Reader TTS

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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more Buy this

article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in

* Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS ENGINEERING BONE/CARTILAGE ORGANOIDS: STRATEGY, PROGRESS, AND

APPLICATION Article Open access 20 November 2024 MECHANISMS OF BONE DEVELOPMENT AND REPAIR Article 08 September 2020 CHARACTERIZATION OF A PLURIPOTENT STEM CELL-DERIVED MATRIX WITH POWERFUL

OSTEOREGENERATIVE CAPABILITIES Article Open access 15 June 2020 REFERENCES * 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  * Lacroix, P. 1945. Recent investigations on the growth of bone. _Nature_ 156:576. Article  Google Scholar  * Urist, M.R. 1965. Bone:

Formation by autoinduction. _Science_ 150:893–899. Article  CAS  Google Scholar  * 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  * Reddi, A.H. 1981. Cell biology and biochemistry of endochondral bone development. _Collagen Rel.

Res._ 1:209–226. Article  CAS  Google Scholar  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * Reddi, A.H. 1994. Bone and cartilage differentiation. _Curr. Opin. Gen. Dev._ 4:937–944.

Article  Google Scholar  * 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  * 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  * 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  *

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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * Caplan, A.I. 1991. Mesenchymal stem

cell. _J. Orthop. Res._ 9:641–650. Article  CAS  Google Scholar  * Prockop, D.J. 1997. Marrow stromal cells and stem cells for non hematopoietic tissues. _Science_ 276:71–74. Article  CAS 

Google Scholar  * Mulligan, R.C. 1993. The basic science of gene therapy. _Science_ 260:926–932. Article  CAS  Google Scholar  * Bank, A. 1996. Human somatic cell gene therapy. _Bioessays_

18:999–1007. Article  CAS  Google Scholar  * 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  * 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  * 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  * Ripamonti, U. 1996. Osteoinduction in porous hydroxyapatite implanted in heterotopic sites of

different animal models. _Biomaterials_ 17:31–35. Article  CAS  Google Scholar  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * Langer, R. and Vacanti,

J.P. 1993. Tissue Engineering. _Science_ 260:930–932. Article  Google Scholar  * Hubbell, J.A. 1995. Biomaterials in tissue engineering. _Biotechnology_ 13:565–575. CAS  PubMed  Google

Scholar  * 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  *

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

Article  CAS  Google Scholar  * 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  * 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  * Khouri, R.K., Koudsi, B. and Reddi, A.H. 1991. Tissue transformation into bone in vivo.

_JAMA_ 266:1953–1955. Article  CAS  Google Scholar  * Duboule, D. 1994. How to make a limb? _Science_ 266:575–576. Article  CAS  Google Scholar  * Johnson, R.L. and Tabin, C.J. 1997.

Molecular models for vertebrate limb development. _Cell_ 90:979–990. Article  CAS  Google Scholar  * 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  * 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  * Reddi, A.H. 1997. BMPs: Actions in flesh and

bone. _Nat. Med._ 3:837–839. Article  CAS  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Center for Tissue Regeneration and Repair and Department of

Orthopedic Surgery, University of California-Davis, Medical Center, Sacramento, CA, 95817 A. Hari Reddi Authors * A. Hari Reddi View author publications You can also search for this author

inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints 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 Download citation * Received: 15 January 1998 * Accepted: 05 February 1998 * Issue Date: 01 March 1998

* DOI: https://doi.org/10.1038/nbt0398-247 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not

currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative