A Study of Yukmijihwangtang-Jahage extract on Regulation of Bone Resorption

Lee, Dong-Nyung;Kim, Hyung-Jun;Kim, Dong-Il;Lee Tae Kyun
이동녕;김형준;김동일;이태균

  • Published : 20030000

Abstract

전통 한약제제인 육미지황탕가자하거(Yukmijihwangtang-Jahage; YJ)는 7가지 약물인 Rehmannia glutinosa LIBOSCH.(熟地黃 : 16 g), Dioscorea japonica THUNB.(山藥 : 8 g), Cornus officinalis SIEB. Et. ZUCC.(山茱萸 : 8 g), poria cocos WOLF.(백복령 : 6 g), Paeonia suffruticosa ANDR.(牡丹皮 : 6 g), Alisma plantago-aquatica var. orientale SAMUELS(澤瀉 : 6 g)} and Placenta hominis(紫河車 : 20 g)로 구성되어 있으며, 본 약제는 면역학적으로 골대사활성이 있는 것으로 알려져 있다. 이에 본 연구에서는 YJ의 항골다공증활성을 사이토카인 활성, prostaglandin 생합성과 관련하여 분자세포생물학적으로 검증하였다. 즉 cyclooxygenase-2(COX-2)와 Tyrosine Kinase가 골아세포에서 IL-1${\beta}$, TNF-${\alpha}$, IL-6에 의해 유발되는 $PGE_2$생합성에 직접관여하는 사실을 밝혔다. IL-1${\beta}$와 IL-6 그리고 약간의 활성만 보이는 TNF-${\alpha}$가 COX-2 m-RNA을 합성을 촉진하였으나 TGF-${\beta}$와 YJ 추출물 및 TGF-${\beta}$+YJ 추출물의 혼합처리로 cytokine 유발 COX-2 mRNA 량 및 PGE2 생성량을 현저히 줄였다. 또한 YJ 추출물로 처리한 경우 Tyrosine Kinase가 peptide 기질의 인산화 반응을 억제함으로서 IN vivo 및 In vitro에서 골재흡수를 억제하엿다. YJ 추출물이 PTH 처리한 골재흡수억제 $IC_{50}$ 용량은 16 ${\mu}g/ml$ 이었다. 이러한 결과들로부터 YJ 추출물은 골대사과정중 골재흡수를 억제하는데 효과적임을 밝히게 되었으며, YJ에 의한 골다공증의 억제기전은 골재흡수관련 단백질들의 전사조절에 있음을 최초로 규명하게 되었다.

Keywords

References

  1. Acta Odontol Scand v.57 no.1 enzydamine reduces prostaglandin production in human gingival fibro-blasts challenged wih interleukin-1${\beta}$ or tumor necrosis factor alpha Modeer, T.;Yuel-Lindberg, T.B.
  2. Biochem. Biophys. Res. Comm. v.257 Involvement of tyrosine kinases on cyclooxygenase expression and prostagland in E$_2$ production in human gingival fibroblasts stimulated with interleukin-1${\beta}$ and epidermal growth factor Yucel-Lindberg, T.;Ahola, H.;Carlstedt-Duke, J.;Modeer, T.
  3. Molecular Cloning: A Laboratory Manual Sambrook, J.;Fritsch, E.F.;Maniatis, T.;
  4. J Clin Invest v.91 Herbimycin A, a pp60c-src tyrosine kinase inhibitor, inhibits osteoclastic bone resorption In vitro and hypercalcemia In vivo Yoneda, T.;Lowe, C.;Lee, C.H.;Gutierrez, G.;Niewolna, M.;Willams, P.J.;Izbicka, E.;Uehara, Y.;Mundy, G.R.
  5. FAXEB J. v.2 Dinarello, C.A.
  6. Drug Discovery Today v.3 IL-6 as a drug discovery target Stein, B.;Sutherland, M.S.K.
  7. Inflammation v.15 Lerner, U.H.;Modeer, T.
  8. Biochem. Biophys. Acta v.1083 Smith, W.L.;Marnet, L.J.
  9. JBC v.267 Diaz, A.;Reginato, A.M.;Jimenez, S.A.
  10. JBC v.267 Fletcher, B.S.;Kujubu, D.A.;Perrin, D.M.;Herschman, H.R.
  11. PNAS v.89 Hla, T.;Neilson, K.
  12. Cytokine v.5 Modeer, T.; Yucel-Lindberg, T.;Iinuma, M.;Lerner, U.H.;Andersson, G.
  13. Pathophysiology of oseoporosis Rodan, G.A.(ed.);Raisz, L.G.(ed.);Bilezikian, J.P.(ed.)
  14. Endocrin Rev v.17 Advances in bone biology: The osteoclast Roodman, G.D.
  15. Cellular and molecular biology of the osteoclast Baron, .;Ravesloot, J.H.;Neff, L.;Chakraborty, M.;Chatterjee, D.;Lomri, A.;Horne, W.;Noda, M.(ed.)
  16. Cell v.64 Targeted distruption of the c-src proto-oncogene leads to osteopetrosis in mice Soriano, P.;Montgomery, C.;Geske R.;Bradley, A.
  17. J Clin Invest v.90 Requiement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice Boyce, B.F.;Yoneda, T.;Lowe, C.;Soriano, P.;Mundy, G.R.
  18. Proc Natl Acad Sci USA v.90 Osteopetosis in Src-deficient mice is due to an autonomous defect of osteoclasts Lowe, C.;Yoneda, T.;Boyce, B.F.;Chen, H.;Mundy, G.R.;Soriano, P.
  19. J Cell Biol v.119 Osteoclasts express high levels of pp60c-src in associated with intracellular membranes Horne, W.C.;Neff, L.;Chatterjee, D.;Lomri, A.;Levy, J.B.;Baron, R.
  20. FEBS Lett v.313 Osteoclasts express high levels of pp60c-src, preferentially on ruffled border membrane Tanaka, S.N.;Takahashi, N.;Udagawa, T.;Sasaki, T.;Fukui, T.;Kurokawa, T.;Suda, T.
  21. Endocrinology v.136 Engagement of the osteoclast integrin alpha v beta 3 by osteopontin stimulates phosphatidylinositol 3-hydroxyl kinase activity Hruska, K.A.;Rolnick, F.;Huskey, M.;Alvarez, U.;Cheresh, D.
  22. J Cell Biol v.137 Substrate recognition by osteoclast precursors induces c-src/microtubule association Abu-Amer, Y.;Ross, F.P.;Schlesinger, P.;Tondravi, M.M.;Teitelbaum, S.L.
  23. Genes Dev v.11 Rescue of osteoclast function by transgenci expression of kinase-deficient Src in src-/- mutant mice Schwartzberg, P.L.;Xing, L.;Hoffmann, O.;Lowell, C.A.;Garrett, L.;Boyce, B.F.;Varmus, H.E.
  24. J Bone Miner Res v.13 Colony stimulating factor -1-induced osteoclast speding depends on substrate and requies the vitronectin receptor and the c-src proto-oncogene Teti, A.;Taranta, A.;Migliaccio, S.;Degiorgi, A.;Santandrea, E.;Villanova, I.;Faraggiana, T.;Chellaiah, M.;Hruska, K.A.
  25. Arch. Biochem. Biophys. v.362 Inhibitory effects of streptozotocin, tumor necrosis factor-a, and interleukin-1b on glucokinase activity in pancreatic islets and gene expression of GLUT2 and glucokinase Park, C.;Shim, J.K.;Nam, K.S.;Lee, Y.C.;Kim, C.H.
  26. Biochem. Biophys. Res. COmm. v.182 Constitutive expression of c-fos gene inhibits type-I collagen synthesis in transfected osteoblasts Kuroki, Y.;Shiozawa, S.;Sugimoto, T.;Fijita, T.
  27. Nature v.373 Catalytic specificity of protein-tyrosine kinases is critical for selective signaling Songyang, Z.;Carraway, K.L.;Eck, III,M.;Harrison, S.C.;Feldman, R.A.;Mohammadi, M.;Schlessinger, J.;Hubbard, S.R.;Smith, D.P.;Eng, C.;Lorenzo, M.J.;Ponder, B.A.J.;Mayer, B.J.;Cantley, L.C.
  28. Biochem J v.287 Purification and biochemical characterization of nonmyristoylated recombinant pp60c-src kinase Lydon, N.B.;Gay, B.;Mett, H.;Muray, B.;Liebetanz, J.;Gutzwiller, A.;Piwnica-Worms, H.;Roberts, T.M.;McGlynn, E.
  29. Biochem Biophys Res Commun v.235 Fluoroaluminate induces pertussis toxin-sensitive protein phosphorylation: differences in MC3T3-E1 osteoblastic and NIH3T3 fibroblastic cells Ua, M.;Standke, G.J.;Jeschke, M.;Rohner, D.
  30. Biochem Biophys Res Commun v.187 N-terminal truncation of salmon calcitonin leads to calcitonin antagonists. Structure ativity relationship of N-terminally truncated salmon calcitonin fragments In vitro and In vivo Feyen, J.H.M.;Cardinaux, F.;Gamse, R.;Bruns, C.;Azria, M.;Trechsel, U.
  31. Proc Natl Acad Sci USA v.85 Infusions of recombinant human interleukin 1a and 1b cause hypercalcemia in normal mice Sabatini, M.;Boyce, B.;Aufdemorte, T.;Bonewald, L.;Mundy, R.G.
  32. J Immunol Methods v.90 Quantitation of serum amyloid P component by an enzyme-linked immunoassay Serban, D.;Rordorf-Adam, C.
  33. Metab Bone Dis Rel Res v.5 Increased trabecular bone mass in rats treated with human synthetic parat-hyroid hormone Gunness-Hey, M.;Hock, J.M.
  34. Anal Biochem v.112 A simple method to determine nanogram levels of 4-hydroxyproline in biological tissues Jamall, I.S.;Finelli, V.N.;Que Hee, S.S.
  35. J Clin Invest v.72 Relationship between surface, volume, and thickness of iliac trabecular bone in aging and osteoporosis Parfitt, A.M.;Mathews, C.H.E.;Villanueva, A.R.;Kleerekoper, M.;Frame, B.;Rao, D.S.
  36. Bone v.13 Trabecular bone pattern factor: a new parameter for simple quantification of bone microarchitecture Hahn, M.;Vogel, M.;Pompesius-Kempa, M.;Delling, G.
  37. Calcif Tissue Int v.58 A microtomographic system for the nondestructive evaluation of bone architecture Rueggsegger, P.;Koller, B.;Muller, R.
  38. Curr Opin Cell Biol v.9 Src family protein tyrosine kinases: Cooperating with growth factor and adhesion signaling pathways Parsons, J.T.;Parsons, S.J.
  39. J Bone Miner Res v.9 pp60c-src expression and activity in MG-63 osteoblastic cells modulated by PTH but ont required for PTH-mediatd adenylate cyclase response Izbicka, E.;Niewolna, M.;Yoneda, T.;Lowe, C.;Boyce, B.;Mundy, G.
  40. J Bone Miner Res v.10 Use of an In vivo model to determine the effects of interleukin-1 on cells at different stages in the osteoclast lineage Uy, H.L.;Dallas, M.;Calland, J.W.;Boyce, B.F.;Mundy, G.R.;Roodman, G.D.
  41. Biochem. J. v.312 Blaco, A.;Habib, A.;Levy-Toledano, S.;Maclouf, J.
  42. Bone Miner v.15 The ovariectomized rat model of postmenopausal bone loss Kalu, D.N.
  43. J. Immunol. v.155 Geng, Y.;Blanco, F.J.;Cornelisson, M.;Lotz, M.
  44. Arch. Oral. Biol. v.41 Chang, K.M.;Lehrhaupt, N.;Lin, L.M.;Feng, J.;Wu-Wang, C.Y.;Wang, S.L.
  45. Genes Dev v.8 Combined deficiencies of Src, Fyn, and Yes tyrosine kinases in mutant mice Stein, P.L.;Vogel, H.;Soriano, P.