The Identification of a Receptor-binding Peptide Derived from Bone Morphogenetic Protein-6 and Its Role in Osteogenesis

  • Choi, Yoon Jung (Dental Regenerative Biotechnology major, School of Dentistry and Dental Research Institute, Seoul National University) ;
  • Lee, Jue Yeon (Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC)) ;
  • Chung, Chong Pyoung (Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC)) ;
  • Park, Yoon Jeong (Dental Regenerative Biotechnology major, School of Dentistry and Dental Research Institute, Seoul National University)
  • 투고 : 2013.08.20
  • 심사 : 2013.10.15
  • 발행 : 2014.03.01

초록

Bone morphogenetic protein (BMP)-6 induces the differentiation of mesenchymal-derived cells into osteochondrogenic cells. Similar to the potent osteochondrogenic growth factor BMP-2, the BMP-6 also contains the "knuckle epitope", which is thought to bind BMP receptor type II. In this study, we analyzed a synthetic peptide, YVPLPCCAPTKLNAISVLYF, namely BMP receptor binding peptide (BRBP), corresponding to residues of XX-YZ of the knuckle epitope of BMP-6. Our data revealed that the BRBP significantly binds to both type I and type II BMP receptors (BMPRs) with a similar affinity to BMP-6. The BRBP also induces osteogenic differentiation of human mesenchymal stem cells (HMSCs) with similar potency to BMP-6 as measured by alkaline phosphatase (ALP) activity, mineralization and osteogenic gene marker expression. Furthermore, the BRBP stimulates the phosphorylation of both the extracellular signal-regulated kinase (ERK1/2), and the Smad1/5/8 proteins. Blocking ERK-signaling with U0126, an inhibitor for MAPK/ERK kinase (MEK), abolishes the oseteogenic effects of the BRBP on human mesenchymal stem cells (HMSCs). Thus our study identifies an osteogenic peptide derived from BMP-6, which may be useful for ossified tissue regeneration.

키워드

참고문헌

  1. A. J. Celeste, J. A. Iannazzi, R. C. Taylor, R. M. Hewick, V. Rosen, E. A. Wang and J. M. Wozney, "Identification of transforming growth factor beta family members present in bone-inductive protein purified from bovine bone," Proc Natl Acad Sci U S A, 87, 9843-7 (1990). https://doi.org/10.1073/pnas.87.24.9843
  2. J. M. Wozney, V. Rosen, A. J. Celeste, L. M. Mitsock, M. J. Whitters, R. W. Kriz, R. M. Hewick and E. A. Wang, "Novel regulators of bone formation: molecular clones and activities," Science, 242, 1528-34 (1988). https://doi.org/10.1126/science.3201241
  3. C. M. Cowan, O. O. Aalami, Y. Y. Shi, Y. F. Chou, C. Mari, R. Thomas, N. Quarto, R. P. Nacamuli, C. H. Contag, B. Wu and M. T. Longaker, "Bone morphogenetic protein 2 and retinoic acid accelerate in vivo bone formation, osteoclast recruitment, and bone turnover," Tissue Eng, 11, 645-58 (2005). https://doi.org/10.1089/ten.2005.11.645
  4. A. H. Reddi, "Role of morphogenetic proteins in skeletal tissue engineering and regeneration," Nat Biotechnol, 16, 247-52 (1998). https://doi.org/10.1038/nbt0398-247
  5. I. Sekiya, B. L. Larson, J. T. Vuoristo, R. L. Reger and D. J. Prockop, "Comparison of effect of BMP-2, -4, and -6 on in vitro cartilage formation of human adult stem cells from bone marrow stroma," Cell Tissue Res, 320, 269-76 (2005). https://doi.org/10.1007/s00441-004-1075-3
  6. N. Tamai, A. Myoui, M. Hirao, T. Kaito, T. Ochi, J. Tanaka, K. Takaoka and H. Yoshikawa, "A new biotechnology for articular cartilage repair: subchondral implantation of a composite of interconnected porous hydroxyapatite, synthetic polymer (PLAPEG), and bone morphogenetic protein-2 (rhBMP-2)," Osteoarthritis Cartilage, 13, 405-17 (2005). https://doi.org/10.1016/j.joca.2004.12.014
  7. T. Kirsch, J. Nickel and W. Sebald, "BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II," EMBO J, 19, 3314-24 (2000). https://doi.org/10.1093/emboj/19.13.3314
  8. T. Kirsch, W. Sebald and M. K. Dreyer, "Crystal structure of the BMP-2-BRIA ectodomain complex," Nat Struct Biol, 7, 492-6 (2000). https://doi.org/10.1038/75903
  9. P. Knaus and W. Sebald, "Cooperativity of binding epitopes and receptor chains in the BMP/TGFbeta superfamily," Biol Chem, 382, 1189-95 (2001).
  10. M. Fujii, K. Takeda, T. Imamura, H. Aoki, T. K. Sampath, S. Enomoto, M. Kawabata, M. Kato, H. Ichijo and K. Miyazono, "Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation," Mol Biol Cell, 10, 3801-13 (1999). https://doi.org/10.1091/mbc.10.11.3801
  11. E. Hay, M. Hott, A. M. Graulet, A. Lomri and P. J. Marie, "Effects of bone morphogenetic protein-2 on human neonatal calvaria cell differentiation," J Cell Biochem, 72, 81-93 (1999). https://doi.org/10.1002/(SICI)1097-4644(19990101)72:1<81::AID-JCB9>3.0.CO;2-N
  12. C. Higuchi, A. Myoui, N. Hashimoto, K. Kuriyama, K. Yoshioka, H. Yoshikawa and K. Itoh, "Continuous inhibition of MAPK signaling promotes the early osteoblastic differentiation and mineralization of the extracellular matrix," J Bone Miner Res, 17, 1785-94 (2002). https://doi.org/10.1359/jbmr.2002.17.10.1785
  13. Y. J. Choi, J. Y. Lee, S. J. Lee, C. P. Chung and Y. J. Park, "Determination of osteogenic or adipogenic lineages in muscle-derived stem cells (MDSCs) by a collagen-binding peptide (CBP) derived from bone sialoprotein (BSP)," Biochem Biophys Res Commun, 419, 326-32 (2012). https://doi.org/10.1016/j.bbrc.2012.02.022
  14. Y. J. Choi, J. Y. Lee, J. H. Park, J. B. Park, J. S. Suh, Y. S. Choi, S. J. Lee, C. P. Chung and Y. J. Park, "The identification of a heparin binding domain peptide from bone morphogenetic protein-4 and its role on osteogenesis," Biomaterials, 31, 7226-38 (2010). https://doi.org/10.1016/j.biomaterials.2010.05.022
  15. J. Y. Lee, J. E. Choo, Y. S. Choi, K. Y. Lee, D. S. Min, S. H. Pi, Y. J. Seol, S. J. Lee, I. H. Jo, C. P. Chung and Y. J. Park, "Characterization of the surface immobilized synthetic heparin binding domain derived from human fibroblast growth factor-2 and its effect on osteoblast differentiation," J Biomed Mater Res A, 83, 970-9 (2007).
  16. J. Y. Lee, J. E. Choo, Y. S. Choi, J. S. Suh, S. J. Lee, C.P . Chung and Y. J. Park, "Osteoblastic differentiation of human bone marrow stromal cells in self-assembled BMP-2 receptor-binding peptide-amphiphiles," Biomaterials, 30, 3532-41 (2009). https://doi.org/10.1016/j.biomaterials.2009.03.018
  17. J. Y. Lee, J. E. Choo, H. J. Park, J. B. Park, S. C. Lee, S. J. Lee, Y. J. Park and C. P. Chung, "Synthetic peptide-coated bone mineral for enhanced osteoblastic activation in vitro and in vivo," J Biomed Mater Res A, 87, 688-97 (2008).
  18. A. Saito, Y. Suzuki, S. Ogata, C. Ohtsuki and M. Tanihara, "Activation of osteo-progenitor cells by a novel synthetic peptide derived from the bone morphogenetic protein-2 knuckle epitope," Biochim Biophys Acta, 1651, 60-7 (2003). https://doi.org/10.1016/S1570-9639(03)00235-8
  19. F. Kugimiya, H. Kawaguchi, S. Kamekura, H. Chikuda, S. Ohba, F. Yano, N. Ogata, T. Katagiri, Y. Harada, Y. Azuma, K. Nakamura and U. I. Chung, "Involvement of endogenous bone morphogenetic protein (BMP) 2 and BMP6 in bone formation," J Biol Chem, 280, 35704-12 (2005). https://doi.org/10.1074/jbc.M505166200
  20. B. O. Diekman, B. T. Estes and F. Guilak, "The effects of BMP6 overexpression on adipose stem cell chondrogenesis: Interactions with dexamethasone and exogenous growth factors," J Biomed Mater Res A, 93, 994-1003 (2010).
  21. B. T. Estes, A. W. Wu and F. Guilak, "Potent induction of chondrocytic differentiation of human adipose-derived adult stem cells by bone morphogenetic protein 6," Arthritis Rheum, 54, 1222-32 (2006). https://doi.org/10.1002/art.21779
  22. M. S. Friedman, M. W. Long and K. D. Hankenson, "Osteogenic differentiation of human mesenchymal stem cells is regulated by bone morphogenetic protein-6," J Cell Biochem, 98, 538-554 (2006). https://doi.org/10.1002/jcb.20719
  23. M. I. Menendez, D. J. Clark, M. Carlton, D. C. Flanigan, G. Jia, S. Sammet, S. E. Weisbrode, M. V. Knopp and A. L. Bertone, "Direct delayed human adenoviral BMP-2 or BMP-6 gene therapy for bone and cartilage regeneration in a pony osteochondral model," Osteoarthritis Cartilage, 19, 1066-75 (2011). https://doi.org/10.1016/j.joca.2011.05.007
  24. S. Vukicevic and L. Grgurevic, "BMP-6 and mesenchymal stem cell differentiation," Cytokine Growth Factor Rev, 20, 441-8 (2009). https://doi.org/10.1016/j.cytogfr.2009.10.020
  25. Z. Soran, R. S. Aydin and M. Gumusderelioglu, "Chitosan scaffolds with BMP-6 loaded alginate microspheres for periodontal tissue engineering," J Microencapsul, 29, 770-80 (2012). https://doi.org/10.3109/02652048.2012.686531
  26. J. Guicheux, J. Lemonnier, C. Ghayor, A. Suzuki, G. Palmer and J. Caverzasio, "Activation of p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase by BMP-2 and their implication in the stimulation of osteoblastic cell differentiation," J Bone Miner Res, 18, 2060-8 (2003). https://doi.org/10.1359/jbmr.2003.18.11.2060
  27. O. Kozawa, D. Hatakeyama and T. Uematsu, "Divergent regulation by p44/p42 MAP kinase and p38 MAP kinase of bone morphogenetic protein-4-stimulated osteocalcin synthesis in osteoblasts," J Cell Biochem, 84, 583-9 (2002). https://doi.org/10.1002/jcb.10056
  28. J. Lou, Y. Tu, S. Li and P. R. Manske, "Involvement of ERK in BMP-2 induced osteoblastic differentiation of mesenchymal progenitor cell line C3H10T1/2," Biochem Biophys Res Commun, 268, 757-62 (2000). https://doi.org/10.1006/bbrc.2000.2210
  29. K. Nakamura, T. Shirai, S. Morishita, S. Uchida, K. Saeki-Miura and F. Makishima, "p38 mitogen-activated protein kinase functionally contributes to chondrogenesis induced by growth/differentiation factor-5 in ATDC5 cells," Exp Cell Res, 250, 351-63 (1999). https://doi.org/10.1006/excr.1999.4535
  30. R. K. Jaiswal, N. Jaiswal, S.P . Bruder, G. Mbalaviele, D. R. Marshak and M. F. Pittenger, "Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase," J Biol Chem, 275, 9645-52 (2000). https://doi.org/10.1074/jbc.275.13.9645
  31. C. F. Lai, L. Chaudhary, A. Fausto, L. R. Halstead, D. S. Ory, L. V. Avioli and S. L. Cheng, "Erk is essential for growth, differentiation, integrin expression, and cell function in human osteoblastic cells," J Biol Chem, 276, 14443-50 (2001). https://doi.org/10.1074/jbc.M010021200