Thymosinβ4が抜歯窩治癒過程に与える効果
thymosinβ4（TB4）は43個のアミノ酸からなるペプチドで，球状アクチン（Gアクチン）と結合し，アクチンフィラメントへと重合するのを妨げる主要な“Gアクチン隔離ペプチド”と見なされている．最近の研究により，TB4は細胞遊走，血管新生，創傷治癒，炎症，形態形成および腫瘍の転移などに関わる多機能のペプチドであることが判明してきた．しかしながら我々が歯胚発生におけるTB4の重要な役割を示した以前の報告以外は，歯学研究に関連した報告はほとんどない．本研究では，TB4の9個のアミノ酸からなるG-アクチン結合モチーフや血管新生能に必須の7個のアミノ酸領域を含む20個のアミノ酸からなる合成ペプチドを...
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| Published in | 九州歯科学会雑誌 Vol. 61; no. 2.3; pp. 67 - 76 |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | Japanese |
| Published |
九州歯科学会
2007
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0368-6833 1880-8719 |
| DOI | 10.2504/kds.61.67 |
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| Abstract | thymosinβ4（TB4）は43個のアミノ酸からなるペプチドで，球状アクチン（Gアクチン）と結合し，アクチンフィラメントへと重合するのを妨げる主要な“Gアクチン隔離ペプチド”と見なされている．最近の研究により，TB4は細胞遊走，血管新生，創傷治癒，炎症，形態形成および腫瘍の転移などに関わる多機能のペプチドであることが判明してきた．しかしながら我々が歯胚発生におけるTB4の重要な役割を示した以前の報告以外は，歯学研究に関連した報告はほとんどない．本研究では，TB4の9個のアミノ酸からなるG-アクチン結合モチーフや血管新生能に必須の7個のアミノ酸領域を含む20個のアミノ酸からなる合成ペプチドを用いて，TB4の抜歯後創傷治癒における効果を検索した．ラットの下顎第一臼歯を抜歯後，合成ペプチドを抜歯時とその後毎日4日間，腹腔内投与した．その処置の対照として同量のリン酸緩衝生理食塩水を同じように投与した．2日，3日，4日例の脱灰した下顎から組織切片を作成した．また必要に応じて組織化学染色や免疫組織化学染色を施した．抜歯窩の肉芽組織よりtotal RNAsを抽出し，matrix metalloproteinase-2（MMP-2）や vascular endothelial growth factor（VEGF）遺伝子に対する半定量的RT-PCRを行った．MMP-2 はTB4処置例においてのみ遺伝子増幅された．VEGFはTB4処置および対照の両サンプルで検出されたが，TB4処置例のほうが発現レベルが低かった．組織学的検索で，合成ペプチドは抜歯後創傷治癒の過程，すなわち血餅の吸収，肉芽組織の形成，再上皮化および骨の新生を早めた．これらの結果は歯科臨床応用におけるTB4の有用性を示した． |
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| AbstractList | thymosinβ4（TB4）は43個のアミノ酸からなるペプチドで，球状アクチン（Gアクチン）と結合し，アクチンフィラメントへと重合するのを妨げる主要な“Gアクチン隔離ペプチド”と見なされている．最近の研究により，TB4は細胞遊走，血管新生，創傷治癒，炎症，形態形成および腫瘍の転移などに関わる多機能のペプチドであることが判明してきた．しかしながら我々が歯胚発生におけるTB4の重要な役割を示した以前の報告以外は，歯学研究に関連した報告はほとんどない．本研究では，TB4の9個のアミノ酸からなるG-アクチン結合モチーフや血管新生能に必須の7個のアミノ酸領域を含む20個のアミノ酸からなる合成ペプチドを用いて，TB4の抜歯後創傷治癒における効果を検索した．ラットの下顎第一臼歯を抜歯後，合成ペプチドを抜歯時とその後毎日4日間，腹腔内投与した．その処置の対照として同量のリン酸緩衝生理食塩水を同じように投与した．2日，3日，4日例の脱灰した下顎から組織切片を作成した．また必要に応じて組織化学染色や免疫組織化学染色を施した．抜歯窩の肉芽組織よりtotal RNAsを抽出し，matrix metalloproteinase-2（MMP-2）や vascular endothelial growth factor（VEGF）遺伝子に対する半定量的RT-PCRを行った．MMP-2 はTB4処置例においてのみ遺伝子増幅された．VEGFはTB4処置および対照の両サンプルで検出されたが，TB4処置例のほうが発現レベルが低かった．組織学的検索で，合成ペプチドは抜歯後創傷治癒の過程，すなわち血餅の吸収，肉芽組織の形成，再上皮化および骨の新生を早めた．これらの結果は歯科臨床応用におけるTB4の有用性を示した． |
| Author | 仲西, 修 福山, 宏 吉田, 充広 林, 知孝 坂本, 和美 松尾, 拡 張, 皿 |
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| References | 9) Philp, D., Badamchian, M., Scheremeta, B., Nguyen, M., Goldstein, A. L. and Kleinman, H. K.: Thymosin beta 4 and a synthetic peptide containing its actin-binding domain promote dermal wound repair in db/db diabetic mice and in aged mice. Wound Repair Regen. 11:19-24, 2003. 6) Grant, D. S., Rose, W., Yaen, C., Goldstein, A., Martinez, J. and Kleinman, H.: Thymosin beta4 enhances endothelial cell differentiation and angiogenesis. Angiogenesis 3:125-135, 1999. 23) Huff, T., Ballweber, E., Humeny, A., Bonk, T., Becker, C., Muller, C. S., Mannherz, H. G. and Hannappel, E.: Thymosin beta(4) serves as a glutaminyl substrate of transglutaminase. Labeling with fluorescent dansylcadaverine does not abolish interaction with G-actin. FEBS Lett. 464:14-20, 1999. 28) Border, B. G., Lin, S. C., Griffin, W. S., Pardue, S. and Morrison-Bogorad, M.: Alterations in actin-binding beta-thymosin expression accompany neuronal differentiation and migration in rat cerebellum. J. Neurochem. 61:2104-2114, 1993. 20) Yamaza, H., Matsuo, K., Kiyoshima, T., Shigemura, N., Kobayashi, I., Wada, H., Akamime, A. and Sakai, H.: Detection of differentially expressed genes in the early developmental stage of the mouse mandible. Int. J. Dev. Biol. 45:675-680, 2001. 3) Matsuo, K., Zhang, M. and Fukuyama, H.: beta-thymosins are versatile wound healers? J. Kyushu Dent. Soc. 59:133-146, 2005. 16) Philp, D., Nguyen, M., Scheremeta, B., St-Surin, S., Villa, A. M., Orgel, A., Kleinman, H. K. and Elkin, M.: Thymosin beta4 increases hair growth by activation of hair follicle stem cells. FASEB J. 18:385-387, 2004. 17) Roth, L. W., Bormann, P., Bonnet, A. and Reinhard, E.: beta-thymosin is required for axonal tract formation in developing zebrafish brain. Development 126:1365-1374, 1999. 19) Akhter, M., Kobayashi, I., Kiyoshima, T., Matsuo, K., Yamaza, H., Wada, H., Honda, J. Y., Ming, X. and Sakai, H.: Possible functional involvement of thymosin beta 4 in developing tooth germ of mouse lower first molar. Histochem. Cell Biol. 124:207-213, 2005. 25) Cha, H. J., Jeong, M. J. and Kleinman, H. K.: Role of thymosin beta4 in tumor metastasis and angiogenesis. J. Natl. Cancer Inst. 95:1674-1680, 2003. 21) Makogonenko, E., Goldstein, A. L., Bishop, P. D. and Medved, L.: Factor XIIIa incorporates thymosin beta4 preferentially into the fibrin(ogen) alphaC-domains. Biochemistry (Mosc). 43:10748-10756, 2004. 1) Hannappel, E. and Huff, T.: The thymosins. Prothymosin alpha, parathymosin, and beta-thymosins: structure and function. Vitam. Horm. 66:257-296, 2003. 15) Bock-Marquette, I., Saxena, A., White, M. D., Dimaio, J. M. and Srivastava, D.: Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature 432:466-472, 2004. 22) Huff, T., Otto, A. M., Muller, C. S., Meier, M. and Hannappel, E.: Thymosin beta4 is released from human blood platelets and attached by factor XIIIa (transglutaminase) to fibrin and collagen. FASEB J. 16:691-696, 2002. 24) Philp, D., Huff, T., Gho, Y. S., Hannappel, E. and Kleinman, H. K.: The actin binding site on thymosin beta4 promotes angiogenesis. FASEB J. 17:2103-2105, 2003. 14) Young, J. D., Lawrence, A. J., MacLean, A. G., Leung, B. P., McInnes, I. B., Canas, B., Pappin, D. J. and Stevenson, R. D.: Thymosin beta 4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids. Nat. Med. 5:1424-1427, 1999. 13) Frohm, M., Gunne, H., Bergman, A. C., Agerberth, B., Bergman, T., Boman, A., Liden, S., Jornvall, H. and Boman, H. G.: Biochemical and antibacterial analysis of human wound and blister fluid. Eur. J. Biochem. 237:86-92, 1996. 8) Grant, D. S., Kinsella, J. L., Kibbey, M. C., LaFlamme, S., Burbelo, P. D., Goldstein, A. L. and Kleinman, H. K.: Matrigel induces thymosin beta 4 gene in differentiating endothelial cells. J. Cell Sci. 108 (Pt 12): 3685-3694, 1995. 4) Van Troys, M., Dewitte, D., Goethals, M., Carlier, M. F., Vandekerckhove, J. and Ampe, C.: The actin binding site of thymosin beta 4 mapped by mutational analysis. EMBO J. 15:201-210, 1996. 27) Vartiainen, N., Pyykonen, I., Hokfelt, T. and Koistinaho, J.: Induction of thymosin beta(4) mRNA following focal brain ischemia. Neuroreport 7:1613-1616, 1996. 12) Malinda, K. M., Sidhu, G. S., Mani, H., Banaudha, K., Maheshwari, R. K., Goldstein, A. L. and Kleinman, H. K.: Thymosin beta4 accelerates wound healing. J. Invest. Dermatol. 113:364-368, 1999. 7) Malinda, K. M., Goldstein, A. L. and Kleinman, H. K.: Thymosin beta 4 stimulates directional migration of human umbilical vein endothelial cells. FASEB J. 11:474-481, 1997. 18) Chen, C., Li, M., Yang, H., Chai, H., Fisher, W. and Yao, Q.: Roles of thymosins in cancers and other organ systems. World J. Surg. 29:264-270, 2005. 26) Choe, J., Sun, W., Yoon, S. Y., Rhyu, I. J., Kim, E. H. and Kim, H.: Effect of thymosin beta15 on the branching of developing neurons. Biochem. Biophys. Res. Commun. 331:43-49, 2005. 11) Sosne, G., Chan, C. C., Thai, K., Kennedy, M., Szliter, E. A., Hazlett, L. D. and Kleinman, H. K.: Thymosin beta 4 promotes corneal wound healing and modulates inflammatory mediators in vivo. Exp. Eye Res. 72:605-608, 2001. 5) Safer, D., Elzinga, M. and Nachmias, V. T.: Thymosin beta 4 and Fx, an actin-sequestering peptide, are indistinguishable. J. Biol. Chem. 266:4029-4032, 1991. 10) Sosne, G., Szliter, E. A., Barrett, R., Kernacki, K. A., Kleinman, H. and Hazlett, L. D.: Thymosin beta 4 promotes corneal wound healing and decreases inflammation in vivo following alkali injury. Exp. Eye Res. 74:293-299, 2002. 2) Huff, T., Muller, C. S., Otto, A. M., Netzker, R. and Hannappel, E.: beta-Thymosins, small acidic peptides with multiple functions. Int. J. Biochem. Cell Biol. 33:205-220, 2001. |
| References_xml | – reference: 18) Chen, C., Li, M., Yang, H., Chai, H., Fisher, W. and Yao, Q.: Roles of thymosins in cancers and other organ systems. World J. Surg. 29:264-270, 2005. – reference: 25) Cha, H. J., Jeong, M. J. and Kleinman, H. K.: Role of thymosin beta4 in tumor metastasis and angiogenesis. J. Natl. Cancer Inst. 95:1674-1680, 2003. – reference: 26) Choe, J., Sun, W., Yoon, S. Y., Rhyu, I. J., Kim, E. H. and Kim, H.: Effect of thymosin beta15 on the branching of developing neurons. Biochem. Biophys. Res. Commun. 331:43-49, 2005. – reference: 23) Huff, T., Ballweber, E., Humeny, A., Bonk, T., Becker, C., Muller, C. S., Mannherz, H. G. and Hannappel, E.: Thymosin beta(4) serves as a glutaminyl substrate of transglutaminase. Labeling with fluorescent dansylcadaverine does not abolish interaction with G-actin. FEBS Lett. 464:14-20, 1999. – reference: 24) Philp, D., Huff, T., Gho, Y. S., Hannappel, E. and Kleinman, H. K.: The actin binding site on thymosin beta4 promotes angiogenesis. FASEB J. 17:2103-2105, 2003. – reference: 5) Safer, D., Elzinga, M. and Nachmias, V. T.: Thymosin beta 4 and Fx, an actin-sequestering peptide, are indistinguishable. J. Biol. Chem. 266:4029-4032, 1991. – reference: 7) Malinda, K. M., Goldstein, A. L. and Kleinman, H. K.: Thymosin beta 4 stimulates directional migration of human umbilical vein endothelial cells. FASEB J. 11:474-481, 1997. – reference: 20) Yamaza, H., Matsuo, K., Kiyoshima, T., Shigemura, N., Kobayashi, I., Wada, H., Akamime, A. and Sakai, H.: Detection of differentially expressed genes in the early developmental stage of the mouse mandible. Int. J. Dev. Biol. 45:675-680, 2001. – reference: 15) Bock-Marquette, I., Saxena, A., White, M. D., Dimaio, J. M. and Srivastava, D.: Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature 432:466-472, 2004. – reference: 14) Young, J. D., Lawrence, A. J., MacLean, A. G., Leung, B. P., McInnes, I. B., Canas, B., Pappin, D. J. and Stevenson, R. D.: Thymosin beta 4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids. Nat. Med. 5:1424-1427, 1999. – reference: 8) Grant, D. S., Kinsella, J. L., Kibbey, M. C., LaFlamme, S., Burbelo, P. D., Goldstein, A. L. and Kleinman, H. K.: Matrigel induces thymosin beta 4 gene in differentiating endothelial cells. J. Cell Sci. 108 (Pt 12): 3685-3694, 1995. – reference: 12) Malinda, K. M., Sidhu, G. S., Mani, H., Banaudha, K., Maheshwari, R. K., Goldstein, A. L. and Kleinman, H. K.: Thymosin beta4 accelerates wound healing. J. Invest. Dermatol. 113:364-368, 1999. – reference: 21) Makogonenko, E., Goldstein, A. L., Bishop, P. D. and Medved, L.: Factor XIIIa incorporates thymosin beta4 preferentially into the fibrin(ogen) alphaC-domains. Biochemistry (Mosc). 43:10748-10756, 2004. – reference: 28) Border, B. G., Lin, S. C., Griffin, W. S., Pardue, S. and Morrison-Bogorad, M.: Alterations in actin-binding beta-thymosin expression accompany neuronal differentiation and migration in rat cerebellum. J. Neurochem. 61:2104-2114, 1993. – reference: 13) Frohm, M., Gunne, H., Bergman, A. C., Agerberth, B., Bergman, T., Boman, A., Liden, S., Jornvall, H. and Boman, H. G.: Biochemical and antibacterial analysis of human wound and blister fluid. Eur. J. Biochem. 237:86-92, 1996. – reference: 2) Huff, T., Muller, C. S., Otto, A. M., Netzker, R. and Hannappel, E.: beta-Thymosins, small acidic peptides with multiple functions. Int. J. Biochem. Cell Biol. 33:205-220, 2001. – reference: 9) Philp, D., Badamchian, M., Scheremeta, B., Nguyen, M., Goldstein, A. L. and Kleinman, H. K.: Thymosin beta 4 and a synthetic peptide containing its actin-binding domain promote dermal wound repair in db/db diabetic mice and in aged mice. Wound Repair Regen. 11:19-24, 2003. – reference: 22) Huff, T., Otto, A. M., Muller, C. S., Meier, M. and Hannappel, E.: Thymosin beta4 is released from human blood platelets and attached by factor XIIIa (transglutaminase) to fibrin and collagen. FASEB J. 16:691-696, 2002. – reference: 1) Hannappel, E. and Huff, T.: The thymosins. Prothymosin alpha, parathymosin, and beta-thymosins: structure and function. Vitam. Horm. 66:257-296, 2003. – reference: 27) Vartiainen, N., Pyykonen, I., Hokfelt, T. and Koistinaho, J.: Induction of thymosin beta(4) mRNA following focal brain ischemia. Neuroreport 7:1613-1616, 1996. – reference: 6) Grant, D. S., Rose, W., Yaen, C., Goldstein, A., Martinez, J. and Kleinman, H.: Thymosin beta4 enhances endothelial cell differentiation and angiogenesis. Angiogenesis 3:125-135, 1999. – reference: 19) Akhter, M., Kobayashi, I., Kiyoshima, T., Matsuo, K., Yamaza, H., Wada, H., Honda, J. Y., Ming, X. and Sakai, H.: Possible functional involvement of thymosin beta 4 in developing tooth germ of mouse lower first molar. Histochem. Cell Biol. 124:207-213, 2005. – reference: 3) Matsuo, K., Zhang, M. and Fukuyama, H.: beta-thymosins are versatile wound healers? J. Kyushu Dent. Soc. 59:133-146, 2005. – reference: 16) Philp, D., Nguyen, M., Scheremeta, B., St-Surin, S., Villa, A. M., Orgel, A., Kleinman, H. K. and Elkin, M.: Thymosin beta4 increases hair growth by activation of hair follicle stem cells. FASEB J. 18:385-387, 2004. – reference: 11) Sosne, G., Chan, C. C., Thai, K., Kennedy, M., Szliter, E. A., Hazlett, L. D. and Kleinman, H. K.: Thymosin beta 4 promotes corneal wound healing and modulates inflammatory mediators in vivo. Exp. Eye Res. 72:605-608, 2001. – reference: 17) Roth, L. W., Bormann, P., Bonnet, A. and Reinhard, E.: beta-thymosin is required for axonal tract formation in developing zebrafish brain. Development 126:1365-1374, 1999. – reference: 4) Van Troys, M., Dewitte, D., Goethals, M., Carlier, M. F., Vandekerckhove, J. and Ampe, C.: The actin binding site of thymosin beta 4 mapped by mutational analysis. EMBO J. 15:201-210, 1996. – reference: 10) Sosne, G., Szliter, E. A., Barrett, R., Kernacki, K. A., Kleinman, H. and Hazlett, L. D.: Thymosin beta 4 promotes corneal wound healing and decreases inflammation in vivo following alkali injury. Exp. Eye Res. 74:293-299, 2002. |
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| Title | Thymosinβ4が抜歯窩治癒過程に与える効果 |
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| ispartofPNX | 九州歯科学会雑誌, 2007, Vol.61(2.3), pp.67-76 |
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