The Skeleton pp 217-227 | Cite as

Soluble Signals and Insoluble Substrata

Novel Molecular Cues Instructing the Induction of Bone
  • Ugo Ripamonti
  • Nathaniel L. Ramoshebi
  • Janet Patton
  • Thato Matsaba
  • June Teare
  • Louise Renton


The repair and regeneration of bone is a complex process that is temporally and spatially regulated by soluble and insoluble signals (1). The initiation of bone formation during embryonic development and postnatal osteogenesis involves a complex cascade of molecular and morphogenetic processes that ultimately lead to the architectural sculpturing of precisely organized multicellular structures.


Bone Formation Bone Morphogenetic Protein Vascular Endothelial Cell Growth Factor Bone Differentiation Endochondral Bone Formation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Reddi, A. H. (2000) Morphogenesis and tissue engineering of bone and cartilage: inductive signals, stem cells, and biomimetic biomaterials. Tissue Eng. 6, 351–359.PubMedCrossRefGoogle Scholar
  2. 2.
    Urist, M. R. (1965) Bone: formation by autoinduction. Science 159, 893–899.CrossRefGoogle Scholar
  3. 3.
    Reddi, A. H. and Huggins, C. B. (1972) Biochemical sequences in the transformation of normal fibroblasts in adolescent rats. Proc. Natl. Acad. Sci. USA 69, 1601–1605.PubMedCrossRefGoogle Scholar
  4. 4.
    Reddi, A. H. (1981) Cell biology and biochemistry of endochondral bone development. Collagen Rel. Res. 1, 209–226.CrossRefGoogle Scholar
  5. 5.
    Sampath, T. K. and Reddi, A. H. (1981) Dissociative extraction and reconstitution of extracellular matrix components involved in local bone differentiation. Proc. Natl. Acad. Sci. USA 78, 7599–7603.PubMedCrossRefGoogle Scholar
  6. 6.
    Wozney, J. M., Rosen, V., Celeste, A. J., Mitsock, L. M., Whitters, M. J., Kriz, R. W., et al. (1988) Novel regulators of bone formation: molecular clones and activities. Science 242, 1528–1534.PubMedCrossRefGoogle Scholar
  7. 7.
    Wozney, J. M. (1992) The bone morphogenetic protein family and osteogenesis. Mol. Repprod. Dev. 32, 160–167.CrossRefGoogle Scholar
  8. 8.
    Reddi, A. H. (1992) Regulation of cartilage and bone differentiation by bone morphogenetic proteins. Curr. Opin. Cell. Biol. 4, 850–855.PubMedCrossRefGoogle Scholar
  9. 9.
    Ripamonti, U. and Reddi, A. H. (1997) Tissue engineering, morphogenesis and regeneration of the periodontal tissues by bone morphogenetic proteins. Crit. Rev. Oral Biol. Med. 8, 154–163.PubMedCrossRefGoogle Scholar
  10. 10.
    Thomadakis, G., Ramoshebi, L. N., Crooks, J., Rueger, D. C., and Ripamonti, U. (1999) Immunolocalization of bone morphogenetic protein-2 and -3 and osteogenic protein-1 during murine tooth root morphogenesis and in other craniofacial structures. Eur. J. Oral Sci. 107. 368–377.PubMedCrossRefGoogle Scholar
  11. 11.
    Ripamonti, U. and Duneas, N. (1998) Tissue morphogenesis and regeneration by bone morphogenetic proteins. Plast. Reconstr. Surg. 101, 227–239.PubMedCrossRefGoogle Scholar
  12. 12.
    Ripamonti, U., van den Heever, B., Crooks, J., Tucker, M. M.., Sampath, T. K., Rueger, D. C., et al. (2000) Long term evaluation of bone formation by osteogenic protein-1 in the baboon and relative efficacy of bone-derived bone morphogenetic proteins delivered by irradiated xenogeneic collagenous matrices. J. Bone Miner. Res. 15, 1798–1809.PubMedCrossRefGoogle Scholar
  13. 13.
    Ripamonti, U., Ma, S., Cunningham, N., Yeates, L., and Reddi, A. H. (1992) Initiation of bone regeneration in adult baboons by osteogenin, a bone morphogenetic protein. Matrix 12, 369–380.PubMedCrossRefGoogle Scholar
  14. 14.
    Ripamonti, U., Ramoshebi, L. N., Matsaba, T., Tasker, J., Crooks, J., and Teare, J. (2001) Bone induction by BMPs/OPs and related family members in primates. The critical role of delivery systems. J. Bone Joint Surg. Am. 83-A, S 1116–S1127.Google Scholar
  15. 15.
    Groeneveld, E. H. J. and Burger, E. H. (2002) Bone morphogenetic proteins in human bone regeneration. Eur. J. Endocrinol. 142, 9–21.CrossRefGoogle Scholar
  16. 16.
    Ferretti, C. and Ripamonti, U. (2002) Human segmental mandibular defect treated with naturally derived bone morphogenetic proteins. J. Craniofacial Sure. 3. 434–444.CrossRefGoogle Scholar
  17. 17.
    Ripamonti, U., van den Heever, B., Heliotis, M., Dal Mas, I., Hähnle, U. R., and Biscardi, A. (2002) Local delivery of bone morphogenetic proteins in primates using a reconstituted basement membrane gel: tissue engineering with Matrigel. S. Afr. J. Sci. 98, 429–433.Google Scholar
  18. 18.
    Ripamonti, U., Heliotis, M., van den Heever B., and Reddi, A. H. (1994) Bone morphogenetic proteins induce periodontal regeneration in the baboon (Papio ursinus). J. Periodont. Res. 29, 439–445.PubMedCrossRefGoogle Scholar
  19. 19.
    Ripamonti, U., Heliotis, M., Rueger, D. C., and Sampath, T. K. (1996) Induction of cementogenesis by recombinant human osteogenic protein-1 (hOP-1/BMP-7) in the baboon. Arch. Oral Biol. 41, 121–126.PubMedCrossRefGoogle Scholar
  20. 20.
    Ripamonti, U., Crooks, J., Teare, J., Petit, J.-C., and Rueger, D. C. (2002) Periodontal tissue regeneration by recombinant human osteogenic protein-1 in periodontally-induced furcation defects of the primate Papio ursinus. S. Afr. J. Sci. 98. 361–368.Google Scholar
  21. 21.
    Centrella, M., Horowitz, M., Wozney, J. M., and McCarthy, T. L. (1994) Transforming growth factor β3 (TGF-ββ) family members and bone. Endocr. Rev. 15, 27–39.PubMedGoogle Scholar
  22. 22.
    Roberts, A. B., Sporn, M. B., Assoian, R. K., Smith, J. M., Roche, N. S., Wakefield, L. M., et al. (1986) Transforming growth factor type rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc. Natl. Acad. Sci. USA 83, 4167–4171.PubMedCrossRefGoogle Scholar
  23. 23.
    Shinozaki, M., Kawara, S., Hayashi, N., Kakinuba, T., Igarashi, A., and Takehara, K. (1997) Induction of subcutaneous tissue fibrosis in newborn mice by transforming growth factor-β3: simultaneous application with basic fibroblast growth factor causes persistent fibrosis. Biochem. Biophys. Res. Commun. 237, 292–296.PubMedCrossRefGoogle Scholar
  24. 24.
    Raven, P. H. and Johnson, G. B. (1989) Evolutionary History of the Earth, in Biology 2nd ed. (Brake, D. K., ed), Times Mirror/Mosby College, St. Louis, pp. 419–441.Google Scholar
  25. 25.
    Ripamonti, U., Duneas, N., van den Heever, B., Bosch, C., and Crooks, J. (1997) Recombinant transforming growth factor-I31 induces endochondral bone in the baboon and synergizes with recombinant osteogenic protein-1 (bone morphogenetic protein-7) to initiate rapid bone formation. J. Bone Miner. Res. 12. 1584–1595.PubMedCrossRefGoogle Scholar
  26. 26.
    Duneas, N., Crooks, J., and Ripamonti, U. (1998) Transforming growth factors ββ1: Induction of bone morphogenetic protein genes expression during endochondral bone formation in the baboon, and synergistic interaction with osteogenic protein-1 (BMP-7) Growth Factors 15, 259–277.PubMedCrossRefGoogle Scholar
  27. 27.
    Ripamonti, U., Crooks, J., Matsaba, T., and Tasker, J. (2000) Induction of endochondral bone formation by recombinant human transforming growth factor-132 in the baboon (Papio ursinus). Growth Factors 17, 269–285.PubMedCrossRefGoogle Scholar
  28. 28.
    Ripamonti U., Teare, J., Matsaba, T., and Renton, L. (2001) Site, tissue and organ specificity of endochondral bone induction and morphogenesis by TGF-ββ isoforms in the primate Papio ursinus. Proceedings FASEB Summer Conference: The TGF-β3 superfamily: signaling and development, Tucson Arizona, USA, July 7–12.Google Scholar
  29. 29.
    Miyazono, K., Ten Dijke, P., and Heldin, C.-H. (2002) TGF-1β signaling by Smad proteins. Adv. Immunol. 75, 115–157.CrossRefGoogle Scholar
  30. 30.
    Ripamonti, U., Crooks, J., and Kirkbride, A. N. (1999) Sintered porous hydroxyapatites with intrinsic osteoinductive activity: geometric induction of bone formation. S. Afr. J. Sci. 95, 335–343.Google Scholar
  31. 31.
    Ripamonti, U. (2000) Smart biomaterials with intrinsic osteoinductivity: geometric control of bone differentiation, in Bone Engineering (Davies, J. E., ed.), EM2 Corporation, Toronto, Canada, pp. 215–222.Google Scholar
  32. 32.
    Ripamonti, U., Crooks, J., and Rueger D. C. (2001) Induction of bone formation by recombinant human osteogenic protein-1 and sintered porous hydroxyapatite in adult primates. Plast. Reconstr. Surg. 107, 977–988.PubMedCrossRefGoogle Scholar
  33. 33.
    Ripamonti, U. and Duneas, N. (1996) Tissue engineering of bone by osteoinductive biomaterials. MRS Bull. 21, 36–39.Google Scholar
  34. 34.
    Gerber, H. P. and Ferrare, N. (2000) Angiogenesis and bone growth. Trends Cardiovasc. Med. 10, 223–228.PubMedCrossRefGoogle Scholar
  35. 35.
    Colnot, C. I. and Helms, J. A. (2001) A molecular analysis of matrix remodeling and angiogenesis during long bone development. Mech. Dynamics 100, 245–250.Google Scholar
  36. 36.
    Paralkar, V. M., Nandedkar, A. K. N., Pointer, 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.PubMedGoogle Scholar
  37. 37.
    Heliotis, M. and Ripamonti, U. (1994) Phenotypic modulation of endothelial cells by bone morphogenetic protein fractions in vitro. In Vitro Cell. Dev. Biol. 30A, 353–355.CrossRefGoogle Scholar
  38. 38.
    Wang, J. S. and Aspenberg, P. (1993) Basic fibroblast growth factor and bone induction in rats. Acta. Orthop. Scand. 64, 557–561.PubMedCrossRefGoogle Scholar
  39. 39.
    Takita, H., Tsuruga, E., Ono, I., and Kuboki, Y. (1997) Enhancement by bFGF of osteogenesis induced by rhBMP-2 in rats. Eur. J. Oral. Sci. 105, 588–592.PubMedCrossRefGoogle Scholar
  40. 40.
    Gerber, H. P., Vu, T. H., Ryan, A. M., Kowalski, J., Werb, Z., and Ferrara, N. (1999) VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat. Med. 5, 623–628.PubMedCrossRefGoogle Scholar
  41. 41.
    Horner A., Bord S., Kelsall, A. W., Coleman, N., and Compston, J. E. (2001) Tie2 ligands angiopoietin-1 and angiopoietin-2 are coexpressed with vascular endothelial cell growth factor in growing human bone. Bone 28, 65–71.PubMedCrossRefGoogle Scholar
  42. 42.
    Delaissé, J. M., Ensig, M. T., Everts, V., del Carmen Ovejero, M., Ferreras, M., Lund, L., et al. (2000) Proteinases in bone resorption: obvious and less obvious roles. Clin. Chim. Acta 291, 223–234.PubMedCrossRefGoogle Scholar
  43. 43.
    Ripamonti, U., van den Heever, B., and Van Wyk, J. (1993) Expression of the osteogenic phenotype in porous hydroxyapatite implanted extraskeletally in baboons. Matrix. 13, 491–502.PubMedCrossRefGoogle Scholar
  44. 44.
    Trueta, J. (1963) The role of the vessels in osteogeneis. J. Bone Joint Surg. 45B, 402–418.Google Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Ugo Ripamonti
  • Nathaniel L. Ramoshebi
  • Janet Patton
  • Thato Matsaba
  • June Teare
  • Louise Renton

There are no affiliations available

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