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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Senn, N. 1889. On the healing of aseptic bone cavities by implantation of antiseptic decalcified bone. Am. J. Med. Sci. 98:219–240.
Lacroix, P. 1945. Recent investigations on the growth of bone. Nature 156:576.
Urist, M.R. 1965. Bone: Formation by autoinduction. Science 150:893–899.
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.
Reddi, A.H. 1981. Cell biology and biochemistry of endochondral bone development. Collagen Rel. Res. 1:209–226.
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.
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.
Reddi, A.H. and Anderson, W.A. 1976. Collagenous bone matrix-induced endo-chondral ossification and hemopoiesis. J. Cell Biol. 69:557–572.
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.
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.
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.
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.
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.
Reddi, A.H. 1994. Bone and cartilage differentiation. Curr. Opin. Gen. Dev. 4:937–944.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Chen, S., Rubbock, M.J. and Whitman, M. 1996. A transcriptional partner for Mad proteins in TGF-β signalling. Nature 383:691–696.
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.
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.
Owen, M.E. and Friedenstein, A.J. 1988. Stromal stem cells: marrow derived osteogenic precursors. CIBA Foundation Symposium 136:42–60.
Caplan, A.I. 1991. Mesenchymal stem cell. J. Orthop. Res. 9:641–650.
Prockop, D.J. 1997. Marrow stromal cells and stem cells for non hematopoietic tissues. Science 276:71–74.
Mulligan, R.C. 1993. The basic science of gene therapy. Science 260:926–932.
Bank, A. 1996. Human somatic cell gene therapy. Bioessays 18:999–1007.
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.
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.
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.
Ripamonti, U. 1996. Osteoinduction in porous hydroxyapatite implanted in heterotopic sites of different animal models. Biomaterials 17:31–35.
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
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.
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.
Wientroub, S., Reddi, A.H. 1988. Influence of irradiation on the osteoinductive potential of demineralized bone matrix. Calcif. Tissue Int. 42:255–260.
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.
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.
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.
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.
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.
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.
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.
Reddi, A.H. 1994. Symbiosis of biotechnology and biomaterials: applications in tissue engineering of bone and cartilage. J. Cell. Biochem. 56:192–195.
Langer, R. and Vacanti, J.P. 1993. Tissue Engineering. Science 260:930–932.
Hubbell, J.A. 1995. Biomaterials in tissue engineering. Biotechnology 13:565–575.
Mosbach, K. and Ramström, O. 1996. The emerging technique of molecular imprinting and its future impact on biotechnology. Biotechnology 14:163–170.
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.
Ruoslahti, E. and Pierschbacher, M.D. 1987. New perspectives in cell adhesion: RGD and integrins. Science 238:491–497.
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.
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.
Khouri, R.K., Koudsi, B. and Reddi, A.H. 1991. Tissue transformation into bone in vivo. JAMA 266:1953–1955.
Duboule, D. 1994. How to make a limb? Science 266:575–576.
Johnson, R.L. and Tabin, C.J. 1997. Molecular models for vertebrate limb development. Cell 90:979–990.
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.
Heldin, C.H., Miyazono, K., ten Dijke, P. 1997. TGFβ signaling from cell membrane to nucleus through Smad proteins. Nature 390:465–471.
Reddi, A.H. 1997. BMPs: Actions in flesh and bone. Nat. Med. 3:837–839.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nbt0398-247
This article is cited by
-
An osteoinductive and biodegradable intramedullary implant accelerates bone healing and mitigates complications of bone transport in male rats
Nature Communications (2023)
-
Unveiling the transcriptomic landscape and the potential antagonist feedback mechanisms of TGF-β superfamily signaling module in bone and osteoporosis
Cell Communication and Signaling (2022)
-
Competition between type I activin and BMP receptors for binding to ACVR2A regulates signaling to distinct Smad pathways
BMC Biology (2022)
-
Long-term posterolateral spinal fusion in rabbits induced by rhBMP6 applied in autologous blood coagulum with synthetic ceramics
Scientific Reports (2022)
-
The importance of cellular and exosomal miRNAs in mesenchymal stem cell osteoblastic differentiation
Scientific Reports (2021)