DOI QR코드

DOI QR Code

In vitro 및 in vivo 퇴행성관절염 모델에서 오미자 에탄올 추출물에 의한 matrix metalloproteinases의 생성 억제

Inhibitory Effects of Schisandrae Fructus Ethanol Extract on the Production of Matrix Metalloproteinases in in vitro and in vivo Osteoarthritis Models

  • 정진우 (동의대학교 근.골격계 질환제어 융합연구실 및 한의과대학 생화학교실) ;
  • 이혜현 (동의대학교 근.골격계 질환제어 융합연구실 및 한의과대학 생화학교실) ;
  • 김홍재 (동의대학교 근.골격계 질환제어 융합연구실 및 한의과대학 생화학교실) ;
  • 이기원 ((주)바이오포터코리아) ;
  • 김기영 ((주)바이오포터코리아) ;
  • 김성구 ((주)바이오포터코리아) ;
  • 홍수현 (동의대학교 근.골격계 질환제어 융합연구실 및 한의과대학 생화학교실) ;
  • 김범회 (동의대학교 한의과대학 해부학교실) ;
  • 박철 (동의대학교 자연과학대학 분자생물학과) ;
  • 최영현 (동의대학교 근.골격계 질환제어 융합연구실 및 한의과대학 생화학교실)
  • Jeong, Jin-Woo (Open Laboratory for Muscular & Skeletal Disease Control, and Department of Biochemistry Dongeui University College of Korean Medicine) ;
  • Lee, Hye Hyeon (Open Laboratory for Muscular & Skeletal Disease Control, and Department of Biochemistry Dongeui University College of Korean Medicine) ;
  • Kim, Hong Jae (Open Laboratory for Muscular & Skeletal Disease Control, and Department of Biochemistry Dongeui University College of Korean Medicine) ;
  • Lee, Ki Won (Research Institute, Bio-Port Korea INC, Marine Bio-industry Development Center) ;
  • Kim, Ki Young (Research Institute, Bio-Port Korea INC, Marine Bio-industry Development Center) ;
  • Kim, Sung Goo (Research Institute, Bio-Port Korea INC, Marine Bio-industry Development Center) ;
  • Hong, Su-Hyun (Open Laboratory for Muscular & Skeletal Disease Control, and Department of Biochemistry Dongeui University College of Korean Medicine) ;
  • Kim, Bum Hoi (Department of Anatomy, Dongeui University College of Korean Medicine) ;
  • Park, Cheol (Department of Molecular Biology, College of Natural Sciences, Dongeui University) ;
  • Choi, Yung Hyun (Open Laboratory for Muscular & Skeletal Disease Control, and Department of Biochemistry Dongeui University College of Korean Medicine)
  • 투고 : 2017.09.06
  • 심사 : 2017.09.11
  • 발행 : 2017.10.30

초록

노화에 따른 퇴행성관절염은 삶의 질을 저하시키는 가장 큰 병리학적 현상 중의 하나이다. 오미자 열매(Schisandrae Fructus)는 오랫동안 전통의학에서 여러 가지 만성질환 치료를 위해 널리 사용되어 왔다. 오미자 추출물이 SW1353 인간 연골세포에서 $IL-1{\beta}$에 의해 유발된 염증 반응을 감소시키는 것으로 최근 보고된 바 있으나, primary culture된 연골세포 및 동물 모델에서의 퇴행성관절염에 대한 보호 및 치료 잠재력은 여전히 명확하지 않다. 따라서 본 연구에서는 $IL-1{\beta}$에 의해 유도된 primary culture된 쥐의 연골세포와 MIA에 의해 유도된 골관절염에 대한 matrix metalloproteinases (MMPs)의 활성에 미치는 오미자 에탄올 추출물의 영향을 조사하였다. 오미자 추출물 처리는 $IL-1{\beta}$로 유도된 연골세포에서 MMP-1, -3 및 -13의 mRNA 발현 및 효소 활성을 유의하게 감소시켰다. 또한 오미자 추출물은 MIA에 의해 증가된 MMP-1 및 -3의 발현을 유의적으로 억제시켰다. 따라서 오미자 추출물은 퇴행성관절염 예방과 치료를 위한 기능성 소재로서의 잠재적 가능성이 있음을 알 수 있었다.

Schisandrae Fructus (SF), the fruit of Schisandra chinensis (Turcz.) Baill., is widely used in traditional medicine for the treatment of a number of chronic diseases. SF extracts have been recently reported to attenuate the inflammatory responses in SW1353 human chondrocyte cells in in vitro and monosodium iodoacetate (MIA)-induced cartilage degradation in in vivo osteoarthritis (OA) models. However, their protective and therapeutic potentials against OA in primary culture chondrocytes and animal models remain unclear. Therefore, we investigated the effects of the ethanol extract of SF on the activity of matrix metalloproteinases (MMPs), biomarkers for diagnosis of OA, on interleukin $(IL)-1{\beta}-induced$ primary cultured rat cartilage chondrocytes and MIA-induced osteoarthritis in a rat model. Our data indicated that SF treatment significantly reduced the mRNA expression and enzyme activity of MMP-1, -3 and -13 in $IL-1{\beta}-induced$ primary cultured rat cartilage chondrocytes. The chondro-protective effects of SF were then analyzed in a rat OA model using a single intra-articular injection of MIA in the right knee joint. According to our results, the elevated levels of MMP-1 and -3 were markedly ameliorated by SF administration. Collectively, these findings indicate that SF could be a candidate for the treatment of OA.

키워드

참고문헌

  1. Bdouet, L., Pascale, F., Bonneau, M., Wassef, M. and Laurent, A. 2011. In vitro evaluation of (S)-ibuprofen toxicity on joint cells and explants of cartilage and synovial membrane. Toxicol. In Vitro 25, 1944-1952. https://doi.org/10.1016/j.tiv.2011.06.018
  2. Billinghurst, R. C., Wu, W., Ionescu, M., Reiner, A., Dahlberg, L., Chen, J., van Wart, H. and Poole, A. R. 2000. Comparison of the degradation of type II collagen and proteoglycan in nasal and articular cartilages induced by interleukin-1 and the selective inhibition of type II collagen cleavage by collagenase. Arthritis Rheum. 43, 664-672. https://doi.org/10.1002/1529-0131(200003)43:3<664::AID-ANR24>3.0.CO;2-D
  3. Boer, T. N., Huisman, A. M., Polak, A. A., Neihoff, A. G., Rinsum, A. C., Saris, D., Bijlsma, J. W. J., Lafeber, F. J. P. G. and Mastbergen, S. C. 2009. The chondroprotective effect of selective COX-2 inhibition in osteoarthritis: Ex vivo evaluation of human cartilage tissue after in vivo treatment. Osteoarthr. Cartil. 17, 482-488. https://doi.org/10.1016/j.joca.2008.09.002
  4. Burrage, P. S., Mix, K. S. and Brinckerhoff, C. E. 2006. Matrix metalloproteinases: Role in arthritis. Front. Biosci. 11, 529-543. https://doi.org/10.2741/1817
  5. Cheng, N., Ren, N., Gao, H., Lei, X., Zheng, J. and Cao, W. 2013. Antioxident and hepatoprotective effects of Schisandra chinensis pollen extract on CCl(4)-induced acute liver damage in mice. Food Chem. Toxicol. 55, 234-240. https://doi.org/10.1016/j.fct.2012.11.022
  6. Dean, D. D., Martel-Pelletier, J., Pelletier, J. P., Howell, D. S. and Woessner, J. F. Jr. 1989. Evidence for metalloproteinase and metalloproteinase inhibitor imbalance in human osteoarthritic cartilage. J. Clin. Invest. 84, 678-685. https://doi.org/10.1172/JCI114215
  7. Garner, B. C., Stoker, A. M., Kuroki, K., Evans, R., Cook, C. R. and Cook, J. L. 2011. Using animal models in osteoarthritis biomarker research. J. Knee Surg. 24, 251-264. https://doi.org/10.1055/s-0031-1297361
  8. Giannelli, G., Erriquez, R., Iannone, F., Marinosci, F., Lapadula, G. and Antonaci, S. 2004. MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in patients with rheumatoid arthritis and psoriatic arthritis. Clin. Exp. Rheumatol. 22, 335-338
  9. Guzman, R. E., Evans, M. G., Bove, S., Morenko, B. and Kilgore, K. 2003. Mono-iodoacetate-induced histologic changes in subchondral bone and articular cartilage of rat femorotibial Joints: An animal model of osteoarthritis. Toxicol. Pathol. 31, 619-624. https://doi.org/10.1080/01926230390241800
  10. Hikino, H., Kiso, Y., Taguchi, H. and Ikeya, Y. 1984. Antihepatotoxic actions of lignoids from Schizandra chinensis fruits. Planta Med. 50, 213-217. https://doi.org/10.1055/s-2007-969681
  11. Jeong, J. W., Kim, J., Choi, E. O., Kwon, D. H., Kong, G. M., Choi, I. W., Kim, B. H., Kim, G. Y., Lee, K. W., Kim, K. Y., Kim, S. G., Choi, Y. W., Hong, S. H., Park, C. and Choi, Y. H. 2017. Schisandrae Fructus ethanol extract ameliorates inflammatory responses and articular cartilage damage in monosodium iodoacetate-induced osteoarthritis in rats. EXCLI J. 16, 265-277.
  12. Jeong, J. W., Lee, H. H., Choi, E. O., Lee, K. W., Kim, K. Y., Kim, S. G., Hong, S. H., Kim, G. Y., Park, C., Kim, H. K., Choi, Y. W. and Choi, Y. H. 2015. Schisandrae Fructus inhibits IL-1${\beta}$-induced matrix metalloproteinases and inflammatory mediators production in SW1353 human chondrocytes by suppressing NF-${\kappa}B$ and MAPK activation. Drug Dev. Res. 76, 474-483. https://doi.org/10.1002/ddr.21283
  13. Kang, Y. S., Han, M. H., Hong, S. H., Park, C., Hwang, H. J., Kim, B. W., Kyoung, K. H., Choi, Y. W., Kim, C. M. and Choi, Y. H. 2014. Anti-inflammatory Effects of Schisandra chinensis (Turcz.) Baill Fruit through the inactivation of nuclear factor-${\kappa}B$ and mitogen-activated protein kinases signaling pathways in lipopolysaccharide-stimulated murine macrophages. J. Cancer Prev. 19, 279-287. https://doi.org/10.15430/JCP.2014.19.4.279
  14. Laine, L., White, W. B., Rostom, A. and Hochberg, M. 2008. COX-2 selective inhibitors in the treatment of osteoarthritis. Semin. Arthritis Rheum. 38, 165-187. https://doi.org/10.1016/j.semarthrit.2007.10.004
  15. Lee, J. H., Fitzgerald, J. B., Dimicco, M. A. and Grodzinsky, A. J. 2005. Mechanical injury of cartilage explants causes specific time-dependent changes in chondrocyte gene expression. Arthritis Rheum. 52, 2386-2395. https://doi.org/10.1002/art.21215
  16. Marker, C. L. and Pomonis, J. D. 2012. The monosodium iodoacetate model of osteoarthritis pain in the rat. Methods Mol. Biol. 851, 239-248.
  17. Martel-Pelletier, J., McCollum, R., Fujimoto, N., Obata, K., Cloutier, J. M. and Pelletier, J. P. 1994. Excess of metalloproteases over tissue inhibitor of metalloprotease may contribute to cartilage degradation in osteoarthritis and rheumatoid arthritis. Lab. Invest. 70, 807-815.
  18. Park, J. H., Kim, J. H., Kim, D. H., Mun, H. C., Lee, H. J., Seo, S. M., Paik, K. H., Ryu, L. H., Park, J. I. and Lee, H. Y. 2004. Comparison of immuno-stimulatory activities by purification process of Schizandra chinensis Baillon fruits. Kor. J. Med. Crop Sci. 12, 141-148.
  19. Park, S. W., Jung, Y. S. and Ko, K. C. 1997. Quantitative analysis of anthocyanins among mulberry cultivars and their pharmacological screening. J. Kor. Soc. Hort. Sci. 38, 722-724.
  20. Patwari, P., Cook, M. N., DiMicco, M. A., Blake, S. M., James, I. E., Kumar, S., Cole, A. A., Lark, M. W. and Grodzinsky, A. J. 2003. Proteoglycan degradation after injurious compression of bovine and human articular cartilage in vitro: interaction with exogenous cytokines. Arthritis Rheum. 48, 1292-1301. https://doi.org/10.1002/art.10892
  21. Piecha, D., Weik, J., Kheil, H., Becher, G., Timmermann, A., Jaworski, A., Burger, M. and Hofmann, M. W. 2010. Novel selective MMP-13 inhibitors reduce collagen degradation in bovine articular and human osteoarthritis cartilage explants. Inflamm. Res. 59, 379-389. https://doi.org/10.1007/s00011-009-0112-9
  22. Salinardi, B. J., Roush, J. K., Schermerhorn, T. and Mitchell, K. E. 2006. Matrix metalloproteinase and tissue inhibitor of metalloproteinase in serum and synovial fluid of osteoarthritic dogs. Vet. Comp. Orthop. Traumatol. 19, 49-55. https://doi.org/10.1055/s-0038-1632973
  23. Shingleton, W. D., Ellis, A. J., Rowan, A. D. and Cawston, T. E. 2000. Retinoic acid combines with interleukin-1 to promote the degradation of collagen from bovine nasal cartilage: Matrix metalloproteinase-1 and 13 are involved in cartilage breakdown. J. Cell. Biochem. 79, 519-531. https://doi.org/10.1002/1097-4644(20001215)79:4<519::AID-JCB10>3.0.CO;2-U
  24. Thandavarayan, R. A., Giridharan, V. V., Arumugam, S., Suzuki, K., Ko, K. M., Krishnamurthy, P., Watanabe, K. and Konishi, T. 2015. Schisandrin B prevents doxorubicin induced cardiac dysfunction by modulation of DNA damage, oxidative stress and inflammation through inhibition of MAPK/p53 signaling. PLoS One 10, e0119214. https://doi.org/10.1371/journal.pone.0119214
  25. Xing, J., Guo, Y., Hu, H., Qu, X. L., Sun, X. Z., Liu, S. H. and Wang, H. 2012. A herbal composition of Semen Hoveniae, Radix Puerariae and Fructus Schisandrae shows potent protective effects on acute alcoholic intoxication in rodent models. Evid. Based Complement. Alternat. Med. 2012, 638197.
  26. Yeo, S. G., Ahn, C. W., Lee, Y. W., Lee, T. G., Park, Y. H. and Kim, S. B. 1995. Antioxidative effect of tea extracts from green tea, Oolong tea and Black tea. J. Kor. Soc. Food Nutr. 24, 299-304.
  27. Zhu, M., Lin, K. F., Yeung, R. Y. and Li, R. C. 2000. Evaluation of the protective effects of Schizandra chinensis on phase I drug metabolism using a CCl4 intoxication model. J. Ethnopharmacol. 67, 928-935.