Journal of Haehwa Medicine (혜화의학회지)

Research Institute of Korean Medicine (대전대학교 한의학연구소)
권호 표지

The Effect of KKBT in Papain-Induced Osteoarthritis Mice Models

건강부자탕(乾薑附子湯)이 papain으로 유도(誘導)된 골관절염(骨關節炎) 생쥐 모델에 미치는 영향(影響)

  • Sung, Yeong-Suk (Dept. of Pathology, College of Oriental Medicine, Daejeon University) ;
  • Choi, Hak-Joo (Dept. of Pathology, College of Oriental Medicine, Daejeon University) ;
  • Oh, Jeong-Min (Dept. of Pathology, College of Oriental Medicine, Daejeon University) ;
  • Ji, Joong-Gu (Dept. of Oriental health care, Joongbu University) ;
  • Bak, Ji Won (Dept. of Pathology, College of Oriental Medicine, Daejeon University) ;
  • Kim, Dong-Hee (Dept. of Pathology, College of Oriental Medicine, Daejeon University)
  • Received : 2012.07.11
  • Accepted : 2012.08.08
  • Published : 2012.08.20
Download PDF
⟨ Previous Next ⟩

Abstract

To evaluate the efficacy of Keonkangbujatang (KKBT) in osteoarthritis treatments, C57BL/10 mice were treated with papain to induce osteoarthritis, and anti-arthritic effects were measured. To ensure safety of the KKBT sample, ALT, AST, BUN, and creatinine levels were measured, and they were all within the normal range. Based on the fact that suppression of inflammatory cytokines leads to the improvement of arthritis, IL-1b, IL-6, TNF-a, and MCP-1 production levels were measured. The cytokines were significantly decreased in serum. Also, mRNA levels of IL-1b, IL-6, and iNOS-II were significantly decreased in joint tissues. PGE2, a usual inflammation vector, and LTB4, TXB2, that are involved in the onset and deterioration of inflammation, were all significantly decreased. The levels of white blood cells, neutrophiles, and mononucleophiles also decreased, although the numbers were not significantly large. I*mmune-modulation of KKBT in the pathological mechanism of cartilage deterioration by inflammatory cells and their vectors was proved. This study should provide basis for the development of effective therapeutics as well as use in clinical practice.

Keywords

References

  1. Altman RD. The syndrome of osteoarthritis. J Rheumatol 24:766-7. 1997.
  2. Buckwalter JA, Mankin HJ. Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation. Instr Course Lect 47:487-504. 1998.
  3. Pritzker KP. Animal models for osteoarthritis: processes, problems and prospects. Ann Rheum Dis 53:406-20. 1994. https://doi.org/10.1136/ard.53.6.406
  4. Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, et al.: OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence. Osteoarthritis Cartilage 15:981-1000, 2007 https://doi.org/10.1016/j.joca.2007.06.014
  5. Yuan PW, Liu DY, Chu XD, Hao YQ, Zhu C, Qu Q. Effects of preventive administration of juanbi capsules on TNF-${\alpha}$, IL-1 and IL-6 contents of joint fluid in the rabbit with knee osteoarthritis. J Tradit Chin Med. Dec;30(4):254-8, 2010. https://doi.org/10.1016/S0254-6272(10)60052-0
  6. Smolen J, Kay J, Doyle MK et al. Golimumab, a new human anti-TNF-${\alpha}$ monoclonal antibody, subcutaneously administered every 4 weeks in patients with active rheumatoid arthritis who were previously treated with anti-TNF-${\alpha}$ agent(s): results of the randomized, double-blind, placebo-controlled, GO-AFTER study. Ann Rheum Dis;67(Suppl II):50. 2008
  7. Takahashi K, et al : The effects of hyaluronan on matorix metalloproteinase-3(MMP-3), interleukin-$1{\beta}$ (IL-$1{\beta}$), and tissue inhibitor of metalloproteinase-1 TIMP-1) gene expression during the development of osteoarthritis. Osteoarthritis Cartilage 7: 182-190, 1999. https://doi.org/10.1053/joca.1998.0207
  8. Kintscher U, Goetze S, Wakino S, Kim S, Nagpal S, Chandraratna RA, Graf K, Fleck E, Hsueh WA, Law RE: Peroxisome proliferator-activated receptor and retinoid X receptor ligands inhibit monocyte chemotactic protein-1-directed migration of monocytes. Eur J Pharmacol, 401(3): 259-270, 2000. https://doi.org/10.1016/S0014-2999(00)00461-1
  9. Qvist P, Bay-Jensen AC, Christiansen C, Dam EB, Pastoureau P, Karsdal MA. The disease modifying osteoarthritis drug (DMOAD): Is it in the horizon? Pharmacol Res. Jul;58(1):1-7. 2008. https://doi.org/10.1016/j.phrs.2008.06.001
  10. Strand V, Simon LS, Dougados M, Sands GH, Bhadra P, Breazna A, Immitt J. Treatment of osteoarthritis with continuous versus intermittent celecoxib. J Rheumatol. Dec;38(12):2625-34, 2011. https://doi.org/10.3899/jrheum.110636
  11. Cameron M, Gagnier JJ, Little CV, Parsons TJ, Blumle A, Chrubasik S. Evidence of effectiveness of herbal medicinal products in the treatment of arthritis. Part I: Osteoarthritis. Phytother Res. Nov;23(11):1497-515, 2009. https://doi.org/10.1002/ptr.3007
  12. Wenz W, Breusch SJ, Graf J, Stratmann U. Ultrastructural findings after intraarticular application of hyaluronan in a canine model of arthropathy. J Orthop Res 18:604-12. 2002
  13. Zahmatkash M, Vafaeenasab MR. Comparing analgesic effects of a topical herbal mixed medicine with salicylate in patients with knee osteoarthritis. Pak J Biol Sci. Jul 1;14(13):715-9, 2011. https://doi.org/10.3923/pjbs.2011.715.719
  14. Lechner M, Steirer I, Brinkhaus B, Chen Y, Krist-Dungl C, Koschier A, Gantschacher M, Neumann K, Zauner-Dungl A. Efficacy of individualized Chinese herbal medication in osteoarthrosis of hip and knee: a double-blind, randomized-controlled clinical study. J Altern Complement Med. Jun;17(6):539-47, 2011. https://doi.org/10.1089/acm.2010.0602
  15. 채인식 : 상한론역전, 고문사, pp.334-335, 1991.
  16. 유길성 : 건강부자탕의 항산화 및 항염증 효능에 관한 연구, 대전대학교대학원, 2012.
  17. 박수현, 권용욱, 이태희 : 황련해독탕과 건강부자탕이 LPS 유도에 의한 마우스 혈중 IL-6와 TNF-${\alpha}$ 변화에 미치는 영향, 대한한의학 방제학회지, 15(1):185-197, 2007.
  18. 고동균, 윤정문, 이태희 : 부자가 LPS의 뇌실 주입으로 유발된 생쥐의 혈중 IL-6와 TNF-${\alpha}$ 변화에 미치는 영향, 대한한의학 방제학회지, 12(1):195-208, 2004.
  19. 이경무 외. 三氣飮이 흰쥐의 Monosodium Iodoacetate 유발 골관절염에 미치는 영향. 한방재활의학과학회지. 18(2):17-31. 2008.
  20. 박동수 외 : 봉독약침이 Monosodium Iodoacetate로 유발된 골관절염 통증 모델에서 중추신경내 NOS, C-fos, Serotonin, Substance P 발현에 미치는 영향. 한방재활의학과학회지 17(3):1-18
  21. Altman RD, Tenenbaum J, Latta L, Riskin W, Blanco LN, Howell DS. Biomechanical and biochemical properties of dog cartilage in experimentally induced osteoarthritis. Ann Rheum Dis 43:83-90. 1984. https://doi.org/10.1136/ard.43.1.83
  22. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Nat Rev Rheumatol. Jan;7(1):33-42. 2011. https://doi.org/10.1038/nrrheum.2010.196
  23. Park H, Lee SK. Association of obesity with osteoarthritis in elderly Korean women. Maturitas. Sep;70(1):65-8, 2011. https://doi.org/10.1016/j.maturitas.2011.05.014
  24. Yang F, Shi Z. A study on papain-induced osteoarthritis in rabbit temporomandibular joint. Hua Xi Kou Qiang Yi Xue Za Zhi 20:330-2. 2002.
  25. Lin YS, Huang MH, Chai CY. Effects of helium-neon laser on the mucopolysaccharide induction in experimental osteoarthritic cartilage. Osteoarthritis Cartilage 14:377-83. 2006. https://doi.org/10.1016/j.joca.2005.10.010
  26. Hasegawa A, Otsuki S, Pauli C, Miyaki S, Patil S, Steklov N, Kinoshita M, Koziol J, D'Lima DD, Lotz MK. Anterior cruciate ligament changes in the human knee joint in aging and osteoarthritis. Arthritis Rheum. Mar;64(3):696-704. 2012. https://doi.org/10.1002/art.33417
  27. Lotz MK, Caramés B. Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA. Nat Rev Rheumatol. Aug 2;7(10):579-87, 2011. https://doi.org/10.1038/nrrheum.2011.109
  28. Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol. Sep;23(5):492-6, 2011. https://doi.org/10.1097/BOR.0b013e3283494005
  29. 김용문. 정수현, 김순중, 서일복 加味消炎湯이 Monosodium Iodoacetate로 유발된 흰쥐의 골관절염에 미치는 영향. 대한한의학 방제학회지 18(1) : 15-32, 2008
  30. 沢田哲司. 関節リウマチ-鑑別と治療選択のポイント. 診断と治療. 94 : 1155-1160. 2006.
  31. 佐野統. 関節リウマチの病態, 診断と最新治療. 兵医大医会誌. 27 : 191-204. 2002.
  32. Iwanami K, et al. : Crucial role of IL-6/IL-17 cytokine axis in the induction of arthritis by glu-cose 6 phosphate isomerase. Arthritis Rheum, 58 : 754-763, 2008. https://doi.org/10.1002/art.23222
  33. Ji H, et al. : Critical roles for interleukin 1 and tumor necrosis factor alpha in antibody-in-duced arthritis. J Exp Med. 196 : 77-85, 2002. https://doi.org/10.1084/jem.20020439
  34. Hounoki H, Sugiyama E, Mohamed SG, Shinoda K, Taki H, Abdel-Aziz HO, Maruyama M, Kobayashi M, and Miyahara T. Activation of peroxisome proliferator-activated receptor${\gamma}$inhibits TNF-${\alpha}$-mediated osteoclast differentiation in human peripheral monocytes in part via suppression of monocyte chemoattractant protein-1 expression. Bone 42: 765-774, 2008. https://doi.org/10.1016/j.bone.2007.11.016
  35. Feldmann M, Maini SR. : Role of cytokines in rheumatoid arthritis. Immunol Rev. 223 : 7-9, 2008 https://doi.org/10.1111/j.1600-065X.2008.00626.x
  36. Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Morinaga T, Higashio K, Martin TJ and Suda T. Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med. 191: 275-286. 2000. https://doi.org/10.1084/jem.191.2.275
  37. Hirohata S and Sakakibara J. Angioneogenesis as a possible elusive triggering factor in rheumatoid arthritis. Lancet. 353: 1331. 1999.
  38. Crofford LJ, Lipsky PE, Brooks P, Abramson SB, Simon LS and van de Putte LB. Basic biology and clinical application of specific cyclooxygenase-2 inhibitors. Arthritis Rheum. 43: 4-13. 2000. https://doi.org/10.1002/1529-0131(200001)43:1<4::AID-ANR2>3.0.CO;2-V
  39. Myers LK, Kang AH, Postlethwaite AE, Rosloniec EF, Morham SG, Shlopov BV, Goorha S and Ballou LR. The genetic ablation of cyclooxygenase-2 prevents the development of autoimmune arthritis. Arthritis Rheum. 43: 2687-2693. 2000. https://doi.org/10.1002/1529-0131(200012)43:12<2687::AID-ANR8>3.0.CO;2-9
  40. Paredes Y, Massicotte F, Pelletier JP, Martel-Pelletier J, Laufer S, Lajeunesse D. Study of the role of leukotriene B()4 in abnormal function of human subchondral osteoarthritis osteoblasts: effects of cyclooxygenase and/or 5-lipoxygenase inhibition. Arthritis Rheum. Jul;46(7):1804-12. 2002. https://doi.org/10.1002/art.10357
  41. Kojima F, Naraba H, Miyamoto S, Beppu M, Aoki H, Kawai S. Membrane-associated prostaglandin E synthase-1 is upregulated by proinflammatory cytokines in chondrocytes from patients with osteoarthritis. Arthritis Res Ther. 6(4):R355-65. 2004. https://doi.org/10.1186/ar1195
  42. Hashimoto A, Endo H, Hayashi I, Murakami Y, Kitasato H, Kono S, Matsui T, Tanaka S, Nishimura A, Urabe K, Itoman M, Kondo H. Differential expression of leukotriene B4 receptor subtypes (BLT1 and BLT2) in human synovial tissues and synovial fluid leukocytes of patients with rheumatoid arthritis. J Rheumatol. Aug;30(8):1712-8. 2003.
  43. Marcouiller P, Pelletier JP, Guevremont M, Martel-Pelletier J, Ranger P, Laufer S, Reboul P. Leukotriene and prostaglandin synthesis pathways in osteoarthritic synovial membranes: regulating factors for interleukin 1beta synthesis. J Rheumatol. Apr;32(4):704-12 2005
  44. Laufer S. Role of eicosanoids in structural degradation in osteoarthritis. Curr Opin Rheumatol. Sep;15(5):623-739. 2003. https://doi.org/10.1097/00002281-200309000-00017
  45. Griffiths RJ, Pettipher ER, Farrell CA, Breslow R, Conklyn MJ, Smith MA, Hackman BC, Wimberly DJ, Milici AJ, Scampoli DN, Cheng JB, Pillar JS, Pazoles CJ, Doherty NS, Melvin LS, Reiter LA, Biggars MS, Falkner FC, Mitchell DY, Liston TE, Showell HJ: Leukotriene B4 plays a critical role in the progression of collagen-induced arthritis. Proc Natl Acad Sci, 92: 517-521, 1995. https://doi.org/10.1073/pnas.92.2.517
  46. Griffiths RJ, Smith M, Roach ML, Stock JL, Stam EJ, Milici AJ, Scampoli DN, Eskra JD, Byrum RS, Koller BH, McNeish JD: Collagen-induced arthritis is reduced in 5-lipoxygenase-activating protein-deficient mice. J Exp Med, 185: 1123-1129, 1997. https://doi.org/10.1084/jem.185.6.1123
  47. Sasaki T, Irie-Sasaki JH, Jones RG et al. : Function of P13K gamma in thymocyte development, T cell activation, and neutrophil migration. science 287 : 1040-1046, 2000. https://doi.org/10.1126/science.287.5455.1040
  48. Del Prete A, Vermi W, Dander E, et al. : Defective dendritic cell migration and activation of adaptive immunity in PI3Kgamma-de$^{\wedge}$cient mice. EMBO J 23 : 3505-3515, 2004. https://doi.org/10.1038/sj.emboj.7600361
  49. LaSargue M, Calvez R, Finan P, et al. : Phosphoinositide 3 kinase gamma is an essential amplier of mast cell function. Immunity 16 : 441-451, 2002. https://doi.org/10.1016/S1074-7613(02)00282-0
  50. Crofford LJ, Lipsky PE, Brooks P, Abramson SB, Simon LS and van de Putte LB. Basic biology and clinical application of specific cyclooxygenase-2 inhibitors. Arthritis Rheum. 2000; 43: 4-13. https://doi.org/10.1002/1529-0131(200001)43:1<4::AID-ANR2>3.0.CO;2-V
  51. Myers LK, Kang AH, Postlethwaite AE, Rosloniec EF, Morham SG, Shlopov BV, Goorha S and Ballou LR. The genetic ablation of cyclooxygenase-2 prevents the develop-ment of autoimmune arthritis. Arthritis Rheum. 43: 2687-2693. 2000. https://doi.org/10.1002/1529-0131(200012)43:12<2687::AID-ANR8>3.0.CO;2-9
  52. 石井宏知. ラット顎[関節滑膜表ｯ層細胞の過剰開口負荷後における cyclooxygenase-2 とHeat shock protein25の発現の経時的変化. 鶴見歯学. 30; 31-40. 2004.
  53. Crofford LJ, Lipsky PE, Brooks P, Abramson SB, Simon LS and van de Putte LB. Basic biology and clinical application of specific cyclooxygenase-2 inhibitors. Arthritis Rheum. 43: 4-13. 2000. https://doi.org/10.1002/1529-0131(200001)43:1<4::AID-ANR2>3.0.CO;2-V
  54. Clancy RM, Amin AR, Abramson SB: The role on nitric oxide in inflammation and immunity. Arthritis Rheum, 41: 1141-1151, 1998. https://doi.org/10.1002/1529-0131(199807)41:7<1141::AID-ART2>3.0.CO;2-S
  55. Salkowski CA, Detore G, McNally R, van Rooijen N, Vogel SN: Regulation of inducible nitric oxide synthase messenger RNA expression and nitric oxide production by lipopolysaccharide in vivo: the roles of macrophages, endogenous IFN-${\gamma}$, and TNF receptor-1-mediated signaling. J Immunol, 158: 905-912, 1997.
  56. Vuolteenaho K, Moilanen T, Knowles RG, Moilanen E. The role of nitric oxide in osteoarthritis. Scand J Rheumatol. Jul-Aug;36(4):247-58, 2007. https://doi.org/10.1080/03009740701483014
  57. McInnes IB, Leung BP, Field M, Wei XQ, Huang FP, Sturrock RD, Kinnimonth A, Weidner J, Mumford R, Liew FY: Production of nitric oxide in the synovial membrane of rheumatoid and osteoarthritis patients. J Exp Med, 184: 1519-1524, 1996. https://doi.org/10.1084/jem.184.4.1519
  58. Qiu B, Liu SQ, Peng H. Influence of sodium hyaluronate on iNOS expression in synovium and NO content in synovial fluid of rabbits with traumatic osteoarthritis. Chin J Traumatol. Oct;11(5):293-6. 2008. https://doi.org/10.1016/S1008-1275(08)60059-0
  59. Santangelo KS, Bertone AL. Effective reduction of the interleukin-$1{\beta}$ transcript in osteoarthritis-prone guinea pig chondrocytes via short hairpin RNA mediated RNA interference influences gene expression of mediators implicated in disease pathogenesis. Osteoarthritis Cartilage. Dec;19(12): 1449-57, 2011. https://doi.org/10.1016/j.joca.2011.09.004