Growth and Morphogenetic Factors in Bone Induction: Role of Osteogenin and Related Bone Morphogenetic Proteins in Craniofacial and Periodontal Bone Repair

Abstract

Bone has considerable potential for repair as illustrated by the phenomenon of fracture healing. Repair and regeneration of bone recapitulate the sequential stages of development. It is well known that demineralized bone matrix has the potential to induce new bone formation locally at a heterotopic site of implantation. The sequential development of bone is reminiscent of endochondral bone differentiation during bone development. The collagenous matrix-induced bone formation is a prototype model for matrix-cell interactions in vivo. The developmental cascade includes migration of progenitor cells by chemotaxis, attachment of cells through fibronectin, proliferation of mesenchymal cells, and differentiation of bone. The bone inductive protein, osteogenin, was isolated by heparin affinity chromatography. Osteogenin initiates new bone formation and is promoted by other growth factors. Recently, the genes for osteogenin and related bone morphogenetic proteins were cloned and expressed. Recombinant osteogenin is osteogenic in vivo. The future prospects for bone induction are bright, and this is an exciting frontier with applications in oral and orthopaedic surgery.

References

Reddi, A.H., Extracellular matrix and development, in Extracellular Matrix Biochemistry, Piez, K. A. and Reddi, A. H., Eds., Elsevier, New York, 1984, 375.

Reddi, A.H., Regulation of bone differentiation by local and systemic factors, in Bone and Mineral Research, Vol. 3, Peck, W. A., Ed., Elsevier Science Publishers, Amsterdam, 1985, 27.

Marks, S.C. and Popoff, S.N., Bone cell biology: the regulation of development, structure, and function in the skeleton, Am. J. Anat., 183, 1, 1988.

Reddi, A.H., Muthukumaran, N., Ma, S., Carrington, J.L., Luyten, F.P., Paralkar, V.M., and Cunningham, N.S., Initiation of bone development by osteogenin and promotion by growth factors, Connect. Tissue Res., 20, 303, 1989.

Urist, M.R., Bone: formation by autoinduction, Science, 159, 893, 1965.

Reddi, A.H. and Huggins, C.B., Biochemical sequences in the transformation of normal fibroblasts in adolescent rats, Proc. Natl. Acad. Sci. U.S.A., 69, 1601, 1972.

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

Sampath, T.R., Muthukumaran, N., and Reddi, A.H., Isolation of osteogenin, an extracellular matrix-associated bone inductive protein, by heparin affinity chromatography, Proc. Natl. Acad. Sci. U.S.A., 84, 7109, 1987.

Wozney, J.M., Rosen, V., Celeste, A.J., Mitsock, L.M., Whitters, M.J., Kriz, R.W., Hewick, R.M., and Wang, E.A., Novel regulators of bone formation: molecular clones and activities, Science, 242, 1528, 1988.

10.

Luyten, F.P., Cunningham, N.S., Ma, S., Muthukumaran, N., Hammonds, R.G., Nevins, W.B., Wood, W.I., and Reddi, A.H., Purification and partial amino acid sequence of osteogenin, protein initiating bone differentiation, J. Biol. Chem., 264, 13377, 1989.

11.

Reddi, A.H. and Huggins, C.B., The formation of bone marrow in fibroblast-transformation ossicles, Proc. Natl. Acad. Sci. U.S.A., 72, 2212, 1975.

12.

Rath, N.C. and Reddi, A.H., Collagenous bone matrix is a local mitogen, Nature, 278, 855, 1979.

13.

Weiss, R.E. and Reddi, A.H., Appearance of fibronectin during the differentiation of cartilage, bone and bone marrow, J. Cell Biol., 88, 630, 1980.

14.

Weiss, R.E. and Reddi, A.H., Role of fibronectin in collagenous matrix-induced mesenchymal cell proliferation and differentiation in vivo, Exp. Cell Res., 133, 247, 1981.

15.

Reddi, A.H., Regulation of local differentiation of cartilage and bone by extracellular matrix: a cascade type mechanism, in Limb Development and Regeneration, Kelly, R. 0., Goetinck, P. F., and Mac-Cabe, J. A., Eds., Alan R. Liss, New York, 1982, 261.

16.

Sampath, T.K. and Reddi, A.H., Dissociative extraction and reconstitution of extracellular matrix components involved in local bone differentiation, Proc. Natl Acad. Sci. U.S.A., 78, 7599, 1981.

17.

Sampath, T.K. and Reddi, A.H., Homology of bone-inductive proteins from human, monkey, bovine and rat extracellular matrix, Proc. Natl. Acad. Sci. U.S.A., 80, 6591, 1983.

18.

Hammonds, G.R., Schwall, R., Dudley, A., Berkemeier, L., Lai, C., Lee, J., Cunningham, N., Reddi, A.H., Wood, W.I., and Mason, A.J., The bone inducing activity of recombinant BMP-2A, BMP-2B, and BMP-3 (osteogenin) and the purification and characterization of mature BMP-2B from a hybrid BMP-2A/2B precursor, Mol. Endocrinol., 5, 149, 1991.

19.

Vukicevic, S., Luyten, F.P., and Reddi, A.H., Stimulation of the expression of osteogenic and chondrogenic phenotypes in vitro by osteogenin, Proc. Natl. Acad. Sci. U.S.A., 86, 8793, 1989.

20.

Vukicevic, S., Luyten, F.P., and Reddi, A.H., Osteogenin inhibits proliferation and stimulates differentiation in mouse osteoblast-like cells (MC3T3-El), Biochem. Biophys. Res. Commun., 166, 750, 1990.

21.

Heine, U.I., Munoz, E.F., Flanders, K.C., Ellingsworth, L.R., Sporn, M.B., and Roberts, A.B., Role of transforming growth factor-β in the development of the mouse embryo, J. Cell Biol., 105, 2861, 1989.

22.

Rosa, F., Roberts, A.B., Danielpour, D., Dart, L.L., Sporn, M.B., and Dawid, I.B., Mesoderm induction in amphibians: the role of TGF-β 2-like factors, Science, 239, 783, 1988.

23.

Seyedin, S.M., Thomas, T.C., Thompson, A.Y., Rosen, D.M., and Piez, K.A., Purification and characterization of two cartilage-inducing factors from bovine demineralized bone, Proc. Natl. Acad. Sci. U.S.A., 82, 2267, 1985.

24.

Seyedin, S.M., Thompson, A.Y., Bentz, H., Rosen, D.M., McPherson, J.M., Conti, A., Siegel, N.R., Galluppi, G.R., and Piez, K.A., Cartilage-inducing factor-A, J. Biol. Chem., 261, 5693, 1986.

25.

Seyedin, S.M., Segarini, P.R., Rosen, D.M., Thompson, A.Y., Bentz, H., and Graycar, J., Cartilage-inducing factor-β is an unique protein structurally and functionally related to transforming growth factor-β, J. Biol. Chem., 262, 1946, 1987.

26.

Sporn, M.B. and Roberts, A.B., The transforming growth factor-β s, in Peptide Growth Factors and their Receptors, Sporn, M. B. and Roberts, A. B., Eds., Springer-Verlag, Berlin, 1990, 419.

27.

Mason, A.J., Hayflick, J.S., Ling, N., Esch, F., Ueno, N., Ying, S.-Y., Guillemin, R., Niall, H., and Seeburg, P.H., Complementary DNA sequences of ovarian follicular fluid inhibin show precursor structure and homology with transforming growth factor-β, Nature, 318, 659, 1985.

28.

Schwall, R.H., Nikolic, K., Szonyi, E., Gorman, C., and Mason, A.J., Recombinant expression and characterization of human activin A, Mol. Endocrinol., 3, 1237, 1988.

29.

Cate, R.L., Mattaliano, R.J., Hession, C., Tizard, R., Farber, N.M., Cheung, A., Ninfa, E.G., Frey, A.Z., Gash, D.J., Chow, E.P., Fisher, R.A., Bertonis, J.M., Torres, G., Wallner, B.P., Ramachandran, K.L., Ragin, R.C., Manganaro, T.F., MacLaughlin, D.T., and Donahue, P.K., Isolation of the bovine and human genes for Mullerian inhibiting substance and expression of the human gene in animal cells, Cell, 45, 685, 1986.

30.

Padgett, R.W., St. Johnston, R.D., and Gelbart, W.M., A transcript from a Drosophila pattern gene predicts a protein homologous to the transforming growth factor-beta family, Nature, 325, 81, 1987.

31.

Weeks, D.L. and Melton, D.A., A maternal mRNA localized to the vegetal hemisphere in Xenopus eggs codes for a growth factor related to TGF-β, Cell, 51, 861, 1987.

32.

Lyons, K.M., Graycar, J.L., Lee, A., Hashmi, S., Lindquist, P.B., Chen, E.Y., Hogan, B.L.M., and Derynck, R., Vgr-1, a mammalian gene related to Xenopus Vg-1 and a new member of the transforming growth factor β superfamily, Proc. Natl. Acad. Sci. U.S.A., 86, 4554, 1989.

33.

Wang, E.A., Rosen, V., D'Alessandro, J.S., Bauduy, M., Cordes, P., Harada, T., Israel, D., Hewick, R.M., Kerns, K., LaPan, P., Luxenberg, D.P., McQuaid, D., Moutsatsos, I., Nove, J., and Wozney, J.M., Recombinant human bone morphogenetic protein induces bone formation, Proc. Natl. Acad. Sci. U.S.A., 87, 2220, 1990.

34.

Lyons, K.M., Pelton, R.W., and Hogan, B.L.M., Patterns of expression of murine Vgr-1 and BMP-2a RNA suggest that transforming growth factor-p-like genes coordinately regulate aspects of embryonic development, Genes Dev., 3, 1657, 1989.

35.

Rosen, V., Wozney, J.M., Wang, E.A., Cordes, P., Celeste, A., McQuaid, D., and Kurtzberg, L., Purification and molecular cloning of a novel group of BMPs and localization of BMP mRNA in developing bone, Connect. Tissue Res., 20, 313, 1989.

36.

Vukicevic, S., Paralkar, V.M., Cunningham, N.S., Gutkind, J.S., and Reddi, A.H., Autoradiographic localization of osteogenin binding sites in cartilage and bone during rat embryonic development, Dev. Biol., 140, 209, 1990.

37.

Lyons, K.M., Pelton, R.W., and Hogan, B.L.M., Organogenesis and pattern formation in the mouse: RNA distribution patterns suggest a role for Bone Morphogenetic Protein-2A (BMP-2A), Development, 109, 833, 1990.

38.

Ma, S., Chen, G., and Reddi, A.H., Collaboration between collagenous matrix and osteogenin is required for bone induction, Ann. N.Y. Acad. Sci., 580, 524, 1990.

39.

Carrington, J.L., Roberts, A.B., Flanders, K.C., Roche, N.S., and Reddi, A.H., Accumulation, localization, and compartmentation of transforming growth factor β during endochondral bone development, J. Cell Biol., 107, 1969, 1988.

40.

Foidart, J.M. and Reddi, A.H., Immunofluorescent localization of type IV collagen and laminin during endochondral bone differentiation and regulation by pituitary growth hormone, Dev. Biol., 75, 130, 1980.

41.

Reddi, A.H. and Kuettner, K.E., Vascular invasion of cartilage: correlation of morphology with lysozyme, glycosaminoglycans, protease and protease inhibitory activity during endochondral bone development, Dev. Biol., 82, 217, 1981.

42.

Trueta, J., The role of the vessels in osteogenesis, J. Bone J. Surg., 45B, 402, 1963.

43.

Simmons, D.J., Fracture healing, in Fundamental and Clinical Bone Physiology, Urist, M. R., Ed., Lippincott, Philadelphia, 1980, 283.

44.

Paralkar, V.M., Nandedkar, A.K.N., Pointer, R.H., Kleinman, H.K., and Reddi, A.H., Interaction of osteogenin, a heparin binding bone morphogenetic protein, with type IV collagen, J. Biol. Chem., 1990, in press.

45.

Paralkar, V.M., Vukicevic, S., and Reddi, A.H., Transforming growth factor β type 1 binds to collagen type IV of basement membrane matrix: implications for development, Dev. Biol., 143, 303, 1991.

46.

Vukicevic, S., Luyten, F.P., Kleinman, H.K., and Reddi, A.H., Differentiation of canalicular cell processes in bone cells by basement membrane matrix components: regulation by discrete domains of laminin, Cell, 63, 437, 1990.

47.

Wolpert, L.J., Positional information and the spatial pattern of cellular differentiation, J. Theoret. Biol., 25, 1, 1969.

48.

Ripamonti, U., Bone induction in nonhuman primates. An experimental study on the baboon (Papio ursinus), Clin. Orthop. Rel. Res., 269, 284, 1991.

49.

Ripamonti, U., Calvarial reconstruction in primates with porous hydroxyapatite replicas, Plast. Reconstr. Surg., in press.

50.

Schmitz, J.P. and Hollinger, J.O., The critical size defect as an experimental model for craniomandibulofacial nonunions, Clin. Orthop. Rel. Res., 205, 1986.

51.

Ripamonti, U., Ma, S., and Reddi, A.H., Partial purification and biological activity of baboon osteogenin, J. Bone Miner. Res., 4 (Suppl. 1), 409, 1168, 1989.

52.

Ripamonti, U., Ma, S., Cunningham, N.S., and Reddi, A.H., Initiation of endochondral bone formation and regeneration of calvarial defects in primates by osteogenin, Matrix, submitted.

53.

Hulbert, S.F., Young, F.A., Mathews, R.S., Klawitter, J.J., Talbert, C.D., and Stelling, F.H., Potential of ceramic materials as permanently implantable skeletal prostheses, J. Biomed. Mater. Res., 4, 433, 1970.

54.

White, R.A., Weber, J.N., and White, E.W., Replamineform: a new process for preparing porous ceramic, metal, and polymer prosthetic materials, Science, 176, 922, 1972.

55.

Weber, J.N. and White, E.W., Carbonate minerals as precursors of new ceramics, metal and polymer materials for biomedical applications, Miner. Sci. Eng., 5, 151, 1973.

56.

Roy, D.M. and Linnehan, S.K., Hydroxyapatite formed from coral skeletal carbonate by hydrothermal exchange, Nature, 247, 220, 1974.

57.

Chiroff, R.T., White, E.W., Weber, J.N., and Roy, D.M., Tissue ingrowth of replamineform implants, J. Biomed. Mater. Res. Symp., 6, 29, 1975.

58.

White, E.W., Weber, J.N., Roy, D.M., and Owen, E.L., Replamineform porous biomaterials for hard tissue implant applications, J. Biomed. Mater. Res. Symp., 6, 23, 1975.

59.

Holmes, R.E., Bone regeneration within a coralline hydroxyapatite implant, Plast. Reconstr. Surg., 63, 626, 1979.

60.

Ripamonti, U., The morphogenesis of bone in porous hydroxyapatite replicas of calcium carbonate coral exoskeletons, J. Bone J. Surg., 1990, submitted.

61.

Ripamonti, U., Ma, S., and Reddi, A.H., Induction of bone in composites of osteogenin and porous hydroxyapatite in baboons, Plast. Reconstr. Surg., in press.

62.

Ripamonti, U., Inductive bone matrix and porous hydroxyapatite composites in rodents and nonhuman primates, in Handbook of Bioactive Ceramics, Vol. 2, Calcium Phosphate and Hydroxylapatite Ceramics, Yamamuro, T., Wilson-Hench, J., and Hench, L. L., Eds., CRC Press, Boca Raton, FL, 1990, 245.

63.

Glowaki, J., Kaban, L.B., Murray, J.E., Folkman, J., and Mulliken, J.B., Application of the biological principle of induced osteogenesis for craniofacial defects, Lancet, 1, 959, 1981.

64.

Terranova, V.P., Jendresen, M., and Young, F., Healing, regeneration, and repair: prospectus for new dental treatment, Adv. Dent. Res., 3, 69, 1989.

65.

Gottlow, J., Nyman, S., Karring, T., and Lindhe, J., New attachment formation as a result of controlled tissue regeneration, J. Clin. Periodontol., 11, 494, 1984.

66.

Magnusson, I., Nyman, S., Karring, T., and Egelberg, J., Connective tissue attachment formation following exclusion of gingival connective tissue and epithelium during healing, J. Periodont. Res., 20,201, 1985.

67.

Terranova, V.P., Franzetti, L., Hie, S., Lyall, R.M., Wikesjo, U.M.E., Baker, P.J., Christersson, L.A., and Genco, R.J., A biochemical approach to periodontal regeneration: tetracycline treatment of dentin promotes fibroblast adhesion and growth, J. Periodont. Res., 21, 330, 1986.

68.

Smith, B.A., Smith, J.S., Caffesse, R.G., Nasjleti, C.E., Lopatin, D.E., and Kowalski, C.J., Effect of citric acid and various concentrations of fibronectin on healing following periodontal flap surgery in dogs, J. Periodontol., 58, 667, 1987.

69.

Smith, B., Caffesse, R., Nasjleti, C., Kon, S., and Castelli, W., Effects of citric acid and fibronectin and laminin application in treating periodontitis, J. Clin. Periodontol., 14, 396, 1987.

70.

Ripamonti, U., Petit, J.-C., Lemmer, J., and Austin, J.C., Regeneration of the connective tissue attachment on surgically exposed roots using a fibrin-fibronectin adhesive system. An experimental study on the baboon (Papio ursinus), J. Periodont. Res., 22, 320, 1987.

71.

Ripamonti, U. and Petit, J.-C., Patterns of healing on replanted baboon incisor coated with a fibrin-fibronectin protein concentrate, J. Periodont. Res., 24, 335, 1989.

72.

Terranova, W.P. and Wikesjo, U.M.E., Extracellular matrices and polypeptides growth factors as mediators of functions of cells of the periodontium. A review, J. Periodontol., 58, 371, 1987.

73.

Garrett, J.S., Crigger, M., and Egelberg, J., Effects of citric acid on diseased root surfaces, J. Periodont. Res., 13, 155, 1978.

74.

Boyko, G.A., Brunette, D.M., and Melcher, A.H., Cell attachment to demineralized root surfaces in vitro, J. Periodont. Res., 15, 297, 1980.

75.

Caffesse, R.G., Holden, M.J., Kon, S., and Nasjleti, C.E., The effect of citric acid and fibronectin application on healing following surgical treatment of naturally occurring periodontal disease in Beagle dogs, J. Clin. Periodontol., 12, 578, 1985.

76.

Lynch, S.E., Williams, R.C., Poison, A.M., Howell, T.H., Reddy, M.S., Zappa, U.E., and Antoniades, H.N., A combination of platelet-derived and insulin-like growth factors enhances periodontal regeneration, J. Clin. Periodontol., 16, 545, 1989.

77.

Howes, R., Bowness, J.M., Grotendorst, G.R., Martin, G.R., and Reddi, A.H., Platelet-derived growth factor enhance demineralized bone matrix-induced cartilage and bone formation, Calcif. Tissue Int., 42, 34, 1988.

78.

Narang, R. and Wells, H., Bone induction in experimental periodontal bony defects in dogs with decalcified allogeneic bone matrix grafts, Oral Surg., 33, 306, 1990.

79.

Libin, B.M., Ward, H.L., and Fishman, L., Decalcified, lyophilized bone allografts for use in human periodontal defects, J. Periodontol., 46, 51, 1975.

80.

Sonis, S.T., Kaban, S.T., and Glowaki, J., Clinical trial of demineralized bone powder in the treatment of periodontal defects, J. Oral Med., 38, 117, 1983.

81.

Bowers, G.M., Granet, M., Stevens, M., Emerson, J., Corio, R., Mellonig, J., Lewis, S.B., Peltzman, B., Romberg, E., and Risom, L., Histologic evaluation of new attachment in humans, J. Periodontol., 56, 381, 1985.

82.

Makris, G.P. and Saffar, J.L., Disturbances in bone remodeling during the progress of hamster periodontitis; a morphological and quantitative study, J. Periodont. Res., 20, 411, 1985.

83.

Ripamonti, U., Ma, S., and Reddi, A.H., unpublished data.