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Role of morphogenetic proteins in skeletal tissue engineering and regeneration

Abstract

Morphogenesis is the developmental cascade of pattern formation and body plan establishment, culminating in the adult form. It has formed the basis for the emerging discipline of tissue engineering, which uses principles of molecular developmental biology and morphogenesis gleaned through studies on inductive signals, responding stem cells, and the extracellular matrix to design and construct spare parts that restore function to the human body. Among the many organs in the body, bone has considerable powers for regeneration and is a prototype model for tissue engineering. Implantation of demineralized bone matrix into subcutaneous sites results in local bone induction. This model mimics sequential limb morphogenesis and has permitted the isolation of bone morphogens, such as bone morphogenetic proteins (BMPs), from demineralized adult bone matrix. BMPs initiate, promote, and maintain chondrogenesis and osteogenesis, but are also involved in the morphogenesis of organs other than bone. The symbiosis of the mechanisms underlying bone induction and differentiation is critical for tissue engineering and is governed by both biomechanics (physical forces) and context (microenvironment/extracellular matrix), which can be duplicated by biomimetic biomaterials such as collagens, hydroxyapatite, proteoglycans, and cell adhesion glycoproteins, including fibronectins and laminin. Rules of tissue architecture elucidated in bone morphogenesis may provide insights into tissue engineering and be universally applicable for all organs/tissues, including bones and joints.

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Zixuan Zhao, Xinyi Chen, … Hanry Yu

References

  1. Senn, N. 1889. On the healing of aseptic bone cavities by implantation of antiseptic decalcified bone. Am. J. Med. Sci. 98:219–240.

    Article  Google Scholar 

  2. Lacroix, P. 1945. Recent investigations on the growth of bone. Nature 156:576.

    Article  Google Scholar 

  3. Urist, M.R. 1965. Bone: Formation by autoinduction. Science 150:893–899.

    Article  CAS  Google Scholar 

  4. Reddi, A.H. and Huggins, C.B. 1972. Biochemical sequences in the transformation of normal fibroblasts in adolescent rat. Proc. Natl. Acad. Sci. USA 69:1601–1605.

    Article  CAS  Google Scholar 

  5. Reddi, A.H. 1981. Cell biology and biochemistry of endochondral bone development. Collagen Rel. Res. 1:209–226.

    Article  CAS  Google Scholar 

  6. Reddi, A.H. 1984. Extracellular matrix and development, pp. 247–291 in Extracellular matrix biochemistry, Piez, K.A. and Reddi, A.H. (eds.). Elsevier, New York.

    Google Scholar 

  7. Weiss, R.E. and Reddi, A.H. 1980. Synthesis and localization of fibronectin during collagenous matrix mesenchymal cell interaction and differentiation of cartilage and bone in vivo. Proc. Natl. Acad. Sci. USA 77:2074–2078.

    Article  CAS  Google Scholar 

  8. Reddi, A.H. and Anderson, W.A. 1976. Collagenous bone matrix-induced endo-chondral ossification and hemopoiesis. J. Cell Biol. 69:557–572.

    Article  CAS  Google Scholar 

  9. Sampath;, T.K. and Reddi, A.H. 1981. Dissociative extraction and reconstitution of bone matrix components involved in local bone differentiation. Proc. Natl. Acad. Sci. USA 78:7599–7603.

    Article  Google Scholar 

  10. Wozney, J.M., Rosen, V., Celeste, A.J., Mitsock, L.M., Whittiers, M., Kriz, W.R. et al. 1988. Novel regulators of bone formation: molecular clones and activities. Science 242:1528–1534.

    Article  CAS  Google Scholar 

  11. Luyten, F., Cunningham, N.S., Ma, S., Muthukumaran, S., Hammonds, R.G., Nevins, W.B. et al. 1989. Purification and partial amino acid sequence of osteogenin, a protein initiating bone differentiation. J. Biol. Chem. 265:13377–13380.

    Google Scholar 

  12. Ozkaynak, E., Rueger, D.C., Drier, E.A., Corbett, C., Ridge, R.J., Sampath, T.K. and Opperman, H. 1990. OP-1 cDNA encodes an osteogenic protein in the TGF-β family. EMBO J. 9:2085–2093.

    Article  CAS  Google Scholar 

  13. Sampath, T.K. and Reddi, A.H. 1983. Homology of bone inductive proteins from human, monkey, bovine, and rat extracellular matrix. Proc. Natl. Acad. Sci. USA 80:6591–6595.

    Article  CAS  Google Scholar 

  14. Reddi, A.H. 1994. Bone and cartilage differentiation. Curr. Opin. Gen. Dev. 4:937–944.

    Article  Google Scholar 

  15. Griffith, D.L., Keck, P.C., Sampath, T.K., Rueger, D.C. and Carlson, W.D. 1996. Three-dimensional structure of recombinant human osteogenic protein-1: structural paradigm for the transforming growth factor-β superfamily. Proc. Natl. Acad. Sci. USA 93:878–883.

    Article  CAS  Google Scholar 

  16. Chang, S.C., Hoang, B., Thomas, J.T., Vukicevic, S., Luyten, F.P., Ryban, N.J.P. et al. 1994. Cartilage-derived morphogenetic proteins. J. Biol. Chem. 269:28227–28234.

    CAS  Google Scholar 

  17. Storm, E.E., Huynh, T.V., Copeland, N.G., Jenkins, N.A., Kingsley, D.M. and Lee, S.-J. 1994. Limb alterations in brachypodism mice due to mutations in a new member of TGF-β superfamily. Nature 368:639–642.

    Article  CAS  Google Scholar 

  18. Chen, P., Carrington, J.L., Hammonds, R.G. and Reddi, A.H. 1991. Stimulation of chondrogenesis in limb bud mesodermal cells by recombinant human BMP-2B and modulation by TGF-β1, and TGF-β2 . Exp. Cell Res. 195:509–515.

    Article  CAS  Google Scholar 

  19. Cunningham, N.S., Paralkar, V. and Reddi, A.H. 1992. Osteogenin and recombinant bone morphogenetic protein-2B are chemotactic for human monocytes and stimulate transforming growth factor-β1, mRNA expression. Proc. Natl. Acad. Sci. USA 89:11740–11744.

    Article  CAS  Google Scholar 

  20. Paralkar, V.M., Nandedkar, A.K.N., Pointers, R.H., Kleinman, H.K. and Reddi, A.H. 1990. Interaction of osteogenin, a heparin binding bone morphogenetic protein, with type IV collagen. J. Biol. Chem. 265:17281–17284.

    CAS  PubMed  Google Scholar 

  21. Hemmati-Brivanlou, A., Kelly, O.G. and Melton, D.A. 1994. Follistatin an antagonist of activin is expressed in the Spemann organizer and displays direct neuralizing activity. Cell 77:283–295.

    Article  CAS  Google Scholar 

  22. Piccolo, S., Sasai, Y., Lu, B. and De Robertis, E.M. 1996. Dorsoventral patterning in Xenopus: inhibition of ventral signals by direct binding of chordin to BMP-4. Cell 86:589–598.

    Article  CAS  Google Scholar 

  23. Zimmerman, L.B., Jesus-Escobar, J.M. and Harland, R.M. 1996. Spemann organizer signal Noggin binds and inactivates bone morphogenetic protein-4. Cell 86:599–606.

    Article  CAS  Google Scholar 

  24. Zhang, H. and Bradley, A. 1996. Mice deficient of BMP-2 are nonviable and have defects in amnion/chorion and cardiac development. Development 122:2977–2986.

    CAS  PubMed  Google Scholar 

  25. Winnier, G., Blessing, M., Labosky, P.A. and Hogan, B.L.M. 1996. Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev. 9:2105–2116.

    Article  Google Scholar 

  26. Dudley, A.T., Lyons, K.M. and Robertson, E.J. 1995. A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev. 9:2795–2807.

    Article  CAS  Google Scholar 

  27. Luo, G., Hoffman, M., Bronckers, A.L.J., Sohuki, M., Bradley, A. and Karsenty, G. 1995. BMP-7 is an inducer of morphogens and is also required for eye development, and skeletal patterning. Genes Dev. 9:2808–2820.

    Article  CAS  Google Scholar 

  28. ten Dijke, P., Yamashita, H., Sampath, T.K., Reddi, A.H., Riddle, D., Heldin, C.H. and Miyazono, K. 1994. Identification of type I receptors for OP-1 and BMP-4. J. Biol. Chem. 269:16986–16988.

    Google Scholar 

  29. Graff, J.M., Bansal, A. and Melton, D.A. 1996. Xenopus Mad proteins transduce distinct subset of signals for the TGF-β superfamily. Cell 85:479–487.

    Article  CAS  Google Scholar 

  30. Chen, S., Rubbock, M.J. and Whitman, M. 1996. A transcriptional partner for Mad proteins in TGF-β signalling. Nature 383:691–696.

    Article  CAS  Google Scholar 

  31. Yamaguchi, K., Shirakabe, K., Shibuya, H., Irie, K., Oishi, I., Ueno, N. et al. 1995. Identification of a member of the MAPKKK family as a potential mediator of TGF-β-signal transduction. Science 270:2008–2011.

    Article  CAS  Google Scholar 

  32. Friedenstein, A.J., Petrakova, K.V., Kurolesova, A.I., Frolora, G.P. 1968. Heterotopic transplants of bone marrow: analysis of precursor cell for osteogenic and hemopoietic tissues. Transplantation 6:230–247.

    Article  CAS  Google Scholar 

  33. Owen, M.E. and Friedenstein, A.J. 1988. Stromal stem cells: marrow derived osteogenic precursors. CIBA Foundation Symposium 136:42–60.

    CAS  PubMed  Google Scholar 

  34. Caplan, A.I. 1991. Mesenchymal stem cell. J. Orthop. Res. 9:641–650.

    Article  CAS  Google Scholar 

  35. Prockop, D.J. 1997. Marrow stromal cells and stem cells for non hematopoietic tissues. Science 276:71–74.

    Article  CAS  Google Scholar 

  36. Mulligan, R.C. 1993. The basic science of gene therapy. Science 260:926–932.

    Article  CAS  Google Scholar 

  37. Bank, A. 1996. Human somatic cell gene therapy. Bioessays 18:999–1007.

    Article  CAS  Google Scholar 

  38. Ma, S., Chen, G. and Reddi, A.H. 1990. Collaboration between collagenous matrix and osteogenin is required for bone induction. Ann. NY Acad. Sci. 580:524–525.

    Article  Google Scholar 

  39. McPherson, J.M. 1992. The utility of collagen-based vehicles in delivery of growth factors for hard and soft tissue wound repair. Clinical Materials 9:225–234.

    Article  CAS  Google Scholar 

  40. Ripamonti, U., Ma, S. and Reddi, A.H. 1992. The critical role of Geometry of Porus Hydroxyapatite delivery system induction of bone by osteogenin, a bone morphogenetic protein. Matrix 12:202–212.

    Article  CAS  Google Scholar 

  41. Ripamonti, U. 1996. Osteoinduction in porous hydroxyapatite implanted in heterotopic sites of different animal models. Biomaterials 17:31–35.

    Article  CAS  Google Scholar 

  42. Ripamonti, U., Van den Heever, B., Sampath, T.K., Tucker, M.M., Rueger, D.C. and Reddi, A.H. 1996. Complete regeneration of bone in the baboon by recombinant human osteogenic protein-1 (hOP-1, bone morphogenetic protein-7). Growth Factors 123:273–289

    Article  Google Scholar 

  43. Hollinger, J., Mayer, M., Buck, D., Zegzula, H., Ron, E., Smith, J. et al. 1996. Poly (α-hydroxy acid) carrier for delivering recombinant human bone morphogenetic protein-2 for bone regeneration. J. Controlled Release 39:287–304.

    Article  CAS  Google Scholar 

  44. Bostrom, M., Lane, J.M., Tomin, E., Browne, M., Berbian, W., Turek, T. et al. 1996. Use of bone morphogenetic protein-2 in the rabbit ulnar nonunion model. Clin. Orthop. Rel. Res. 327:272–282.

    Article  Google Scholar 

  45. Wientroub, S., Reddi, A.H. 1988. Influence of irradiation on the osteoinductive potential of demineralized bone matrix. Calcif. Tissue Int. 42:255–260.

    Article  CAS  Google Scholar 

  46. Wientroub, S., Weiss, J.F., Catravas, G.N., Reddi, A.H. 1990. Influence of whole body irradiation and local shielding on matrix-induced endochondral bone differentiation. Calcif. Tissue Int. 46:38–45.

    Article  CAS  Google Scholar 

  47. Damien, C.J. and Parson, J.R. 1991. Bone graft and bone graft substitutes: a review of current technology and applications. J. Applied Biomaterials 2:187–208.

    Article  CAS  Google Scholar 

  48. Kim, W.S., Vacanti, J.P., Cima, L., Mooney, D., Upton, J., Puelacher, W.C. et al. 1994. Cartilage engineered in predetermined shapes employing cell transplantation on synthetic biodegradable polymers. Plast. Reconstruc. Surgery 94:233–237.

    Article  CAS  Google Scholar 

  49. Mow, V.C., Ratcliffe, A. and Poole, A.R. 1992. Cartilage and diarthrodial joints as paradigms for hierarchical materials and structures. Biomaterials 13:67–97.

    Article  CAS  Google Scholar 

  50. Brittberg, M., Lindahl, A., Nilsson, A., Ohlsson, C., Isaksson, O. and Peterson, L. 1994. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N. Eng. J. Med. 331:889–895.

    Article  CAS  Google Scholar 

  51. Grande, D.A., Southerland, S.S., Manji, R., Pate, D.W., Schwartz, R.E. and Lucas, P.A. 1995. Repair of articular cartilage defects using mesenchymal stem cells. Tissue Engineering 1:345–353.

    Article  CAS  Google Scholar 

  52. Hunziker, E.B. and Rosenberg, L.C. 1996. Repair of partial-thickness defects in articular cartilage: cell recruitment from the synovial membrane. J. Bone Jt. Surg. 78A:721–733.

    Article  Google Scholar 

  53. Reddi, A.H. 1994. Symbiosis of biotechnology and biomaterials: applications in tissue engineering of bone and cartilage. J. Cell. Biochem. 56:192–195.

    Article  CAS  Google Scholar 

  54. Langer, R. and Vacanti, J.P. 1993. Tissue Engineering. Science 260:930–932.

    Article  Google Scholar 

  55. Hubbell, J.A. 1995. Biomaterials in tissue engineering. Biotechnology 13:565–575.

    CAS  PubMed  Google Scholar 

  56. Mosbach, K. and Ramström, O. 1996. The emerging technique of molecular imprinting and its future impact on biotechnology. Biotechnology 14:163–170.

    CAS  Google Scholar 

  57. Vukicevic, S., Luyten, F.P., Kleinman, H.K. and Reddi, A.H. 1990. Differentiation of canalicular cell processes in bone cells by basement membrane matrix component: Regulation by discrete domains of laminin. Cell 64:437–445.

    Article  Google Scholar 

  58. Ruoslahti, E. and Pierschbacher, M.D. 1987. New perspectives in cell adhesion: RGD and integrins. Science 238:491–497.

    Article  CAS  Google Scholar 

  59. Livnah, O., Stura, E.A., Johnson, D.L., Middleton, S.A., Mulcahy, L.S., Wrighton, N.D. et al. 1996. Functional mimicry of a protein hormone by a peptide agonist: the EPO receptor complex at 2.8°C. Science 273:464–471.

    Article  CAS  Google Scholar 

  60. Bowden, N., Terfort, A., Carbeck, J. and Whitesides, G.M. 1997. Self-assembly of mesoscale objects into ordered-two-dimensional arrays. Science 276:233–235.

    Article  CAS  Google Scholar 

  61. Khouri, R.K., Koudsi, B. and Reddi, A.H. 1991. Tissue transformation into bone in vivo. JAMA 266:1953–1955.

    Article  CAS  Google Scholar 

  62. Duboule, D. 1994. How to make a limb? Science 266:575–576.

    Article  CAS  Google Scholar 

  63. Johnson, R.L. and Tabin, C.J. 1997. Molecular models for vertebrate limb development. Cell 90:979–990.

    Article  CAS  Google Scholar 

  64. Hayashi, H., Abdollah, S., Qiu, Y., Cai, J., Xu, Y.Y., Grinnell, B.W. et al. 1997. The MAD-related protein Smad 7 associates with the TGFβ receptor and functions as an antagonist of TGFβ signaling. Cell 89:1165–1173.

    Article  CAS  Google Scholar 

  65. Heldin, C.H., Miyazono, K., ten Dijke, P. 1997. TGFβ signaling from cell membrane to nucleus through Smad proteins. Nature 390:465–471.

    Article  CAS  Google Scholar 

  66. Reddi, A.H. 1997. BMPs: Actions in flesh and bone. Nat. Med. 3:837–839.

    Article  CAS  Google Scholar 

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Reddi, A. Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nat Biotechnol 16, 247–252 (1998). https://doi.org/10.1038/nbt0398-247

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