PART1.
骨關節炎（OA）是關節炎中最常發生的疾病，主要的成因是長期的使用和年紀的增長等，並造成關節軟骨的物理性磨損和引起蛋白分解酵素降解軟骨組織，使得軟骨中的膠原蛋白纖維和醣蛋白降解，Matrix metalloproteinases（MMPs）被認為在骨關節炎中是降解軟骨組織過程中重要物質。近來報告指出，在OA 中表現的MMPs mRNA 主要有MMP-1, MMP-3, MMP-9, 和MMP-13 。在本實驗目的，證明Hyaluronan (HA), chondroitin sulfate A（CA）和indomethacin 可以抑制在interleukin-1β (IL-1β ) 刺激人類chondrosarcoma SW-1353細胞之下所產生的MMP-3。結果顯示，HA和 CA會隨著劑量的增加有效的抑制MMP-3產生；indomethacin可以有效抑制的MMP-3分泌，但不抑制細胞內的表現。此外，NO是軟骨細胞分化和細胞凋亡的重要調節因子之一，並且可經由前發炎激素像是IL-1β所活化產生。結果也顯示，HA和 CA 會隨著劑量的增加，明顯有效的抑制iNOS表現和 NO產生；HA和 CA只抑制NO產生但沒有抑制iNOS表現。結論， HA和 CA可以有效的阻止OA的發展 ，這可再次證明，目前臨床使用可以有效治療關節炎。Indomethacin不但減少MMP-3的分泌，也藉由抑制NO產生並能夠降低發炎現象，這都有助於治療OA。因此實驗結果提供新的證據印證HA、CA和 indomethacin可以有效幫助OA治療。

PART2.
本篇實驗的目的，研究經由玻尿酸（hyaluronan）和indomethacin共同作用治療抗原所引起的關節炎（antigen-induced arthritic ,AIA）兔子實驗動物模式。在玻尿酸和indomethacin注射關節中治療的期間，觀察兔子關節的腫脹，血清中C-reactive protein levels (CRP), 和prostaglandin E2 的變化，並且觀察血清中matrix metalloproteinases-3（MMP-3）活性、巨觀和微觀觀察關節的變化。玻尿酸和indomethacin會使CRP下降，低劑量的indomethacin結合玻尿酸一起治療(Low I-H 5.6 μM indomethacin and hyaluronan)，比單獨玻尿酸治療更能降低局部的發炎反應。 對 prostaglandin E2 的抑制效果有隨著劑量的增高，在High I-H (High I-H560 μM indomethacin and hyaluronan) 的治療組最明顯。在Western blot analysis 中各組的 MMP-3 表現皆是持續增加的，而在血清中抑制MMP-3效果，在Low I-H的治療組最明顯。巨觀和病理切片觀察中，單獨玻尿酸、Low I-H 和High I-H 治療皆有相當的治療效果。 結論，此實驗證明在臨床前用玻尿酸結合 indomethacin 注射關節治療，比單獨服用indomethacin（或MMP inhibitors）治療類風濕性關節炎提供更好的臨床效果。

PART1.
Osteoarthritis (OA) is the most prevalent disease of articular joints and is the major cause of disability in the elderly. Pathophysiologic changes occur in OA cartilage due to the excessive expression of cartilage degrading proteinases, the resultant progressive breakdown of collagen fibers, and the degradation of proteoglycan, mainly aggrecan . Matrix metalloproteinases （MMPs）are considered to be important in the chondrolytic processes that contribute to the degenerative changes in OA cartilage. Recent studies have identified the mRNA for some MMPs, such as MMP-1, MMP-3, MMP-9, and MMP-13, in human OA cartilage. In this study, we investigated the inhibitory effects of hyaluronan (HA), chondroitin sulfate A（CA） and indomethacin on the interleukin-1β (IL- 1β)–stimulated expression of MMP-3 in human chondrosarcoma SW-1353. The results showed that HA and CA effectively inhibited MMP-3 expression.. Indomethacin decreased MMP-3 protein secretion, but not inhibited the intracelluar protein expression . Besides, NO is generally believed to be an important mediator of the dedifferentiation and apoptosis of articular chondrocytes by the action of proinflammatory cytokines, such as interleukin- 1β.The results showed that HA and CA significantly inhibited the iNOS expression and nitric oxide production by the dose-dependent mamer. Indomethacin only inhibited nitric oxide production, but not inhibited the iNOS expression. In conclusion, HA and CA could effectively inhibit OA, which supports the clinical use in the treatment. Indomethacin reduced MMP-3 secretion in the mediun and
decreased the inflammatory response by inhibition of nitric oxide production were helpful to cure OA. Therefore, our study provides new data on the mechanism of action of these drugs, which could help to explain their clinical efficacy in OA patients.

PART2.
The combined effect of hyaluronan and indomethacin in the treatment of arthritis using antigen-induced arthritic (AIA) rabbits as a model was evaluated in this study. AIA was monitored by assessing joint swelling, C-reactive protein levels (CRP), and prostaglandin E2 in New Zealand white rabbits for 40 days during the course of special interval treatment by intra-articular injections of hyaluronan and indomethacin. The contralateral knee joint that was not treated served as an internal control. End-point analyses included a matrix metalloproteinases-3 activity assay, and macroscopic and microscopic joint examinations. Hyaluronan (H) and indomethacin (I)-treated rabbits showed a reduction in serum CRP levels with respect to hyaluronan-treated ones. The results of although there was no significant therapeutic effect, an intra-articular injection of low I-H (5.6 μM indomethacin and hyaluronan) was a little more efficient than hyaluronan alone in reducing local inflammation in the knee joint. Clinical assessments of the drug treatments (4 intra-articular injections in the right knee joint) on AIA in rabbits, there were no statistically significant differenc of the experiment, but the effect of indomethacin and hyaluronan on serum CRP, PGE2, and MMP-3 were statistically significant difference. Statistically significant inhibition of serum CRP was only observed in the low I-H group. Inhibition of serum PGE2 was dose-dependent in the low I-H group (13.3% ± 2.9%) and high I-H group
(35.9% ± 3.3%). The order of serum MMP-3 inhibition was the low I-H group (-64.6% ± 12.0%) > high I-H group (-75.8% ± 5.0%) > hyaluronan group (-81.7% ± 26.7%). In Western blot analysis of MMP-3, there was a continual increase in serum pro-form MMP-3 protein in all treatment groups (immunization) from days 1 to 40. Macroscopic analysis and histological analysis of the joints, there were improved efficiency in the hyaluronan treatment group , in the low I-H group and high I-H group . Conclusion of this study provides preclinical support for the hypothesis that an intra-articular injection of hyaluronan in combination with indomethacin (and/or MMP inhibitors) might provide substantially greater clinical benefits to rheumatoid arthritis patients than indomethacin (and/or MMP inhibitors) alone at the systemic level than are achievable with current therapies.

PART1.
Abstract
中文摘要
TABLE of CONTENT：
Chapter 1 ： INTRODUCTION
1、The summary of osteoarthritis (OA
2、The cytokine interleukin-1 (IL-1)
3、NO
4、Hyaluronic acid
5、Chondroitin sulfate
6、Non-steroidal anti-inflammatory drugs
7、The purpose of this study
Chapter 2：MATERIALS AND METHODS
1.、Materials
2、Methods
（1）Cell lines
（2）MTT assay for cell proliferation
（3）Nitric Oxide Colorimetric Assay
（4）SDS–PAGE and Western blot analysis
Chapter 3：RESULTS
1、Effects of IL-1β on MMP-3 expression in SW-1353
2、The extent of cell viability
3、Hyaluronic acid sodium salt（HA）inhibit IL-1β-induced MMP-3
4、 Hyaluronic Acid FCH sodium hyaluronate FCH200 inhibit IL-1β-induced MMP-3
5、Chondroitin sulfate A Sodium salt（CA）inhibit IL-1β-induced MMP-3
6、Indomethacin inhibit IL-1β-induced MMP-3
7、Inhibition of NO production in cultured medium
8、Effects of IL-1β induced iNOS expression
9、Inhibition effects of IL-1β induced iNOS expression
Chapter 4：DISCUSSION
Chapter 5：REFERNCES
Chapter 6：FIGURES

PART2.
Abstract
中文摘要
TABLE of CONTENT：
Chapter 1 ： INTRODUCTION
1、The summary of arthritis.
2、The effect and function of Hyaluronan
3、Non-steroidal anti-inflammatory drugs
4、Antigen-induced arthritis (AIA) model
5、The index marker of arthritis
6、The purpose of this study
Chapter 2：MATERIALS AND METHODS
1.、Materials
2.、Methods
（1）Preparation of the hyaluronan and indomethacin intra-articular injection
（2）AIA animal model
（3）Clinical assessments of AIA
（4）CRP assay
（5）PGE2 assay
（6）Quantification of MMP-3
（7）Inhibition of therapeutic responses formula
（8）Western blot analysis
（9）Macroscopic analysis of the joints
Chapter 3：RESULTS
1、Development of arthritis
2、Weight of the rabbits
3、Effect of indomethacin and hyaluronan on joint swelling
4、Effect of indomethacin and hyaluronan on serum CRP, PGE2, and MMP-3
5、Inhibition of therapeutic responses
6、Western blot analysis of MMP-3
7、Macroscopic analysis of the joints
8、Histological analysis of the joints
Chapter 4：DISCUSSION
Chapter 5：REFERNCES

PART1.
1. Sandell, L. J., and Aigner, I. (2001) Arthritis Res. 3, 107–113 5.
2. Poole AR. Cartilage in health and disease. In: Koopman WJ, editor. Arthritis and allied conditions: a textbook of rheumatology. 14th ed. Baltimore: Lippincott Williams & Wilkins; 2001. p. 226–84.
3. Woessner JF Jr, Gunja-Smith Z. Role of metalloproteinases in human osteoarthritis. J Rheumatol 1991;18:99–101.
4. Shlopov BV, Lie W-R, Mainardi CL, Cole AA, Chubinskaya S, Hasty KA. Osteoarthritic lesions: involvement of three different collagenases. Arthritis Rheum 1997;40:2065–74.
5. Freemont AJ, Hampson V, Tilman R, Goupille P, Taiwo Y, Hoyland JA. Gene expression of matrix metalloproteinase 1, 3, and 9 by chondrocytes in osteoarthritic human knee articular cartilage is zone and grade specific. Ann Rheum Dis 1997;56:542–9.
6. Yuan GH, Masuko-Hongo K, Kato T, Nishioka K.. Immunologic intervention in the pathogenesis of osteoarthritis. Arthritis Rheum 2003 48:602–611.
7. Shlopov BV, Gumanovskaya ML, Hasty KA. Autocrine regulation of collagenase 3 (matrix metalloproteinase 13) during osteoarthritis. Arthritis Rheum 2000;43:195–205.
8. Freemont AJ, Byers RJ, Taiwo YO, Hoyland JA. In situ zymographic localisation of type II collagen degrading activity in osteoarthritic human cartilage. Ann Rheum Dis 1999;58:357–65.
9. Billinghurst RC, Dahlberg L, Ionescu M, Reiner A, Bourne R, Rorabeck C, et al. Enhanced cleavage of type II collagen bycollagenases in osteoarthritic cartilage. J Clin Invest 1997;99: 1534–45.
10. Tetlow LC, Adlam DJ, Woolley DE. Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. Arthritis Rheum 2001;44:585–94.
11. Arend, W. P., Malyak, M., Guthridge, C. J. & Gabay, C. Interleukin-1 receptor antagonist: role in biology. Annu. Rev. Immunol. 16, 27–55 (1998).
12. Hallegua, D. S. & Weisman, M. H. Potential therapeutic uses of interleukin-1 receptor antagonists in human diseases. Ann. Rheum. Dis. 61, 960–967 (2003).
13. Cominelli, F. & Pizarro, T. T. Interleukin-1 and interleukin-1 receptor antagonist in inflammatory bowel disease. Aliment. Pharmacol. Ther. 10, 49–53 (1996).
14. Rothwell, N. J. Interleukin-1 and neuronal injury: mechanisms, modification and therapeutic potential. Brain Behav. Immun. 17, 152–157 (2003).
15. Dayer, J. M. The saga of the discovery of IL-1 and TNF and their specific inhibitors in the pathogenesis and treatment of rheumatoid arthritis. Joint Bone Spine 69, 123–132 (2002).
16. Firestein, G. S. et al. IL-1 receptor antagonist production and gene expression in rheumatoid arthritis and osteoarthritis synovium. Arthritis Rheum. 149, 1054–1062 (1992).
17. Kahle, P. et al. Determination of cytokines in synovial fluids: correlation with diagnosis and histommorphological characteristics of synovial fluid. Ann. Rheum. Dis. 51, 731–734 (1992).
18. Koch, A. E., Kunkel, S. L., Chensue, S. W., Haines, G. K. & Streiter, R. M. Expression of interleukin-1 and interleukin-1 receptor antagonist by human rheumatoid synovial tissue macrophages. Clin. Immunol. Immunopathol. 65, 23–29 (1992).
19. Nouri, A. M., Panayi, G. S. & Goodman, S. M. Cytokines and the chronic inflammation of inflammatory disease. I. The presence of interleukin-1 in synovial fluids. Clin. Exp. Immunol. 55, 295–302 (1984)
20.. Amin, A. R., and Abramson, S. B. (1998) Curr. Opin. Rheumatol. 10,29263–268
21. Blanco, F. J., Guitian, R., Vazquez-Martul, E., de Toro, F. J., and Galdo, F. (1998) Arthritis Rheum. 41, 284–289
22. Hashimoto, S., Oche, R. L., Komiya, S., and Lotz, M. (1998) Arthritis Rheum. 41, 1632–1638
23. Amin, A. R., Attur, M., Abramson, S. B. (1999) Curr. Opin. Rheumatol. 11, 202–209
24. Abramson, S. B., Attur, M., Amin, A. R., and Clancy, R. (2001) Curr. Rheumatol.Rep. 3, 535–541
25. Tamura, T., Nakanishi, T., Kimura, Y., Hattori, T., Sasaki, K., Norimatsu, H., Takahashi, K., and Takigawa, M. (1996) Endocrinology. 137, 3729–3737
26. Jouzeau, J. Y., Pacquelet, S., Boileau, C., Nedelec, E., Presle, N., Netter, P., and Terlain, B. (2002) Biorheology. 39, 201–214
27. Cao, M., Westerhausen-Larson, A., Niyibizi, C., Kavalkovich, K., Georgescu, H. I., Rizzo, C. F., Hebda, P. A., Stefanovic-Racic, M., and Evans, C. H. (1997) Biochem. J. 324, 305–310
28. Taskiran, D., Stefanovic-Racic, M., Georgescu, H. I., and Evans, C. H. (1994) Biochem. Biophys. Res. Commun. 200, 142–148
29. Notoya, K., Jovanovic, D. V., Reboul, P., Johanne, M. P., Mineau, F., and Pelletier, J. P. (2000) J. Immunol. 165, 3402–3410
30. Peyron JG. Intraarticular hyaluronan injections in the treatment of osteoarthritis: state-of-the-art review. J Rheumatol 1993;20 Suppl39:10–5.
31. Homandberg GA, Meyers R, Xie DL. Fibronectin fragments cause chondrolysis of bovine articular cartilage slices in culture. J BiolChem 1992;267:3597–604.
32. Yasuda T, Poole AR. A fibronectin fragment induces type II collagen degradation by collagenase through an interleukin-1–mediated
30pathway. Arthritis Rheum 2002;46:138–48.
33. Fukuda K, Dan H, Takayama M, Kumano F, Saitoh M, Tanaka S. Hyaluronic acid increases proteoglycan synthesis in bovine articular cartilage in the presence of interleukin-1. J Pharmacol Exp Ther 1996;277:1672–5.
34. Salter DM, Godolphin JL, Gourlay MS, Lawson MF, Hughes DE, Dunne E. Analysis of human articular chondrocyte CD44 isoform expression and function in health and disease. J Pathol 1996;179: 396–402.
35. Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell 1990;61: 1303–13.
36. Toba T, Mizusawa N, Tajima G, Horiuchu S. Upregulation of CD44 mRNA expression by interleukin- 1 in cultured rabbit articular chondrocytes. J Bone Miner Metab 1997;15:84–93.
37. Nishida Y, D’Souza AL, Thonar EJ-MA, Knudson W. Stimulation of hyaluronan metabolism by interleukin- 1 in human articular cartilage. Arthritis Rheum 2000;43:1315–26.
38. Mikecz K, Dennis K, Shi M, Kim JH. Modulation of hyaluronan receptor (CD44) function in vivo in a murine model of rheumatoid arthritis. Arthritis Rheum 1999;42:659–68.
39. Neidhart M, Gay RE, Gay S. Anti–interleukin-1 and anti-CD44 interventions producing significant inhibition of cartilage destruction in an in vitro model of cartilage invasion by rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 2000;43:1719–28.
40. McCourt PA, Ek B, Forsberg N, Gustafson S. Intercellular adhesion molecule-1 is a cell surface receptor for hyaluronan. J Biol Chem 1994;269:30081–4.
41. Davies ME, Dingle JT, Pigott R, Power C, Sharma H. Expression of intercellular adhesion molecule 1 (ICAM-1) on human articular cartilage chondrocytes. Connect Tissue Res 1991;26:207–16.31
42. Kienzle G, von Kempis J. Vascular cell adhesion molecule 1 (CD106) on primary human articular chondrocytes: functional regulation by cytokines and comparison with intercellular adhesion molecule 1 (CD54) and very late activation antigen 2. Arthritis Rheum 1998;41:1296–305.
43. Hardingham TE. Chondroitin sulfate and joint disease. Osteoarthritis Cartilage1998, 6:3–5.
44. Hardingham TE, Fosang AJ: Proteoglycans. Many forms, many functions. FASEB J 1992, 6:861–870.
45. Bassleer CT, Comban JPA, Bougaret S, et al.: Effects of chondroitin sulfate and interleukin- 1 on human articular chondrocytes cultivated in clusters. Osteoarthritis Cartilage 1998, 6:196–204.
46. Nerucci F, Fioravanti A, Cicero MR, et al.: Effects of chondroitin sulfate and interleukin- 1 on human chondrocyte cultures exposed to pressurization: a biochemical and morphological study. Osteoarthritis Cartilage 2000, 8:279–287
47. Dubois, R. N., Abramson, S. B., Crofford, L., Gupta, R. A., Simon, L. S., Van De Putte, L. B., and Lipsky, P. E. (1998) FASEB J. 12, 1063–1073
48. Ding, C. (2002) Inflammation 26, 139–142
49. Dingle, J. T. (1999) Rheumatology. 58, 125–129
50. Mukherjee, P., Rachita, C., Aisen, P. S., and Pasinetti, G. M. (2001) Clin. Exp. Rheumatol. 19, S7–11
51. Tegeder, I., Pfeilschifter, J., Geisslinger, G. (2001) FASEB J. 15, 2057–2072
52. Monfort J, Nacher M, Montell E, Vila J, Verges J, Benito P. Chondroitin sulfate and hyaluronic acid (500-730 kda) inhibit stromelysin-1 synthesis in human osteoarthritic chondrocytes. Drugs Exp Clin Res. 2005;31(2):71-6.
53.Martel-Pelletier, J., Alaaeddine, N., and Pelletier, J. P. (1999) Frontiers32Biosci.4, 694–703
54. Farrell, A. J., Blake, D. R., Palmer, R. M., and Moncada, S. (1992) Ann. Rheum. Dis. 51, 1219–1222

PART2.
1. Walker JM, Helewa A. Physical therapy in arthritis. Philadelphia, PA: Saunders, 1996.
2. Shahbaz H, James WS. Septic arthritis. Curr Treat Opt Infect Dis 3:279-86;2001.
3. Goldring SR, Gravallese EM. Mechanisms of bone loss in inflammatory arthritis: diagnosis and therapeutic implications. Arthritis Res 2(1):33-7;2000.
4. Brandt KD, Smith GN, Jr., Simon LS. Intraarticular injection of hyaluronan as treatment for knee osteoarthritis: What is the evidence? Arthritis Rheum 43(6):1192-203;2000.
5. Ceponis A, Waris E, Monkkonen J, Laasonen L, Hyttinen M, Solovieva SA, et al. Effects of low-dose, noncytotoxic, intraarticular liposomal clodronate on development of erosions and proteoglycan loss in established antigen-induced arthritis in rabbits. Arthritis Rheum 44(8):1908-16;2001.
6. Campo GM, Avenoso A, Campo S, Ferlazzo AM, Altavilla D, Calatroni A. Efficacy of treatment with glycosaminoglycans on experimental collagen-induced arthritis in rats. Arthritis Res Ther 5(3):R122-31;2003.
7. Moreland LW. Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: mechanisms of action. Arthritis Res Ther 5(2):54-67;2003.
8. Aggarwal A, Sempowski IP. Hyaluronic acid injections for knee osteoarthritis. Systematic review of the literature. Can Fam Physician 50:249-56;2004.
9. Yasui T, Akatsuka M, Tobetto K, Hayaishi M, Ando T. The effect of hyaluronan on interleukin-1 alpha-induced prostaglandin E2 production in human osteoarthritic synovial cells. Agents Actions 37(1-2):155-6;1992.
10. Tobetto K, Yasui T, Ando T, Hayaishi M, Motohashi N, Shinogi M, et al. Inhibitory effects of hyaluronan on [14C] arachidonic acid release from labeled human synovial fibroblasts. Jpn J Pharmacol 60(2):79-84;1992.
11. Larsen NE, Lombard KM, Parent EG, Balazs EA. Effect of hylan on cartilage and chondrocyte cultures. J Orthop Res 10(1):23-32;1992.
12. Presti D, Scott JE. Hyaluronan-mediated protective effect against cell damage caused by enzymatically produced hydroxyl (OH.) radicals is dependent on hyaluronan molecular mass. Cell Biochem Funct 12(4):281-8;1994. 21
13. Gomis A, Pawlak M, Balazs EA, Schmidt RF, Belmonte C. Effects of different molecular weight elastoviscous hyaluronan solutions on articular nociceptive afferents. Arthritis Rheum 50(1):314-26;2004.
14. Williams HJ, Ward JR, Egger MJ, Neuner R, Brooks RH, Clegg DO, et al. Comparison of naproxen and acetaminophen in a two-year study of treatment of osteoarthritis of the knee. Arthritis Rheum 36(9):1196-206;1993.
15. Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis 63(8):901-7;2004.
16. Wolfe F, Zhao S, Lane N. Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients: a survey of 1,799 patients with osteoarthritis, rheumatoid arthritis, and fibromyalgia. Arthritis Rheum 43(2):378-85;2000.
17. Huang SH. Rheumatology: 7. Basics of therapy. CMAJ 163(4):417-23;2000.
18. Yoon JB, Kim SJ, Hwang SG, Chang S, Kang SS, Chun JS. Non-steroidal anti-inflammatory drugs inhibit nitric oxide-induced apoptosis and dedifferentiation of articular chondrocytes independent of cyclooxygenase activity. J Biol Chem 278(17):15319-25;2003.
19. Ceponis A, Waris E, Monkkonen J, Laasonen L, Hyttinen M, Solovieva SA, et al. Effects of low-dose, noncytotoxic, intraarticular liposomal clodronate on development of erosions and proteoglycan loss in established antigen-induced arthritis in rabbits. Arthritis Rheum 44(8):1908-16;2001.
20. Posthumus MD, Limburg PC, Westra J, Cats HA, Stewart RE, van Leeuwen MA, et al. Serum levels of matrix metalloproteinase-3 in relation to the development of radiological damage in patients with early rheumatoid arthritis. Rheumatology (Oxford) 38(11):1081-7;1999.
21. Kidd BL, Urban LA. Mechanisms of inflammatory pain. Br J Anaesth 87(1):3-11;2001.
22. Shafer-Weaver KA, Sayers T, Kuhns DB, Strobl SL, Burkett MW, Baseler M, et al. Evaluating the cytotoxicity of innate immune effector cells using the GrB ELISPOT assay. J Transl Med 2(1):31;2004.
23. Hanke JH, Gardner JP, Dow RL, Changelian PS, Brissette WH, Weringer EJ, et al. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J Biol Chem 271(2):695-701;1996.
24. Dawson J, Engelhardt P, Kastelic T, Cheneval D, MacKenzie A, Ramage P. Effects 22 of soluble interleukin-1 type II receptor on rabbit antigen-induced arthritis: clinical, biochemical and histological assessment. Rheumatology (Oxford) 38(5):401-6;1999.
25. Trifan OC, Hla T. Cyclooxygenase-2 modulates cellular growth and promotes tumorigenesis. J Cell Mol Med 2003;7(3):207-22.
26. Johnson LL, Bornemeier DA, Janowicz JA, Chen J, Pavlovsky AG, Ortwine DF. Effect of species differences on stromelysin-1 (MMP-3) inhibitor potency. An explanation of inhibitor selectivity using homology modeling and chimeric proteins. J Biol Chem 274(35):24881-7;1999.
27. Yamanaka H, Matsuda Y, Tanaka M, Sendo W, Nakajima H, Taniguchi A, et al. Serum matrix metalloproteinase 3 as a predictor of the degree of joint destruction during the six months after measurement, in patients with early rheumatoid arthritis. Arthritis Rheum 43(4):852-8;2000.