Synovitis in Osteoarthritic Patients: Morphological and Virological Evidence of its Contribution to Development of the Disease


The role of inflammation in the development of osteoarthritic joint degeneration is not completely understood. Recent data suggest that processes that cause and orchestrate inflamed synovial lesions may be implicated in the development of the disease. The morphological changes of the synovium in patients with osteoarthritis (OA), as well as the level of synovial inflammation cautiously graded, in association to the presence of human parvovirus B19 (B19V) infection markers, were evaluated. Qualitative and quantitative detection of B19V genomic sequence was performed in OA and rheumatoid arthritis (RA) groups. The expression of CD68, S100 (Ca2+ binding proteins soluble in 100% ammonium sulfate) and B19 VP1/VP2 capsid proteins found in the synovium were investigated by single and double immunolabeling, whereas fine features of synoviocytes — by electron microscopy. One-third of OA and RA patients demonstrated synovial expression of B19V antigen, which was confirmed in both types of synoviocytes. The overall expression of B19V in OA patients was weaker than that found in RA subjects. Positive correlation between B19V-positive vascular endothelial cells, sublining infiltrating lymphocytes, macrophages, and B19V-positive synoviocytes was established. No correlation between synovitis score indices as well as the expression of S100 and expression of B19V was found. The results suggest that the synovial membrane maintains local joint homeostasis, and that virus mediated synovitis is implicated in the development of OA.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • Adamson-Small, L. A., Ignatovich, I. V., Laemmerhirt, M. G., Hobbs, J. A. (2014). Persistent parvovirus B19 infection in non-erythroid tissues: Possible role in the inflammatory and disease process. Virus Res., 190, 8–16.

  • Altman, R., Asch, E., Bloch, D., Bole, G., Borenstein, D., Brandt, K., Christy, W. (1986). Development of criteria for the classification and reporting of osteoarthritis classification of osteoarthritis of the knee. Arthr. Rheum., 29, 1039–1049.

  • Altman, R., Howell, D., Ike, R., Kapila, P., Kaplan, D., Koopman, W., Marino, C. (1991). The American College of Rheumatology Criteria for the Classification and Reporting of Osteoarthritis of the Hip. Offic. J. Amer. Coll. Rheumatol., 34 (5), 505–514.

  • Arden, N., K., Leyland K. M. (2013). Osteoarthritis year 2013 in review: Clinical. Osteoarthritis and Cartilage, 21 (10), 1409–1413.

  • Aslan, B., Mehmet, S. S., Gonul, A., Aydiner, K., Ahmet, N. Y., Seda, T., Gurol, E. (2008). Detection of parvovirus B19 in synovial fluids of patients with osteoarthritis. Diagn. Microbiol. Infect. Dis., 60, 381–385.

  • Atukorala, I., Kwoh, C.K., Guermazi, A., F., Roemer, W., Boudreau, M., J., Hannon, R., M., Hunter, D. (2016.) Synovitis in knee osteoarthritis: A precursor of disease? Ann. Rheum. Dis., 75, 390–395.

  • Bartok, B., Firestein, G. S. (2011). Fibroblast-like synovioctyes: Key effector cells in rheumatoid arthritis. Immunol. Rev., 233, 233–255.

  • Benito, M. J., Veale, D. J., O. FitzGerald, W. B. Van Den Berg, and B. Bresnihan. (2005). Synovial tissue inflammation in early and late osteoarthritis. Ann. Rheum. Dis., 64, 1263–67.

  • Bjork, A., Vogl, T., Stenstro, M., Liberg, M., Olsson, A., Roth, J., Ivars, F., Leanderson, T. (2009). Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to Quinoline-3-Carboxamides. PLoS Biol., 7 (4), e97.

  • Bottini, N., Firestein, G. S. (2014). Duality of fibroblast-like synoviocytes in RA: Passive responders and imprinted aggressors. Nat. Rev. Rheumatol., 9, 24–33.

  • Bultmann, B. D., Klingel K., Sotlar K., Bock C. T., Kandolf R. (2003). Parvovirus B19: A pathogen responsible for more than hematologic disorders. Virchows Arch., 442, 8–17.

  • Cecil, D. L., Johnson, K., Rediske, J., Lotz, M., Schmidt, A. M., Terkeltaub, R. (2005). Inflammation-induced chondrocyte hypertrophy is driven by receptor for advanced glycation end products. J. Immunol., 175, 8296–8302.

  • Chen, Y. S., Chou, P. H., Li, S. N., Tsai, W. C., Lin, K. H., Tsai, K. B., Yen, J. H., Liu, H. W. (2006). Parvovirus B19 infection in patients with rheumatoid arthritis in Taiwan. J. Rheumatol., 33, 887–891.

  • Cooling, L., Koerner, T., Naides, S. (1995). Multiple glycosphingolipids determine the tissuetropism of parvovirus B19. J. Infect. Dis., 172, 1198–1205.

  • Donato, R., Cannon, B., Sorci, G., Riuzzi, F., Hsu, K., Weber, D. J., Geczy, D. (2013). Functions of S100 proteins. Curr. Mol. Med., 13, 24–57.

  • Ehlermann, P., Eggers, K., Bierhaus, A., Most, P., Weichenhan, D., Greten, J., Nawroth, P. P., Katus, H. A., Remppis, A. (2006). Increased proinflammatory endothelial response to S100A8/A9 after preactivation through advanced glycation end products. Cardiovasc. Diabetol., 5 (1), 6.

  • Gallinella, G. (2013). Parvovirus B19 achievements and challenges. Int. Schol. Res. Notices Virol., 2013, 1–33.

  • Gallinella, G. (2017). Parvovirus B19: Recent insights and implications for pathogenesis, diagnosis and therapy. Microbiol. Med., 32, 97–107.

  • Kerr, J. R. (2000). Pathogenesis of human parvovirus B19 in rheumatic disease. Ann. Rheum. Dis., 59, 672–683.

  • Kerr, J. R. (2016). The role of parvovirus B19 in the pathogenesis of autoimmunity and autoimmune disease. J. Clin. Pathol., 69, 279–291.

  • Krenn, V. L. Morawietz, G. R. Burmester, R. W. Kinne, U. Mueller-Ladner, B. Muller, T. Haupl. (2006). Synovitis score: Discrimination between chronic low-grade and high-grade synovitis. Histopathology, 49, 358–364.

  • Landenberg, P., Hartwig, W., Lehmann, Modrow, S. (2007). Human Parvovirus B19 infection and antiphospholipid antibodies. Autoimmun. Rev., 6, 278–285.

  • Lange-Brokaar, B., Ioan-Facsinay, A., van Osch, G., Zuurmond, M., Schoones, J., Toes, R. E., Huizinga, T. W., Kloppenburg, M. (2012). Synovial inflammation, immune cells and their cytokines in osteoarthritis: A review. Osteoarthritis Cartilage, 20, 1484–1499.

  • Lennerz, C., Madry, H., Ehlhardt, S., Venzke, T., Zang, K. D., Mehraein, Y. (2004). Parvovirus B19-related chronic monoarthritis: Immunohisto-chemical detection of virus-positive lymphocytes within the synovial tissue compartment: Two reported cases. Clin. Rheumatol., 23 (1), 59–62.

  • Claire L. H., David L. S. (1993). Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins. Blood, 81, 1607–1613.

  • Lu, J., Zhi, N., Wong, S., Brown, K. (2006). Activation of synoviocytes by the secreted phospholipase A2 motif in the VP1-unique region of parvovirus B19 minor capsid protein. J. Infect. Dis., 193, 582–590.

  • Mainil-Varlet, P., Aigner, T., Brittberg, M. (2003). Histological assessment of cartilage repair. J. Bone Joint Surg., 85, 45–57.

  • Manferdini, C., Paolella, F., Gabusi, E., Silvestri, Y., Gambri, L., Cattini, L., Filardo, G., Fleury-Cappellesso, S., Lisignoli, G. (2016). From osteoarthritic synovium to synovialderived cells characterization: Synovial macrophages are key effector cells. Arthr. Res. Ther., 18, 1–13.

  • Marks, M., Marks, J. (2016). Viral arthritis. Clin. Med., 16, 399–400.

  • Mauermann, M., Hochauf-Stange, K., Kleymann, A., Conrad, K., Aringer, M. (2016). Parvovirus infection in early arthritis. Clin. Exper. Rheumatol., 34, 207–213.

  • Mehraein, Y., Wagner, M., Remberger, K., Füzesi, L., Middel, P., Kaptur, S., Schmitt, K., Meese, E. (2006). Parvovirus B19 detected in Rosai-Dorfman disease in nodal and extranodal manifestations. J. Clin. Pathol., 59, 1320–1326.

  • Mor, A., Abramson, S. B., Pillinger, M. (2005). The fibroblast-like synovial cell in rheumatoid arthritis: A key player in inflammation and joint destruction. Clin. Immunol., 115, 118–128.

  • Naciute, M., Mieliauskaite, D., Rugiene, R., Nikitenkiene, R., Jancoriene, L., Mauricas, M., Nora-Krukle, Z., Murovska, M., Girkontaite, I. (2016). Frequency and significance of parvovirus B19 infection in patients with rheumatoid arthritis. J. Gen. Virol., 97, 3302–3312.

  • Naciute, M., Maciunaite, G., Mieliauskaite, D., Rugiene, R., Zinkeviciene, A., Mauricas, M., Murovska, M., Girkontaite, I. (2017). Increased numbers of CD4(+)CD25(+) and CD8(+)CD25(+) T-Cells in peripheral blood of patients with rheumatoid arthritis with parvovirus B19 infection. In Vivo, 31, 181–185.

  • Naciute, M., Mieliauskaite, D., Rugiene, R., Maciunaite, G., Mauricas, M., Murovska, M., Girkontaite, I., (2017). Parvovirus B19 infection modulates the levels of cytokines in the plasma of rheumatoid arthritis patients. Cytokine, 96, 41–48.

  • Motoshige, N., Sakai, T., Hiraiwa, H., Hamada, T., Omachi, T., Ono, Y., Inukai, N., Ishizuka, S., Matsukawa, T., Oda, T., Takamatsu, A., Yamashita, S., Ishiguro, N. (2012). Role of S100A12 in the pathogenesis of osteoarthritis. Biochem. Biophys. Res. Comm., 422, 508–514.

  • Ray, N. B., Nieva, D. R., Seftor, E. A., Khalkhali-Ellis, Z., Naides, S. J. (2001). Induction of an invasive phenotype by human parvovirus B19 in normal human synovial fibroblasts. Arthr. Rheum., 44, 1582–1586.

  • Rollín, R., Álvarez-Lafuente, R., Marco, F., Jover, J. A., Hernández-García, C., Rodríguez-Navas, C., López-Durán, L., Fernández-Gutiérrez, B. (2007). Human parvovirus B19, varicella zoster virus, and human herpesvirus-6 in mesenchymal stem cells of patients with osteoarthritis: Analysis with quantitative real-time polymerase chain reaction. Osteoarthritis Cartilage, 15, 475–478.

  • Schelbergen, R. F., Blom, A. B., van Den Bosch, M. H., Slöetjes, A., Abdollahi-Roodsaz, S., Schreurs, B. W., Mort, J. S., Vogl, T., Roth, J., van den Berg, W. B., van Lent, P. L. (2012). Alarmins S100A8 and S100A9 elicit a catabolic effect in human osteoarthritic chondrocytes that is dependent on toll-like receptor 4. Arthr. Rheum., 64, 1477–1487.

  • Schmid, S., Bossart, W., Michel, B. A., Brühlmann, P. (2007). Outcome of patients with arthritis and parvovirus B19 DNA in synovial membranes. Rheumatol. Int., 27 (8), 747–751.

  • Sellam, J., Berenbaum, F. (2010). The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol., 6, 625–635.

  • Senolt, L., Grigorian, M., Lukanidin, E., Michel, B., Gay, R., Steffen Gay, Pavelka, K., Neidhart, M. (2006). S100A4 (Mts1): Is there any relation to the pathogenesis of pheumatoid arthritis? Autoimmun. Rev., 5, 129–131.

  • Söderlund-Venermo, M., Hokynar, K. Nieminen, J., Rautakorpi, H., Hedman, K. (2002). Persistence of human parvovirus B19 in human tissues. Pathol. Biol., 50, 307–316.

  • Söderlund, M., Von Essen, R., Haapasaari, J., Kiistala, U., Kiviluoto, O., Hedman, K. (1997). Persistence of parvovirus B19 DNA in synovial membranes of young patients with and without chronic arthropathy. Lancet, 349, 1063–1065.

  • Steenvoorden, M., Bank, R., Ronday, H. K., Toes, R. E., Huizinga, T. W., DeGroot, J. (2007). Fibroblast-like synoviocyte-chondrocyte interaction in cartilage degradation. Clin. Exper. Rheumatol., 25, 239–245.

  • Stoppiello, L. A., Mapp, P. I., Wilson, D., Hill, R., Scammell, B. E., Walsh, D. A. (2014). Structural associations of symptomatic knee osteoarthritis. Arthr. Rheumatol., 66 (11), 3018–3027.

  • Sulzbacher, I. (2012). Osteoarthritis: Histology and pathogenesis. Wien Med. Wochenschr., 163 (9–10), 212–219.

  • Munakata, Y., Saito-Ito, T., Kumura-Ishii, K., Huang, J., Kodera, T., Ishii, T., Hirabayashi Y, Koyanagi Y, Sasaki T. (2018). Ku80 autoantigen as a cellular coreceptor for human parvovirus B19 infection. Blood, 106 (10), 3449–57.

  • Yuichi, T., Murai, C., Shibata, S., Munakata, Y., Ishii, T., Ishii, K., Saitoh, T., Sawai, T., Sugamura, K., Sasaki, T. (1998). Human parvovirus B19 as a causative agent for rheumatoid arthritis. Proc. Natl. Acad. Sci., 95 (14), 8227–8232.

  • Tolboom, T. C. A., Pieterman, E., Van der Laan, W. H., Toes, R. E. M., Huidekoper, A. L., Nelissen, R., Breedveld, F. C. Huizinga, T. W. J. (2002). Invasive properties of fibroblast-like synoviocytes: Correlation with growth characteristics and expression of MMP-1, MMP-3, and MMP-10. Ann. Rheum. Dis., 61, 975–980.

  • Tzang, B. S., Chiu, C. C., Tsai, C. C., Lee, Y. J., Lu, J., Shi, J. Y., Hsu, T. C. (2009). Effects of human parvovirus B19 VP1 unique region protein on macrophage responses. J. Biomed. Sci., 9, 1–9.

  • Vila, S. (2017). Inflammation in osteoarthritis. Puerto Rico Health Sci. J., 36, 123–129.

  • Vogl, T., Klaus, T., Ludwig, S., Leukert, N., Ehrhardt, C., Zoelen, M., Nacken, W. Foell, D. Poll, T., Sorg, C., Roth, J. (2007). Mrp8 and Mrp14 are endogenous activators of toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat. Med., 13 (9), 1042–1049.

  • Wang, X., Hunter, D. J., Jin, X., Ding, C. (2017). The importance of synovial inflammation in osteoarthritis: Current evidence from imaging assessments and clinical trials. Osteoarthritis Cartilage, 26 (2), 165–174.

  • Watanabe, K., Koji O., Norio, S., Keiichirou, K., Mitsuru, M., Hisako, K., Hideyuki, K., Ichiro, S. (2018). High-sensitivity virus and mycoplasma screening test reveals high prevalence of parvovirus B19 infection in human synovial tissues and bone marrow. Stem Cell Res. Ther., 9, 1–10.

  • Wenham, C. Y. J., Philip, G. C. (2010). The role of synovitis in osteoarthritis. Ther. Adv. Musculoskel. Dis., 2, 349–359.

  • Xia, C., Braunstein, Z., Toomey, A. C., Zhong, J., Rao, X. (2018). S100 proteins as an important regulator of macrophage inflammation. Frontiers Immunol., 8, 1–11.


Journal + Issues