. Curr Opin Rheumatol, 18(4):427–432.CrossRefPubMedGoogle Scholar
  6. 6.
    Bradfield, P.F., Amft, N., Vernon-Wilson, E., Exley, A.E., Parsonage, G., Rainger, G.E. et al. (2003). Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue. Arthritis Rheum, 48(9):2472–2482.CrossRefPubMedGoogle Scholar
  7. 7.
    Conaghan, P.G., McQueen, F.M., Peterfy, C.G., Lassere, M.N., Ejbjerg, B., Bird, P. et al. (2005). The evidence for magnetic resonance imaging as an outcome measure in proof-of-concept rheumatoid arthritis studies. J Rheumatol, 32(12):2465–2469.PubMedGoogle Scholar
  8. 8.
    Dohn, U.M., Ejbjerg, B.J., Court-Payen, M., Hasselquist, M., Narvestad, E., Szkudlarek, M. et al. (2006). Are bone erosions detected by magnetic resonance imaging and ultrasonography true erosions? A comparison with computed tomography in rheumatoid arthritis metacarpophalangeal joints. Arthritis Res Ther, 8(4):R110.CrossRefPubMedGoogle Scholar
  9. 9.
    Feldmann, M., & Maini, R.N. (2003). Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med, 9(10):1245–1250.CrossRefPubMedGoogle Scholar
  10. 10.
    Haavardsholm, E.A., Ostergaard, M., Ejbjerg, B.J., Kvan, N.P., Uhlig, T.A., Lilleas, F.G. et al. (2005). Reliability and sensitivity to change of the OMERACT rheumatoid arthritis magnetic resonance imaging score in a multireader, longitudinal setting. Arthritis Rheum, 52(12):3860–3867.CrossRefPubMedGoogle Scholar
  11. 11.
    Jimenez-Boj, E., Nobauer-Huhmann, I., Hanslik-Schnabel, B., Dorotka, R., Wanivenhaus, A.H., Kainberger, F. et al. (2007). Bone erosions and bone marrow edema as defined by magnetic resonance imaging reflect true bone marrow inflammation in rheumatoid arthritis. Arthritis Rheum, 56(4):1118–1124.CrossRefPubMedGoogle Scholar
  12. 12.
    Jimenez-Boj, E., Redlich, K., Turk, B., Hanslik-Schnabel, B., Wanivenhaus, A., Chott, A. et al. (2005). Interaction between synovial inflammatory tissue and bone marrow in rheumatoid arthritis. J Immunol, 175(4):2579–2588.PubMedGoogle Scholar
  13. 13.
    Keffer, J., Probert, L., Cazlaris, H., Georgopoulos, S., Kaslaris, E., Kioussis, D. et al. (1991). Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. Embo J, 10(13):4025–4031.PubMedGoogle Scholar
  14. 14.
    Kirkham, B.W., Lassere, M.N., Edmonds, J.P., Juhasz, K.M., Bird, P.A., Lee, C.S. et al. (2006). Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort). Arthritis Rheum, 54(4):1122–1131.CrossRefPubMedGoogle Scholar
  15. 15.
    Kitaura, H., Zhou, P., Kim, H.J., Novack, D.V., Ross, F.P., & Teitelbaum, S.L.(2005). M-CSF mediates TNF-induced inflammatory osteolysis. J Clin Invest, 115(12):3418–3427CrossRefPubMedGoogle Scholar
  16. 16.
    Kuek, A., Hazleman, B.L., & Ostor, A.J. (2007). Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolution. Postgrad MedJ, 83(978):251–260.CrossRefGoogle Scholar
  17. 17.
    Li, P., Schwarz, E.M., O‘Keefe, R.J., Ma, L., Boyce, B.F., & Xing, L. (2004). RANK signaling is not required for TNFalpha-mediated increase in CD11(hi) osteoclast precursors but is essential for mature osteoclast formation in TNFalpha-mediated inflammatory arthritis. J Bone Miner Res, 19(2):207–213.CrossRefPubMedGoogle Scholar
  18. 18.
    Li, P., Schwarz, E.M., O‘Keefe, R.J., Ma, L., Looney, R.J., Ritchlin, C.T. et al. (2004). Systemic tumor necrosis factor alpha mediates an increase in peripheral CD11bhigh osteoclast precursors in tumor necrosis factor alpha-transgenic mice. Arthritis Rheum, 50(1):265–276.CrossRefPubMedGoogle Scholar
  19. 19.
    Martinez-Martinez, M.U., Cuevas-Orta, E., Reyes-Vaca, G., Baranda, L., Gonzalez-Amaro, R., & Abud-Mendoza, C. (2007). Magnetic resonance imaging in patients with rheumatoid arthritis with complete remission treated with disease-modifying antirheumatic drugs or anti-tumour necrosis factor alpha agents. Ann Rheum Dis, 66(1):134–135.CrossRefPubMedGoogle Scholar
  20. 20.
    Maruyama, K., Asai, J., Ii, M., Thorne, T., Losordo, D.W., & D‘Amore, P.A. (2007). Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am J Pathol, 170(4):1178–1191CrossRefPubMedGoogle Scholar
  21. 21.
    McGonagle, D., Conaghan, P.G., O‘Connor, P., Gibbon, W., Green, M., Wakefield, R. et al. (1999). The relationship between synovitis and bone changes in early untreated rheumatoid arthritis: a controlled magnetic resonance imaging study. Arthritis Rheum, 42(8):1706–1711.CrossRefPubMedGoogle Scholar
  22. 22.
    McQueen, F.M. (2000). Magnetic resonance imaging in early inflammatory arthritis: what is its role? Rheumatology, 39(7):700–706.CrossRefPubMedGoogle Scholar
  23. 23.
    McQueen, F.M., & Ostendorf, B. (2006). What is MRI bone oedema in rheumatoid arthritis and why does it matter? Arthritis Res Ther, 8(6):222.CrossRefPubMedGoogle Scholar
  24. 24.
    Oliver, G., & Detmar, M. (2002). The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature. Genes Dev, 16(7):773–783.CrossRefPubMedGoogle Scholar
  25. 25.
    Ostergaard, M., Hansen, M., Stoltenberg, M., Gideon, P., Klarlund, M., Jensen, K.E., & Lorenzen, I. (1999). Magnetic resonance imaging-determined synovial membrane volume as a marker of disease activity and a predictor of progressive joint destruction in the wrists of patients with rheumatoid arthritis. Arthritis Rheum, 42(5):918–929.CrossRefPubMedGoogle Scholar
  26. 26.
    Pablos, J.L., Santiago, B., Galindo, M., Torres, C., Brehmer, M.T., Blanco, F.J. et al. (2003). Synoviocyte-derived CXCL12 is displayed on endothelium and induces angiogenesis in rheumatoid arthritis. J Immunol, 170(4):2147–2152.PubMedGoogle Scholar
  27. 27.
    Ponomaryov, T., Peled, A., Petit, I., Taichman, R.S., Habler, L., Sandbank, J. et al. (2000). Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J Clin Invest, 106(11):1331–1339.CrossRefPubMedGoogle Scholar
  28. 28.
    Proulx, S.T., Kwok, E., You, Z., Beck, C.A., Shealy, D.J., Ritchlin, C.T. et al. (2007). MRI and quantification of draining lymph node function in inflammatory arthritis. Ann N Y Acad Sci, 1117:106–123.CrossRefPubMedGoogle Scholar
  29. 29.
    Proulx, S.T., Kwok, E., You, Z., Papuga, M.O., Beck, C.A., Shealy, D.J. et al. (2008). Elucidating bone marrow edema and myelopoiesis in murine arthritis using contrast-enhanced magnetic resonance imaging. Arthritis Rheum, 58(7):2019–2029.CrossRefPubMedGoogle Scholar
  30. 30.
    Proulx, S.T., Kwok, E., You, Z., Papuga, M.O., Beck, C.A., Shealy, D.J. et al. (2007). Longitudinal assessment of synovial, lymph node, and bone volumes in inflammatory arthritis in mice by in vivo magnetic resonance imaging and microfocal computed tomography. Arthritis Rheum, 56(12):4024–4037.CrossRefPubMedGoogle Scholar
  31. 31.
    Ritchlin, C.T., Haas-Smith, S.A., Li, P., Hicks, D.G., & Schwarz, E.M. (2003). Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest, 111(6):821–831.PubMedGoogle Scholar
  32. 32.
    Salven, P., Lymboussaki, A., Heikkila, P., Jaaskela-Saari, H., Enholm, B., Aase, K. et al. (1998). Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors. Am J Pathol, 153(1):103–108.PubMedGoogle Scholar
  33. 33.
    Schwarz, E.M., Looney, R.J., Drissi, M.H., O‘Keefe, R.J., Boyce, B.F., Xing, L., & Ritchlin, C.T. (2006). Autoimmunity and bone. Ann N Y Acad Sci, 1068:275–283.CrossRefPubMedGoogle Scholar
  34. 34.
    Shealy, D.J., Wooley, P.H., Emmell, E., Volk, A., Rosenberg, A., Treacy, G. et al. (2002). Anti-TNF-alpha antibody allows healing of joint damage in polyarthritic transgenic mice. Arthritis Res, 4(5):R7.CrossRefPubMedGoogle Scholar
  35. 35.
    Su, J.L., Yen, C.J., Chen, P.S., Chuang, S.E., Hong, C.C., Kuo, I.H. et al. (2007). The role of the VEGF-C/VEGFR-3 axis in cancer progression. Br J Cancer, 96(4):541–545.CrossRefPubMedGoogle Scholar
  36. 36.
    Yu, X., Huang, Y., Collin-Osdoby, P., & Osdoby, P. (2003). Stromal cell-derived factor-1 (SDF-1) recruits osteoclast precursors by inducing chemotaxis, matrix metalloproteinase-9 (MMP-9) activity, and collagen transmigration. J Bone Miner Res, 18(8):1404–1418.CrossRefPubMedGoogle Scholar
  37. 37.
    Xing, L., Schwarz, E.M., & Boyce, B.F. (2005). Osteoclast precursors, RANKL/RANK, and immunology. Immunol Rev, 208:19–29.CrossRefPubMedGoogle Scholar
  38. 38.
    Yao, Z., Li, P., Zhang, Q., Schwarz, E.M., Keng, P., Arbini, A. et al. (2006). Tumor Necrosis Factor-{alpha} Increases Circulating Osteoclast Precursor Numbers by Promoting Their Proliferation and Differentiation in the Bone Marrow through Up-regulation of c-Fms Expression. J Biol Chem, 281(17):11846–11855.CrossRefPubMedGoogle Scholar
  39. 39.
    Zhang, Q., Guo, R., Lu, Y., Zhao, L., Zhou, Q., Schwarz, E.M. et al. (2008). VEGF-C, a Lymphatic Growth Factor, Is a RANKL Target Gene in Osteoclasts That Enhances Osteoclastic Bone Resorption through an Autocrine Mechanism. J Biol Chem, 283(19):13491–13499.CrossRefPubMedGoogle Scholar
  40. 40.
    Zhang, Q., Guo, R., Schwarz, E.M., Boyce, B.F., & Xing, L. (2008). TNF inhibits production of SDF-1 by bone stromal cells and increases osteoclast precursor mobilization from bone marrow to peripheral blood. Arthritis Res Ther, 10(2):R37.CrossRefPubMedGoogle Scholar
  41. 41.
    Zhang, Q., Lu, Y., Proulx, S., Guo, R., Yao, Z., Schwarz, E.M. et al. (2007). Increased lymphangiogenesis in joints of mice with inflammatory arthritis. Arthritis Res Ther, 9(6):R118.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Edward M. Schwarz
    • 1
  • Steven T. Proulx
    • 2
  • Christopher T. Ritchlin
    • 2
  • Brendan F. Boyce
    • 2
  • Lianping Xing
    • 2
  1. 1.The Center for Musculoskeletal Research, University of Rochester Medical CenterRochesterUSA
  2. 2.The Center for Musculoskeletal Research,University of RochesterRochesterUSA

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