**8. Acknowledgment**

We are grateful to Dr. Jun Hashimoto, Dr. Tetsuya Tomita, and Professor Hideki Yoshikawa in Department of orthopaedics (Osaka University) for collaboration on our study of FLS in

Molecular Mechanisms of Rheumatoid Arthritis

Ther *11*, R42.

5587-5595.

Rheumatol *28*, 708-14.

analysis. Arthritis Rheum *54*, 1209-1221.

chemotaxin. J Biol Chem *265*, 2973-2978.

Gastroenterology *135*, 889-898, 898 e881-883.

ELSEVIER, 978-1-4160-3285-4, Philadelphia

Acad Sci U S A *94*, 10895-10900.

hypermutation. Annu Rev Biochem *76*, 1-22.

Revealed by Categorizing Subtypes of Fibroblast-Like Synoviocytes 87

Titer in Adults with Rheumatoid Arthritis. Molecular Medicine *15*, 136-143. De Bari, C., Dell'Accio, F., Tylzanowski, P., & Luyten, F.P. (2001). Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum *44*, 1928-1942. De Bari, C., Dell'Accio, F., Vanlauwe, J., Eyckmans, J., Khan, I.M., Archer, C.W., Jones, E.A.,

Di Noia, J.M., & Neuberger, M.S. (2007). Molecular mechanisms of antibody somatic

Dieguez-Gonzalez, R., Calaza, M., Perez-Pampin, E., Balsa, A., Blanco, F.J., Cañete, J.D.,

Dixit, V.M., Green, S., Sarma, V., Holzman, L.B., Wolf, F.W., O'Rourke, K., Ward, P.A.,

Elsby, L. M., Orozco, G., Denton, J., Worthington, J., Ray, D. W., & Donn, R. P. (2010)

Endo, H., Akahoshi, T., Nishimura, A., Tonegawa, M., Takagishi, K., Kashiwazaki, S.,

Endo, Y., Marusawa, H., Kinoshita, K., Morisawa, T., Sakurai, T., Okazaki, I.M., Watashi, K.,

Endo, Y., Marusawa, H., Kou, T., Nakase, H., Fujii, S., Fujimori, T., Kinoshita, K., Honjo, T.,

Firestein, G.S. (2009). 65, In: *Kelly's Textbook of Rheumatology,* Firestein,G.S, Budd, R.C.,

Firestein, G.S., Echeverri, F., Yeo, M., Zvaifler, N.J., & Green, D.R. (1997). Somatic mutations

Firestein, G.S. (2007). Biomedicine. Every joint has a silver lining. Science *315*, 952-953. Freudenberg, J., Lee, H.S., Han, B.G., Shin, H.D., Kang, Y.M., Sung, Y.K., Shim, S.C., Choi,

correlates with disease activity. Genes Immun *8,* 480-491.

Rheumatoid Arthritis in Koreans. Arthritis and Rheumatism *63*, 884-893. Galligan, C.L., Baig, E., Bykerk, V., Keystone, E.C., & Fish, E.N. (2007). Distinctive gene

infusion of IL-8 into rabbit knee joints. Clin Exp Immunol *96*, 31-35.

Association Study of Determinants of Anti-Cyclic Citrullinated Peptide Antibody

McGonagle, D., Mitsiadis, T.A., Pitzalis, C.*, et al.* (2006). Mesenchymal multipotency of adult human periosteal cells demonstrated by single-cell lineage

Caliz, R., Carreño, L., de la Serna, A.R., Fernandez-Gutierrez, B., *et al.* (2009). Analysis of TNFAIP3, a feedback inhibitor of nuclear factor-kappaB and the neighbor intergenic 6q23 region in rheumatoid arthritis susceptibility. Arthritis Res

Prochownik, E.V., & Marks, R.M. (1990). Tumor necrosis factor-alpha induction of novel gene products in human endothelial cells including a macrophage-specific

Functional evaluation of TNFAIP3 (A20) in rheumatoid arthritis. Clin Exp

Matsushima, K., & Kondo, H. (1994). Experimental arthritis induced by continuous

Shimotohno, K., Honjo, T., & Chiba, T. (2007). Expression of activation-induced cytidine deaminase in human hepatocytes via NF-kappaB signaling. Oncogene *26*,

& Chiba, T. (2008). Activation-induced cytidine deaminase links between inflammation and the development of colitis-associated colorectal cancers.

Harris, Jr. E.D., McInnes, I.B., Ruddy, S., Sergent, J.S., 1035-1086, SAUNDERS

in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proc Natl

C.B., Lee, A.T., Gregersen, P.K.*, et al.* (2011). Genome-Wide Association Study of

expression signatures in rheumatoid arthritis synovial tissue fibroblast cells:

RA. We thank Dr. Masaaki Murakami and colleagues in the Laboratory for Developmental Immunology (Osaka University) for co-operation in the study of gp130F759. We are indebted to Professor Toshio Hirano (Osaka University) for instruction, encouragement, and long-term collaboration on our research into RA. We also thank Ms. Reina Tanaka and Ms. Yuka Kenmotsu for technical assistance. This work was partly supported by Research Project Grants from Kawasaki Medical School, and Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, Culture, and Technology of Japan.

#### **9. References**


RA. We thank Dr. Masaaki Murakami and colleagues in the Laboratory for Developmental Immunology (Osaka University) for co-operation in the study of gp130F759. We are indebted to Professor Toshio Hirano (Osaka University) for instruction, encouragement, and long-term collaboration on our research into RA. We also thank Ms. Reina Tanaka and Ms. Yuka Kenmotsu for technical assistance. This work was partly supported by Research Project Grants from Kawasaki Medical School, and Grants-in-Aid for Scientific Research

Aidinis, V., Plows, D., Haralambous, S., Armaka, M., Papadopoulos, P., Kanaki, M.Z.,

Aikawa, Y., Morimoto, K., Yamamoto, T., Chaki, H., Hashiramoto, A., Narita, H., Hirono, S.,

Atsumi, T., Ishihara, K., Kamimura, D., Ikushima, H., Ohtani, T., Hirota, S., Kobayashi, H.,

Babbage, G., Ottensmeier, C.H., Blaydes, J., Stevenson, F.K., & Sahota, S.S. (2006).

Beekman, B., van El, B., Drijfhout, J.W., Ronday, H.K., & TeKoppele, J.M. (1997). Highly

Wordsworth, B.P., Lanchbury, J.S., Sakkas, L.I., Welsh, K.I., Panayi, G.S., & Bell,J.I. (1989).

Brennan, F.M., & McInnes, I.B. (2008). Evidence that cytokines play a role in rheumatoid

Cha, H.S., Rosengren, S., Boyle, D.L., & Firestein, G.S. (2006). PUMA regulation and proapoptotic effects in fibroblast-like synoviocytes. Arthritis Rheum *54*, 587-592. Chan-On, W., Kuwahara, K., Kobayashi, N., Ohta, K., Shimasaki, T., Sripa, B., Leelayuwat,

Cho, M.L., Cho, C.S., Min, S.Y., Kim, S.H., Lee, S.S., Kim, W.U., Min, D.J., Min, J.K., Youn, J.,

Cui, J., Taylor, K.E., DeStefano, A.L., Criswell, L.A., Izmailova, E.S., Parker, A., Roubenoff,

Koczan, D., Thiesen, H.J., & Kollias, G. (2003). Functional analysis of an

& Shiozawa, S. (2008). Treatment of arthritis with a selective inhibitor of c-

Park, S.J., Saeki, Y., Kitamura, Y.*, et al.* (2002). A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis. J

Immunoglobulin heavy chain locus events and expression of activation-induced cytidine deaminase in epithelial breast cancer cell lines. Cancer Res *66*, 3996-4000. Bartok, B., & Firestein, G.S. (2010). Fibroblast-like synoviocytes:key effector cells in

increased levels of active stromelysin in rheumatoid synovial fluid determined by a

HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region. Proc Natl Acad Sci U S A.

C., & Sakaguchi, N. (2009). Cholangiocarcinomas associated with long-term inflammation express the activation-induced cytidine deaminase and germinal center-associated nuclear protein involved in immunoglobulin V-region

Hwang, S.Y.*, et al.* (2002). Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts. Arthritis Rheum *46*, 1202-

R., Plenge, R.M., Weinblatt, M.E., Shadick, N.A.*, et al.* (2009). Genome-Wide

from the Ministry of Education, Science, Sports, Culture, and Technology of Japan.

arthritogenic synovial fibroblast. Arthritis Res Ther *5*, R140-157.

Fos/activator protein-1. Nat Biotechnol *26*, 817-823.

rheumatoid arthritis. Immunol Rev *233,* 233-255.

selective fluorogenic assay. FEBS Lett *418,* 305-309.

arthritis. J Clin Invest *118*, 3537-3545.

diversification. Int J Oncol *35*, 287-295.

Exp Med *196*, 979-990.

*86*, 10049–10053.

1209.

**9. References** 

Association Study of Determinants of Anti-Cyclic Citrullinated Peptide Antibody Titer in Adults with Rheumatoid Arthritis. Molecular Medicine *15*, 136-143.


Molecular Mechanisms of Rheumatoid Arthritis

Rheumatol 13:717-723.

arthritis. Arthritis Rheum *50*, 817-827.

is cathepsin L. Nucleic Acids Res *15*, 3186.

Commun 324:3-7

*52*, 430-441.

Rheum *41*, 1378-1387.

Revealed by Categorizing Subtypes of Fibroblast-Like Synoviocytes 89

Iwamoto, T., Okamoto, H., Kobayashi, S., Ikari, K., Toyama, Y., Tomatsu, T., Kamatani, N.,

Jeong, J.G., Kim, J.M., Cho, H., Hahn, W., Yu, S.S., Kim, S.(2004) Effects of IL-1beta on gene

Jones, E.A., English, A., Henshaw, K., Kinsey, S.E., Markham, A.F., Emery, P., & McGonagle,

Joseph, L., Lapid, S., & Sukhatme, V. (1987). The major ras induced protein in NIH3T3 cells

Kasperkovitz, P.V., Timmer, T.C., Smeets, T.J., Verbeet, N.L., Tak, P.P., van Baarsen, L.G.,

Kawane, K., Ohtani, M., Miwa, K., Kizawa, T., Kanbara, Y., Yoshioka, Y., Yoshikawa, H., &

Kawane, K., Tanaka, H., Kitahara, Y., Shimaoka, S., & Nagata, S. (2010). Cytokine-dependent

Keffer, J., Probert, L., Cazlaris, H., Georgopoulos, S., Kaslaris, E., Kioussis, D., & Kollias, G.

Kehlen, A., Thiele, K., Riemann, D., & Langner, J. (2002). Expression, modulation and

Keyszer, G.M., Heer, A.H., Kriegsmann, J., Geiler, T., Trabandt, A., Keysser, M., Gay, R.E., &

and osteoarthritis, by in situ hybridization. Arthritis Rheum *38*, 976-984. Keyszer, G., Redlich, A., Haupl, T., Zacher, J., Sparmann, M., Engethum, U., Gay, S., &

from degradation in macrophages. Nature *443,* 998-1002.

degradation. Proc Natl Acad Sci U S A *107,* 19432-19437.

genetic model of arthritis. EMBO J *10*, 4025-4031.

rheumatoid arthritis. Clin Exp Immunol *127*, 539-546.

& Momohara, S. (2007). A role of monocyte chemoattractant protein-4 (MCP-4)/CCL13 from chondrocytes in rheumatoid arthritis. FEBS J *274,* 4904-4912. Iwamoto, T., Okamoto, H., Toyama, Y., & Momohara, S. (2008). Molecular aspects of rheumatoid arhtiritis:chemokines in the joints of patients. FEBS J *275,* 4448-4455. Jacob, R.A., Perrett, D., Axon, J.M., Herbert, K.E., Scott, D.L.(1995) Rheumatoid synovial cell

proliferation, transformation and fibronectin secretion in culture. Clin Exp

expression in human rheumatoid synovial fibroblasts. Biochem Biophys Res

D. (2004). Enumeration and phenotypic characterization of synovial fluid multipotential mesenchymal progenitor cells in inflammatory and degenerative

Baltus, B., Huizinga, T.W., Pieterman, E., Fero, M.*, et al.* (2005). Fibroblast-like synoviocytes derived from patients with rheumatoid arthritis show the imprint of synovial tissue heterogeneity: evidence of a link between an increased myofibroblast-like phenotype and high-inflammation synovitis. Arthritis Rheum

Nagata, S. (2006). Chronic polyarthritis caused by mammalian DNA that escapes

but acquired immunity- independent arthritis caused by DNA escaped from

(1991). Transgenic mice expressing human tumour necrosis factor: a predictive

signalling of IL-17 receptor in fibroblast-like synoviocytes of patients with

Gay, S. (1995). Comparative analysis of cathepsin L, cathepsin D, and collagenase messenger RNA expression in synovial tissues of patients with rheumatoid arthritis

Burmester, G.R. (1998). Differential expression of cathepsins B and L compared with matrix metalloproteinases and their respective inhibitors in rheumatoid arthritis and osteoarthritis: a parallel investigation by semiquantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. Arthritis


Garcia-Vicuna, R., Gomez-Gaviro, M.V., Dominguez-Luis, M.J., Pec, M.K., Gonzalez-Alvaro,

Goila-Gaur, R., & Strebel, K. (2008). HIV-1 Vif, APOBEC, and intrinsic immunity.

Gracie, J.A., Forsey, R.J., Chan, W.L., Gilmour, A., Leung, B.P., Greer, M.R., Kennedy, K.,

Gudkov, A.V., & Komarova, E.A. (2010). Pathologies associated with the p53 response. Cold

Han, Z., Boyle, D.L., Shi, Y., Green, D.R., & Firestein, G.S. (1999). Dominant-negative p53

Honjo, T., Muramatsu, M., & Fagarasan, S. (2004). AID: how does it aid antibody diversity?

Horai, R., Saijo, S., Tanioka, H., Nakae, S., Sudo, K., Okahara, A., Ikuse, T., Asano, M., &

Hosaka, S., Akahoshi, T., Wada, C., & Kondo, H. (1994). Expression of the chemokine superfamily in rheumatoid arthritis. Clin Exp Immunol *97*, 451-457. Huet, G., Flipo, R.M., Colin, C., Janin, A., Hemon, B., Collyn-d'Hooghe, M., Lafyatis, R.,

Igarashi, H., Yahagi, A., Saika, T., Hashimoto, J., Tomita, T., Yoshikawa, H., & Ishihara, K.

fibroblast-like synoviocytes in rheumatoid arthritis. Immunol Lett., in press. Igarashi, H., Hashimoto, J., Tomita, T., Yoshikawa, H., & Ishihara, K. (2010) TP53 mutations

Inazuka, M., Tahira, T., Horiuchi, T., Harashima, S., Sawabe, T., Kondo, M., Miyahara, H., &

Ishihara, K., Sawa, S., Ikushima, H., Hirota, S., Atsumi, T., Kamimura, D., Park, S.J.,

rheumatoid arthritis synovium. Rheumatology *39*, 262-266.

Iwakura, Y. (2000). Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J Exp Med

Duquesnoy, B., & Degand, P. (1993). Stimulation of the secretion of latent cysteine proteinase activity by tumor necrosis factor alpha and interleukin-1. Arthritis

(2011). A pro-inflammatory role for A20 and ABIN family proteins in human

coincide with the ectopic expression of activation-induced cytidine deaminase in the fibroblast-like synoviocytes derived from a fraction of patients with rheumatoid

Hayashi, K. (2000). Analysis of p53 tumor suppressor gene somatic mutations in

Murakami, M., Kitamura, Y., Iwakura, Y., & Hirano, T. (2004) The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 synergizes with HTLV-1 *pX* in promoting rheumatoid arthritis-like arthritis. Int Immunol *16*, 455-465. Iwakura, Y., Tosu, M., Yoshida, E., Takiguchi, M., Sato, K., Kitajima, I., Nishioka, K.,

Yamamoto, K., Takeda, T., Hatanaka, M.*, et al.* (1991). Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-I. Science

mutations in rheumatoid arthritis. Arthritis Rheum *42*, 1088-1092.

Arthritis Rheum *50*, 3866-3877.

Spring Harb Perspect Biol 2:a001180

arthritis. Clin Exp Immunol *161*, 71-80.

rheumatoid arthritis. J Clin Invest *104*, 1393-1401.

Retrovirology *5*, 51.

Immunity *20*, 659-668.

*191*, 313-320.

Rheum *36*, 772-780.

*253*, 1026-1028.

I., Alvaro-Gracia, J.M., & Diaz-Gonzalez, F. (2004). CC and CXC chemokine receptors mediate migration, proliferation, and matrix metalloproteinase production by fibroblast-like synoviocytes from rheumatoid arthritis patients.

Carter, R., Wei, X.Q., Xu, D.*, et al.* (1999). A proinflammatory role for IL-18 in


Molecular Mechanisms of Rheumatoid Arthritis

arthritis. Science *315*, 1006-1010.

1594-1600.

Revealed by Categorizing Subtypes of Fibroblast-Like Synoviocytes 91

Kuwana, M., Okazaki, Y., Kodama, H., Izumi, K., Yasuoka, H., Ogawa, Y., Kawakami Y., &

Lefevre, S., Knedla, A., Tennie, C., Kampmann, A., Wunrau, C., Dinser, R., Korb, A.,

Lemaire, R., Huet, G., Zerimech, F., Grard, G., Fontaine, C., Duquesnoy, B., & Flipo, R.M.

Li, X., Makarov, S. S. (2006). An essential role of NF-kappaB in the "tumor-like" phenotype of arthritic synoviocytes. Proc Natl Acad Sci U S A *103*, 17432-17437. Lindberg, J., af Klint, E., Catrina, A. I., Nilsson, P., Klareskog, L., Ulfgren, A. K., &

Lindy, O., Konttinen, Y.T., Sorsa, T., Ding, Y., Santavirta, S., Ceponis, A., & Lopez-Otin, C.

Liu, C.Y., Batliwalla, F., Li, W.T., Lee, A., Roubenoff, R., Beckman, E., Khalili, H., Damle, A.,

Maeda, S., Sawai, T., Uzuki, M., Takahashi, Y., Omoto, H., Seki, M., & Sakurai, M. (1995).

Manicourt, D.H., Fujimoto, N., Obata, K., & Thonar, E.J. (1995). Levels of circulating

Martin, J.E., Alizadeh, B.Z., Gonzalez-Gay, M.A., Balsa, A., Pascual-Salcedo, D., Fernandez-

Min, D.J., Cho, M.L., Lee, S.H., Min, S.Y., Kim, W.U., Min, J.K., Park, S.H., Cho, C.S., & Kim,

Miranda-Carus, M.E., Balsa, A., Benito-Miguel, M., Perez de Ayala, C., & Martin-Mola, E.

that exhibit mesenchymal cell differentiation. Leukoc Biol *74*, 833-845. Lee, D.M., Kiener, H.P., Agarwal, S.K., Noss, E.H., Watts, G.F., Chisaka, O., Takeichi, M.,

rheumatoid arthritis to unaffected joints. Nat Med *15*, 1414-1420.

tissue of rheumatoid arthritis patients. Arthritis Res Ther *8*, R179.

synovial fibroblast-like cells. Br J Rheumatol *36*, 735-743.

synovium. Arthritis Rheum *40*, 1391-1399.

arthritis. Ann Rheum Dis *54*, 970-975.

Rheumatism *62*, 3183-3190.

1031-1039.

1146-1155.

rheumatoid arthritis. Molecular Medicine *14*, 575-581.

suppressor gene in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum *42*,

Ikeda, Y. (2003). Human circulating CD14+ monocytes as a source of progenitors

Brenner, M.B. (2007). Cadherin-11 in synovial lining formation and pathology in

Schnaker, E.M., Tarner, I.H., Robbins, P.D.*, et al.* (2009). Synovial fibroblasts spread

(1997). Selective induction of the secretion of cathepsins B and L by cytokines in

Lundeberg, J. (2006). Effect of infliximab on mRNA expression profiles in synovial

(1997). Matrix metalloproteinase 13 (collagenase 3) in human rheumatoid

Kern, M., Furie, R.*, et al.* (2008). Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in

Determination of interstitial collagenase (MMP-1) in patients with rheumatoid

collagenase, stromelysin-1, and tissue inhibitor of matrix metalloproteinases 1 in patients with rheumatoid arthritis. Relationship to serum levels of antigenic keratan sulfate and systemic parameters of inflammation. Arthritis Rheum *38*,

Gutierrez, B., Raya, E., Franke, L., van't Slot, R., Coenen, M.J.H.*, et al.* (2010). Identification of the Oxidative Stress-Related Gene MSRA as a Rheumatoid Arthritis Susceptibility Locus by Genome-Wide Pathway Analysis. Arthritis and

H.Y. (2004). Augmented production of chemokines by the interaction of type II collagen-reactive T cells with rheumatoid synovial fibroblasts. Arthritis Rheum *50*,

(2004). IL-15 and the initiation of cell contact-dependent synovial fibroblast-T


Kitagawa, A., Miura, Y., Saura, R., Mitani, M., Ishikawa, H., Hashiramoto, A., Yoshiya, S.,

Koch, A.E., Kunkel, S.L., Burrows, J.C., Evanoff, H.L., Haines, G.K., Pope, R.M., & Strieter,

Koch, A.E., Polverini, P.J., Kunkel, S.L., Harlow, L.A., DiPietro, L.A., Elner, V.M., Elner, S.G.,

Koch, A.E., Kunkel, S.L., Harlow, L.A., Mazarakis, D.D., Haines, G.K., Burdick, M.D., Pope,

Koch, A.E., Kunkel, S.L., Shah, M.R., Hosaka, S., Halloran, M.M., Haines, G.K., Burdick,

Kojima, F., Naraba, H., Sasaki, Y., Beppu, M., Aoki, H., & Kawai, S. (2003). Prostaglandin E2

Komori, J., Marusawa, H., Machimoto, T., Endo, Y., Kinoshita, K., Kou, T., Haga, H., Ikai, I.,

duct inflammation to human cholangiocarcinoma. Hepatology *47*, 888-896. Kontoyiannis, D., Pasparakis, M., Pizarro, T.T., Cominelli, F., & Kollias, G. (1999). Impaired

Konttinen, Y.T., Ainola, M., Valleala, H., Ma, J., Ida, H., Mandelin, J., Kinne, R.W.,

profiles in trauma and rheumatoid arthritis. Ann Rheum Dis *58*, 691-697. Korb, A., Pavenstadt, H., & Pap, T. (2009). Cell death in rheumatoid arthritis. Apoptosis *14*,

Korganow, A.S., Ji, H., Mangialaio, S., Duchatelle, V., Pelanda, R., Martin, T., Degott, C.,

Kou, T., Marusawa, H., Kinoshita, K., Endo, Y., Okazaki, I.M., Ueda, Y., Kodama, Y., Haga,

Ko, L. J., & Prives, C. (1996). p53: puzzle and paradigm. Genes Dev. *10*, 1054-1072.

apoptosis. Ann Rheum Dis *65*, 721-727.

angiogenesis. Science *258*, 1798-1801.

8. J Immunol *147*, 2187-2195.

928.

3666.

398.

447-454

*10*, 451-461.

2819-2828.

Shiozawa, S., & Kurosaka, M. (2006). Anchorage on fibronectin via VLA-5 (alpha5beta1 integrin) protects rheumatoid synovial cells from Fas-induced

R.M. (1991). Synovial tissue macrophage as a source of the chemotactic cytokine IL-

& Strieter, R.M. (1992). Interleukin-8 as a macrophage-derived mediator of

R.M., & Strieter, R.M. (1994). Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. J Clin Invest *93*, 921-

M.D., Pope, R.M., & Strieter, R.M. (1995). Growth-related gene product alpha. A chemotactic cytokine for neutrophils in rheumatoid arthritis. J Immunol *155*, 3660-

is an enhancer of interleukin-1beta-induced expression of membrane-associated prostaglandin E synthase in rheumatoid synovial fibroblasts. Arthritis Rheum *48*,

Uemoto, S., & Chiba, T. (2008). Activation-induced cytidine deaminase links bile

on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity *10*, 387-

Santavirta, S., Sorsa, T., Lopez-Otin, C.*, et al.* (1999). Analysis of 16 different matrix metalloproteinases (MMP-1 to MMP-20) in the synovial membrane: different

Kikutani, H., Rajewsky, K., Pasquali, J.L.*, et al.* (1999). From systemic T cell selfreactivity to organ-specific autoimmune disease via immunoglobulins. Immunity

H., Ikai, I., & Chiba, T. (2007). Expression of activation-induced cytidine deaminase in human hepatocytes during hepatocarcinogenesis. Int J Cancer *120*, 469-476. Kullmann, F., Judex, M., Neudecker, I., Lechner, S., Justen, H.P., Green, D.R., Wessinghage,

D., Firestein, G.S., Gay, S., Scholmerich, J.*, et al.* (1999). Analysis of the p53 tumor

suppressor gene in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum *42*, 1594-1600.


Molecular Mechanisms of Rheumatoid Arthritis

RA at 6q23. Hum Mol Genet *18*, 2693-2699.

rheumatoid arthritis. Arthritis Rheum *50*, 2794-2802.

ELSEVIER, 978-1-4160-3285-4, Philadelphia.

factor-1 receptor. J Immunol *173*, 3564-3569.

Semin Immunopathol *25*, 65-78.

Rheumatism *63*, 645-653.

Chem *268*, 5834-5839.

Immunol *111*, 353-358.

Immunol *101*, 398-407.

Revealed by Categorizing Subtypes of Fibroblast-Like Synoviocytes 93

Pap, T., Shigeyama, Y., Kuchen, S., Fernihough, J.K., Simmen, B., Gay, R.E., Billingham, M.,

metalloproteinases in rheumatoid arthritis. Arthritis Rheum *43*, 1226–1232. Pap, T., Franz, J.K., Hummel, K.M., Jeisy, E., Gay, R., & Gay, S. (2000b). Activation of

Pap, T., Nawrath, M., Heinrich, J., Bosse, M., Baier, A., Hummel, K.M., Petrow, P., Kuchen,

Pap,T., & Gay, S. (2009). 11, In: *Kelly's Textbook of Rheumatology,* Firestein,G.S, Budd, R.C.,

Pauklin, S., Sernandez, I.V., Bachmann, G., Ramiro, A.R., & Petersen-Mahrt, S.K. (2009). Estrogen directly activates AID transcription and function. J Exp Med *206*, 99-111. Pierer, M., Muller-Ladner, U., Pap, T., Neidhart, M., Gay, R.E., & Gay, S. (2003). The SCID

Plant, D., Bowes, J., Potter, C., Hyrich, K.L., Morgan, A.W., Wilson, A.G., Isaacs,

Pohlers, D., Beyer, A., Koczan, D., Wilhelm, T., Thiesen, H.J., & Kinne, R.W. (2007).

Pritchard, J., Tsui, S., Horst, N., Cruikshank, W.W., & Smith, T.J. (2004). Synovial fibroblasts

Rathanaswami, P., Hachicha, M., Sadick, M., Schall, T.J., & McColl, S.R. (1993). Expression of

Reme, T., Travaglio, A., Gueydon, E., Adla, L., Jorgensen, C., & Sany, J. (1998). Mutations of

Robinson, E., Keystone, E.C., Schall, T.J., Gillett, N., & Fish, E.N. (1995). Chemokine

rheumatoid arthritis synovial fibroblasts. Arthritis Res Ther *9*, R59.

Combined effects of three independent SNPs greatly increase the risk estimate for

Gay, S. (2000a). Differential expression pattern of membrane-type matrix

synovial fibroblasts in rheumatoid arthritis: lack of Expression of the tumour suppressor PTEN at sites of invasive growth and destruction. Arthritis Res *2*, 59-64.

S., Michel, B.A., Gay, R.E.*, et al.* (2004). Cooperation of Ras- and c-Myc-dependent pathways in regulating the growth and invasiveness of synovial fibroblasts in

Harris, Jr. E.D., McInnes, I.B., Ruddy, S., Sergent, J.S., 201-214, SAUNDERS

mouse model: novel therapeutic targets - lessons from gene transfer. Springer

J.D.,;Wellcome Trust Case Control Consortium; British Soc Rheumatology Biologics Register, & Barton, A.(2011). Genome-Wide Association Study of Genetic Predictors of Anti-Tumor Necrosis Factor Treatment Efficacy in Rheumatoid Arthritis Identifies Associations With Polymorphisms at Seven Loci. Arthritis and

Constitutive upregulation of the transforming growth factor-� pathway in

from patients with rheumatoid arthritis, like fibroblasts from Graves' disease, express high levels of IL-16 when treated with Igs against insulin-like growth

the cytokine RANTES in human rheumatoid synovial fibroblasts. Differential regulation of RANTES and interleukin-8 genes by inflammatory cytokines. J Biol

the p53 tumour suppressor gene in erosive rheumatoid synovial tissue. Clin Exp

expression in rheumatoid arthritis (RA): evidence of RANTES and macrophage inflammatory protein (MIP)-1 beta production by synovial T cells. Clin Exp

lymphocyte cross-talk in rheumatoid arthritis: effect of methotrexate. J Immunol *173*, 1463-1476.


Mor, A., Abramson, S.B., & Pillimger, M.H. (2005). The fibroblast-like synovial cell in

Morisawa, T., Marusawa, H., Ueda, Y., Iwai, A., Okazaki, I.M., Honjo, T., & Chiba, T. (2008).

Muller-Ladner, U., Gay, R.E., & Gay, S. (2000). Activation of synoviocytes. Curr Opin

Muller-Ladner, U., Kriegsmann, J., Franklin, B.N., Matsumoto, S., Geiler, T., Gay, R.E., &

Murakami, M., Okuyama, Y., Ogura, H., Asano, S., Arima, Y., Tsuruoka, M., Harada, M.,

Nanki, T., Hayashida, K., El-Gabalawy, H.S., Suson, S., Shi, K., Girschick, H.J., Yavuz, S., &

Niki, Y., Yamada, H., Seki, S., Kikuchi, T., Takaishi, H., Toyama, Y., Fujikawa, K., & Tada, N.

Nishimoto, N., & Kishimoto, T. (2006). Interleukin 6: from bench to bedside. Nat Clin Pract

Ogura, H., Murakami, M., Okuyama, Y., Tsuruoka, M., Kitabayashi, C., Kanamoto, M.,

Ohshima, S., Mima, T., Sasai, M., Nishioka, K., Shimizu, M., Murata, N., Yoshikawa, H.,

and a clinical benefit of anti-TNF-alpha therapy for RA. Cytokine *12*, 281-288. Ohtani, T., Ishihara, K., Atsumi, T., Nishida, K., Kaneko, Y., Miyata, T., Itoh, S., Narimatsu,

Okada, Y.(2009). 7, In: *Kelly's Textbook of Rheumatology,* Firestein,G.S, Budd, R.C., Harris, Jr.

Orozco, G., Hinks, A., Eyre, S., Ke, X., Gibbons, L.J., Bowes, J., Flynn, E., Martin, P., Wilson,

cytidine deaminase expression. Int J Cancer *123*, 2735-2740.

*173*, 1463-1476.

Immunol *115*, 118-128.

Rheumatol *12*, 186-194.

Rheumatol *2*, 619-626.

Immunity *29*, 628-636.

responses. Immunity *12*, 95-105.

4160-3285-4, Philadelphia.

activated T cells. J Exp Med *208*, 103-114.

synovium. J Immunol *165*, 6590-6598.

transgenic mice. J Clin Invest *107*, 1127-1135.

*149*, 1607-1615.

lymphocyte cross-talk in rheumatoid arthritis: effect of methotrexate. J Immunol

rheumatoid arthritis: a key player in inflammation and joint destruction. Clin

Organ-specific profiles of genetic changes in cancers caused by activation-induced

Gay, S. (1996). Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am J Pathol

Kanamoto, M., Sawa, Y., Iwakura, Y.*, et al.* (2011). Local microbleeding facilitates IL-6- and IL-17-dependent arthritis in the absence of tissue antigen recognition by

Lipsky, P.E. (2000). Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis

(2001). Macrophage- and neutrophil-dominant arthritis in human IL-1 alpha

Nishihara, M., Iwakura, Y., & Hirano, T. (2008). Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction.

Nakanishi, K., Suemura, M., McCloskey, R.V.*, et al.* (2000). Tumour necrosis factor alpha (TNF-alpha) interferes with Fas-mediated apoptotic cell death on rheumatoid arthritis (RA) synovial cells: a possible mechanism of rheumatoid synovial hyperplasia

M., Maeda, H., Fukada, T.*, et al.* (2000). Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3- and SHP2-mediated signals in immune

E.D., McInnes, I.B., Ruddy, S., Sergent, J.S., 115-134, SAUNDERS ELSEVIER, 978-1-

A.G., Bax, D.E., Morgan, A.W., Emery, P., Steer, S., Hocking, L., Reid, D.M., Wordsworth, P., Harrison, P., Thomson, W., Barton, A., Worthington, J. (2009). Combined effects of three independent SNPs greatly increase the risk estimate for RA at 6q23. Hum Mol Genet *18*, 2693-2699.


Molecular Mechanisms of Rheumatoid Arthritis

Oncogene *28*, 469-478.

activity. Ann Rheum Dis *53*, 768-772.

2305-2321.

1602-1607.

*159*, 1521-1530.

Rheum *42*, 1517-1527.

Revealed by Categorizing Subtypes of Fibroblast-Like Synoviocytes 95

Tamiya, G., Shinya, M., Imanishi, T., Ikuta, T., Makino, S., Okamoto, K., Furugaki, K.,

Taylor, D.J., Cheung, N.T., & Dawes, P.T. (1994). Increased serum proMMP-3 in

Tetlow, L.C., Lees, M., Ogata, Y., Nagase, H., and Woolley, D.E. (1993). Differential

Thomas, J.W., Thieu, T.H., Byrd, V.M., & Miller, G.G. (2000). Acidic fibroblast growth factor

Tolboom, T.C., Pieterman, E., van der Laan, W.H., Toes, R., Huidekoper, A., Nelissen, R.,

van Baarsen, L.G., Wijbrandts, C.A., Timmer, T.C., van der Pouw Kraan, T.C., Tak, P.P., &

van der Pouw Kraan, T.C., van Gaalen, F.A., Kasperkovitz, P.V., Verbeet, N.L., Smeets, T.J.,

Vereecke, L., Beyaert, R., & van Loo, G. (2009). The ubiquitin-editing enzyme A20

Volin, M.V., Woods, J.M., Amin, M.A., Connors, M.A., Harlow, L.A., & Koch, A.E. (2001).

Wakisaka, S., Suzuki, N., Takeba, Y., Shimoyama, Y., Nagafuchi, H., Takeno, M., Saito, N.,

patients with rheumatoid arthritis (RA). Clin Exp Immunol *114*, 119-128. Wang, C.R., Liu, M.F., Huang, Y.H., & Chen, H.C. (2004). Up-regulation of XCR1 expression

Westhoff, C.S., Freudiger, D., Petrow, P., Seyfert, C., Zacher, J., Kriegsmann, J., Pap, T., Gay,

Weyand, C.M., Hicok, K.C., Conn, D.L., Goronzy, J.J. (1992). The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann Intern Med *117*,801-6.

synovial cells in vitro and in vivo. Rheumatol Int *13*, 53-59.

in synovial cells. Arthritis Rheum *43*, 2152-2159.

MMP-3, and MMP-10.Ann Rheum Dis 61:975-980.

rheumatoid tissues. Arthritis Rheum *48*, 2132-2145.

in rheumatoid joints. Rheumatology *43*, 569-573.

hepatocarcinogenesis triggered by AID causing deleterious p53 mutations.

Matsumoto, T., Mano, S., Ando, S.*, et al.* (2005). Whole genome association study of rheumatoid arthritis using 27 039 microsatellites. Human Molecular Genetics *14*,

inflammatory arthritides: a potential indicator of synovial inflammatory monokine

expression of gelatinase B (MMP-9) and stromelysin-1 (MMP-3) by rheumatoid

Breedveld, F., & Huizinga, T. (2002). Invasive properties of fibroblast-like synoviocytes: correlation with growth characteristics and expression of MMP-1,

Verweij, C.L. (2010). Synovial tissue heterogeneity in rheumatoid arthritis in relation to disease activity and biomarkers in peripheral blood. Arthritis Rheum *62*,

Kraan, M.C., Fero, M., Tak, P.P., Huizinga, T.W., Pieterman, E., Breedveld, F.C., Alizadeh, A.A., & Verweij, C.L.(2003). Rheumatoid arthritis is a heterogeneous disease: evidence for differences in the activation of the STAT-1 pathway between

(TNFAIP3) is a central regulator of immunopathology. Trend Immunol *30*, 383-391.

Fractalkine: a novel angiogenic chemokine in rheumatoid arthritis. Am J Pathol

Yokoe, T., Kaneko, A., Asai, T.*, et al.* (1998). Modulation by proinflammatory cytokines of Fas/Fas ligand-mediated apoptotic cell death of synovial cells in

S., Stiehl, P., Gromnica-Ihle, E.*, et al.* (1999). Characterization of collagenase 3 (matrix metalloproteinase 13) messenger RNA expression in the synovial membrane and synovial fibroblasts of patients with rheumatoid arthritis. Arthritis


Roivainen, A., Pirila, L., Yli-Jama, T., Laaksonen, H., & Toivanen, P. (1999). Expression of the

Sakaguchi, N., Takahashi, T., Hata, H., Nomura, T., Tagami, T., Yamazaki, S., Sakihama, T.,

Salcedo, R., Wasserman, K., Young, H.A., Grimm, M.C., Howard, O.M., Anver, M.R.,

Salcedo, R., Ponce, M.L., Young, H.A., Wasserman, K., Ward, J.M., Kleinman, H.K.,

Sawa, S., Kamimura, D., Jin, G.H., Morikawa, H., Kamon, H., Nishihara, M., Ishihara, K.,

Scott, B.B., Zaratin, P.F., Colombo, A., Hansbury, M.J., Winkler, J.D., & Jackson, J.R. (2002).

Szekanecz, Z., & Koch, A.E. (2007). Mechanisms of Disease: angiogenesis in inflammatory

Sorsa, T., Konttinen, Y.T., Lindy, O., Ritchlin, C., Saari, H., Suomalainen, K., Eklund, K.K., &

Stahl, E.A., Raychaudhuri, S., Remmers, E.F., Xie, G., Eyre, S., Thomson, B.P., Li, Y.H.,

Sugino, H., Lee, H.M., & Nishimoto, N. (2010). DNA microarray analysis of rheumatoid

Sun, Y., Zeng, X.R., Wenger, L., Firestein, G.S., & Cheung, H.S. (2004). P53 down-regulates

Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-

Takai, A., Toyoshima, T., Uemura, M., Kitawaki, Y., Marusawa, H., Hiai, H., Yamada, S.,

basal transcription complex. J Cell Biochem *92*, 258-269.

rheumatoid arthritis. Nat Genet *34*, 395-402.

Scand J Rheumatol *28*, 314-318.

progression. Blood *96*, 34-40.

Rheumatol *29*, 230-239.

Arthritis Rheum *22*, 44-53.

Nature Genetics *42*, 508-U556.

Arthritis Res Ther *12*, 401.

factor-1alpha. Am J Pathol *154*, 1125-1135.

proliferation of CD4+ T cells. J Exp Med *203*, 1459-1470.

diseases. Nat Clin Pract Rheumatol *3*, 635-643.

*426*, 454-460.

myc-family proto-oncogenes and related genes max and mad in synovial tissue.

Matsutani, T., Negishi, I., Nakatsuru, S.*, et al.* (2003). Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature

Kleinman, H.K., Murphy, W.J., & Oppenheim, J.J. (1999). Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: In vivo neovascularization induced by stromal-derived

Oppenheim, J.J., & Murphy, W.J. (2000). Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor

Murakami, M., & Hirano, T. (2006). Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic

Constitutive expression of angiopoietin-1 and -2 and modulation of their expression by inflammatory cytokines in rheumatoid arthritis synovial fibroblasts. J

Santavirta, S. (1992). Collagenase in synovitis of rheumatoid arthritis. Semin

Kurreeman, F.A.S., Zhernakova, A., Hinks, A.*, et al.* (2010). Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.

arthritis susceptibility genes identified by genome-wide association studies.

matrix metalloproteinase-1 by targeting the communications between AP-1 and the

Hamada M, Kawaida R, Ono M, *et al.* (2003). Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with

Okazaki, I.M., Honjo, T., Chiba, T.*, et al.* (2009). A novel mouse model of

hepatocarcinogenesis triggered by AID causing deleterious p53 mutations. Oncogene *28*, 469-478.


**6** 

*Poland* 

**Lysosomal Glycosidases in** 

Janusz Popko1, Tomasz Guszczyn1,

*1Medical University, Białystok,* 

Sławomir Olszewski1, Krzysztof Zwierz2

*2Medical College of the Universal Education Society, Łomza,* 

**Degradation of Human Articular Cartilage** 

Joint diseases cause serious medical problems for several million people world-wide and therefore the World Health Organization has designated years 2000-2010 as the Decade of

Osteoarthritis (OA) is the most common, and increasingly prevalent, human joint disorder (Dieppe, 2000). It has been estimated that in 1990 12 % of Americans, nearly 21 million

Rheumatoid arthritis (RA) affects about 0.3 to 1.5% of the world population(Chikanza et.al., 1998). Juvenile idiopatic arthritis (JIA) is one of the most common rheumatic diseases in children, which causes pain and functional disability. According to a 2008 study performed by the National Arthritis Data Workgroup, there were close to 3000,000 children in the

Lyme arthritis (LA) caused by spirochete Borrelia burgdorferi, is increasing in prevalence disease involving the musculoskeletal system, particularly affecting knee joints (Pancewicz

RA and JIA are chronic autoimmune inflammatory diseases primarily affecting the synovial membrane, leading to joint damage and destruction. OA is the most common joint disorder

Clinical and epidemiological studies on OA have recognized a series of etiologic factors including local factors (such as malformations or joint injuries) and systemic factors (such as overweight, race, gender, or metabolic diseases). OA is associated with a loss of proper balance between synthesis and degradation of the macromolecules that gives articular cartilage its biomechanical and functional properties. Concomitantly in OA, changes occur

Progressive destruction of articular cartilage is a common feature of OA, RA, and LA. The articular cartilage from patients with OA and RA has decreased concentrations of proteoglycans and glycosaminoglycans (GAGs), and the size of GAG molecules is also

and a major public health problem in western populations (Lawrence et al. 1998).

in the structure and metabolism of the synovium and subchondral bone of the joint.

people had clinical symptoms of osteoarthritis (Lawrence et al., 1998).

U.S.A. with some form of juvenile arthritis (Giannini et al., 2010).

**2. Degradation of human articular cartilage** 

**1. Introduction** 

et. al.2009).

the Bone and Joint (Popko et al.2011).

