“Tissue Induction”
DOI:
https://doi.org/10.17159/sadj.v80i04.22714Keywords:
bioreactor ultimately, osteonectinsAbstract
This contribution to the induction of tissue formation starts with seemingly simple questions, “Why Bone?” and “Why Cartilage?”, the essential ingredients to compose the skeleton ad thus the speciation of the vertebrates,
the induction of long bone via endochondral ossification, the induction of the growth plate, body erection and the speciation thus of the Homo clade, walking upright toward the spectacular creativity of extant Homo sapiens. The title wishes to pay tribute to grand pioneer scientists such as Pollettini, Levander, Moss, Urist and Reddi who persevered to study the induction of bone formation as initiated by devitalized demineralized bone matrices. “Tissue Induction” is the title of a seminal paper by Gustav Levander in Nature,
1945. Levander hypothesized that unknown substances from heterotopically implanted bone matrices would activate
recipient resident cells to initiate the induction of bone formation, where there is no bone. Levander went further by using the term “Tissue Induction” linking the induction of bone formation to embryonal development as described by Hans Spemann and Hilde Mangold, the 1935 Nobel Prize for Medicine and Physiology. Phylogenetically, bones were an ancestral character, and cartilage developed later, providing the growth plate, to growth vertebrate’ long bones establishing body erection in selected hominid’ clades. The TGF-β supergene family includes several osteogenic proteins endowed with the remarkable capacity to initiate the heterotopic induction of bone. Besides the sub-family of the bone morphogenetic proteins (BMPs), in primates and in primates only, the three mammalian TGF-β isoforms also initiate the induction of bone formation. Heterotopic implantation of recombinant hTGF-β3
initiates the induction of bone formation by priming resident intramuscular cells, pericytes, myoendothelial cells and myoblastic cells to express and secrete BMPs genes and gene products; the expression and synthesis of BMPs initiate the induction of bone formation regulated by Noggin expression. Combined morphological and molecular analyses have indicated that doses of hTGF-β3 in Matrigel®Matrix set into motion the in vivo development of multiple tissues and multicellular organoids within the implanted furcation bioreactors. Organoids form by gene expression pathways from available different cellular populations within the exposed furcation bioreactor. Our molecular and morphological data using undecalcified whole mounted sections cut by the Exakt diamond saw technique have indicated that hTGF-β3 in Matrigel®Matrix induces distinct supracellular phases that together with morphological transformation and organogenesis result in the generation of intramuscular mineralized bone organoids.
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References
1. Romer AS. The “Ancient History” of bone. Ann NY Acad Sci 1963; 109: 168-176.
2. Ripamonti U, Roden L, van den Heever B. Sharks, shark cartilages and shark teeth: A collaborative Africa-USA study to attempt to induce “Bone: formation by autoinduction” in] cartilaginous fishes. South Afr Dent J. 2018; 73: 11-21.
3. Ripamonti U. The Induction of Bone Formation and the Osteogenic Proteins of the Transforming Growth Factor-β Supergene family. Pleiotropism and Redundancy. In: U. Ripamonti (ed.) The Geometric Induction of Bone Formation CRC Press, Taylor & Francis Group. Boca Raton FL, USA, 2021, Chapter 3, 51-68.
4. Lim AW. The emerging era of cell engineering: Harnessing the modularity of cells to program complex biological functions. Science 2022, 378: 848-852.
5. Massagué J. The transforming growth factor-beta family. Annu Rev Cell Biol. 1990:6:597-641.doi: 10.1146/annurev.cb.06.110190.003121.
6. Kingsley DM. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms Genes Dev. 1994 8(2):133-46. doi: 10.1101/gad.8.2.133.
7. Feng XH, Derynck R. Specificity and versatility in TGF-beta signaling through Smads. Ann Rev Cell Develop Biology 2005; 21: 659-93. http://dx.doi.org/10.1146/annurev.cellbio.21.022404.142018
8. Pakyari M, Farrokhi A, Maharlooei MK, Ghahary A. Critical Role of Transforming Growth Factor Beta in Different Phases of Wound Healing. Advances in Wound Care Volume 2, 5, 2013 © 2013, Mary Ann Liebert, Inc. https://doi.org/10.1089/wound.2012.0406
9. Richardson L, Wilcockson SG, Guglielmi L. Hill C. Context-dependent TGFβ family signalling in cell fate regulation. Nature Rev Mol Cell Biol. 2023, 24: 876–94 https://doi.org/10.1038/s41580-023-00638-3
10. Levander G. Tissue induction. Nature 1945: 155: 148-49.
11. Ripamonti U. Biomimetic functionalized surfaces and the induction of bone formation. Invited Expert Opinion Tissue Engineering 2017; 23: 1197-1209.
12. Langer R, Brem H, Kalterman K, Klein M, Folkm an J. Isolations of a cartilage factor that inhibits tumor neovascularization. Science 1976; 193, 4247: 70-72, DOI: 10.1126/science.93585
13. Lee A, Langer R. Shark cartilage contains inhibitors of tumour angiogenesis. Science 1983; 16;221(4616):1185-7. doi: 10.1126/science.6193581.
14. Moses MA, Sudhalter J, Langer R. Identification of an inhibitor of neovascularization from cartilage. Science 1990. 15;248(4961):1408-10.DOI: 10.1126/science.1694043
15. Moses MA, Langer R. Inhibitors of angiogenesis. Biotechnology 1991; 9(7): 630-34, doi: 10.1038/nbt0791-630
16. Ripamonti U. Soluble osteogenic molecular signals and the induction of bone formation. Biomaterials 2006; 27: 807-822.
17. Ripamonti U, Ferretti C, Heliotis M. Soluble and insoluble signals and the induction of bone formation: Molecular therapeutics recapitulating development. J Anat. 2006; 209: 447-468.
18. Ripamonti U, Heliotis M, Ferretti C. Bone morphogenetic proteins and the induction
of bone formation: From laboratory to patients. Oral Maxillofac Surg Clin North Am. 2007; 19: 575-589.
19. Trueta, J. The role of the vessels in osteogenesis. J Bone Joint Surg. 1963, 45B,
402-18
20. Ripamonti U. Regenerative Medicine, the Induction of Bone Formation, Bone Tissue Engineering, and the Osteogenic Proteins of the Transforming Growth Factor-βSupergene Family. In: Ripamonti U (ed.) CRC Press Taylor & Francis, Boca Raton USA, Induction of Bone Formation in Primates. The Transforming Growth Factorbeta3; 2016, Chapter 2, 15-46.
21. Urist MR. Bone: formation by autoinduction. Science 1965 150(3698):893-899 doi: 10.1126/science.150.3698.893.
22. Turing AM. The Chemical Basis of Morphogenesis. Turing Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, Vol. 237, No. 641. (Aug. 14, 1952), pp. 37-72.
23. Ripamonti U, Ramoshebi LN, Patton J, Matsaba T, Teare J, Renton L. Soluble signals and insoluble substrata: Novel molecular cues instructing the induction of bone. In: EJ Massaro and JM Rogers (Eds.), Chapter 15, The Skeleton. Humana Press, 2004; pp 217-227.
24. Sampath TK, Rashka KE, Doctor JS, Tucker RF, Hoffman FM. Drosophila transforming growth factor beta superfamily proteins induce endochondral bone formation in mammals. Proc Natl Acad Sci. USA 1993; 90(13), 6004-6008 https://doi.org/10.1073/pnas.90.13.6004
25. Ripamonti U. Developmental patterns of periodontal tissue regeneration. Developmental diversities of tooth morphogenesis do also map capacity of periodontal tissue regeneration? J Periodont Res. 2019; 54: 10-26; doi: 10.1111/jre.12596
26. Pääbo S. The Human condition—A molecular approach. Cell 2014; 157:216-26.doi:https://doi.org/ 10.1016/j.cell.2013.12.036
27. Ripamonti U, Duarte R, Ferretti C, Reddi AH. Osteogenic competence and potency of the Bone induction principle: Inductive substrates that initiate “Bone: Formation by autoinduction”. J Craniofac Surg. 2022; 33(3): 971-984.
28. Levander G. A study of bone regeneration. Surg Gynec Obst. 1938; 67(6): 705-14.
29. Reddi AH, Huggins CB. Biochemical sequences in the transformation of normal fibroblasts in adolescent rats. Proc Natl Acad Sci U S A. 1972, 69(6):1601-05. doi: 10.1073/pnas.69.6.1601.
30. Urist MR, Silverman BF, Büring K, Dubuc FL, Rosemberg JM. The bone induction principle Clin Orthop Relat Res. 1967 53: 243-83.
31. Sampath, T. K.; Reddi, A. H. Dissociative extraction and reconstitution of extracellular matrix components involved in local bone differentiation. Proc Natl Acad Sci. USA 1981; 78:7599-7603.
32. Sampath, T. K.; Reddi, A. H. Homology of bone-inductive proteins from human,= monkey, bovine, and rat extracellular matrix. Proc Natl Acad Sci. USA 1983, 80, 6591-95.
33. Ripamonti U, Reddi AH. Bone morphogenetic proteins: Applications in plastic and reconstructive surgery. Adv Plast Reconst Surg. 1995; Vol. 11: 47-65.
34. Urist MR, Strates BS. Bone morphogenetic protein. J Dent Res. 1971; 50: 1392-1406.
35. Urist MR, Hou YK, Brownell AG, Hohl WM, Buyske J, Lietze A, Tempst P, Hunkapiller M, DeLange RJ. Purification of bovine bone morphogenetic protein by hydroxyapatite chromatography. Proc Natl Acad Sci. U S A 1984; 81(2):371-5. doi: 10.1073/pnas.81.2.371.
36. Sampath TK, Muthukumaran N, Reddi AH. Isolation of ostogenin, an extracellular matrix-associated, bone-inductive protein, by heparin affinity chromatography. Proc Natl Acad Sci. USA 1987; 84(20):7109-13. doi: 10.1073/pnas.84.20.7109.
37. Wang EA, Rosen V, Cordes P, Hewick RM, Kriz MJ, Luxenberg DP, Sibley BS, Wozney JM. Purification and characterization of other distinct bone-inducing factors. Proc Nat Acad Sci USA, 1988, 85 (24): 9484-9488, https://doi.org/10.1073/pnas.85.24.9484
38. Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA. Novel regulators of bone formation: molecular clones and activities.Science. 1988; 42(4885):1528-34. doi: 10.1126/science.3201241.PMID: 3201241
39. Celeste AJ, Iannazzi JA, Taylor RC, Hewick RM, Rosen V, Wang EA, Wozney JM Identification of transforming growth factor beta family members present in boneinductive protein purified from bovine bone. Proc Natl Acad Sci, U S A. 1990 Dec;87(24):9843-7. doi: 10.1073/pnas.87.24.9843.
40. Urist MR. The reality of a nebulous, enigmatic myth. Clin Orthop Rel Res. 1968; 59:3-6. 49.
41. Åberg T, Wozney J, Thesleff I. Expression patterns of bone morphogenetic proteins (Bmps) in the developing mouse tooth suggest roles in morphogenesis and cell differentiation. Dev Dyn. 1997; 210:383–3. https://doi.org/10.1002/(SICI)1097-0177(199712)210:4<383::AID-AJA3>3.0.CO;2-C
42. Ripamonti U, Duneas N. Tissue morphogenesis and regeneration by bone morphogenetic proteins. Plast Reconst Surg. 1998; 101: 227-239.
43. Thomadakis G, Crooks J, Rueger D, Ripamonti U. Immunolocalization of bone morphogenetic protein-2, -3 and osteogenic protein-1 during murine tooth morphogenesis and other craniofacial structures. Eur J Oral Sci. 1999; 107: 368-377.
44. Reddi AH. Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nat Biotechnol 1988; 16(3): 247-52. doi: 10.1038/nbt0398-247.
45. Ripamonti U. Soluble, insoluble and geometric signals sculpt the architecture of mineralized issues. J Cell Mol Med. 2004; 8: 169-180.
46. Ripamonti U, Duneas N, van den Heever B, Bosch C, Crooks J. Recombinant transforming growth factor-β1 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. 1997; 12: 1584-1595.
47. Ripamonti U, Crooks J, Matsaba T, Tasker J. Induction of endochondral bone formation by recombinant human transforming growth factor-ß2 in the baboon (Papio ursinus). Growth Factors 2000; 17: 269-285.
48. Ripamonti U. Osteogenic Proteins of the Transforming Growth Factor-ß Superfamily. In: HL Henry and AW Norman (Eds.), Encyclopedia of Hormones. Academic Press, 2003, pp 80-86.
49. Ripamonti U, Ramoshebi LN, Teare J, Renton L, Ferretti C. The induction of endochondral bone formation by transforming growth factor-β3: Experimental studies in the non-human primate Papio ursinus. J Cell Mol Med. 2008; 12: 1029-1048.
50. Ripamonti U. Bone induction by recombinant human osteogenic protein-1 (hOP-1, BMP-7) in the primate Papio ursinus with expression of mRNA of gene products of the TGF-β superfamily. J Cell Mol Med. 2005; 9: 911-928.
51. Ripamonti U, Heliotis M, van den Heever B, Reddi AH. Bone morphogenetic proteins induce periodontal regeneration in the baboon (Papio ursinus). J Periodont Res. 1994; 29: 439-445.
52. Ripamonti U, Heliotis M, Sampath TK, Rueger D. Induction of cementogenesis by recombinant human osteogenic protein-1 (hOP-1/BMP-7) in the baboon (Papioursinus). Archives of Oral Biology 1996; 41: 121-126.
54. Ripamonti U, Petit J-C. Bone morphogenetic proteins, cementogenesis, myoblastic stem cells and the induction of periodontal tissue regeneration. Cyt Grow Fact Rev. 2009; 20: 489-499.
55. Ripamonti U, Reddi AH. Periodontal regeneration: Potential role of bone morphogenetic proteins. J Periodont Res. 1994; 29: 225-235.
56. Ripamonti U. The induction of bone formation: From bone morphogenetic proteins to the transforming growth factor-β3 protein – Redundancy, pleiotropy, and the induction of cementogenesis. The South Afr Dent J. 2021; 76(6): 331-356.
57. Ripamonti U, Crooks J, Petit J-C, Rueger D. Periodontal tissue regeneration by combined applications of recombinant human osteogenic protein-1 and bone morphogenetic protein-2. A pilot study in Chacma baboons (Papio ursinus). Eur J Oral Sci. 2001; 109: 241-248.
58. Ripamonti U, Crooks J, Teare J, Petit J-C, Rueger DC. Periodontal tissue regeneration by recombinant human osteogenic protein-1 in periodontally-induced furcation defects of the primate Papio ursinus. S Afr J Sci. 2002; 98: 361-368.
59. Ripamonti U. Re-defi ning the induction of periodontal tissue regeneration in primates by the osteogenic proteins of the transforming growth factor-β supergene family. J Periodont Res. 2016; 51: 699-715.
60. Ripamonti U, Parak R, Klar RM, Dickens C, Dix-Peek T, Duarte R. Cementogenesis and osteogenesis in periodontal tissue regeneration by recombinant human transforming growth factor-β3
: a pilot study in Papio ursinus. J Clin Periodont. 2017; 44: 83-95.
61. Teare J, Ramoshebi LN, Ripamonti U. Periodontal tissue regeneration by recombinant human transforming growth factor-β3 in Papio ursinus. J Periodont Res. 2008; 43:
1-8.
62. Ripamonti U, Parak R, Petit J-C. Induction of cementogenesis and periodontal ligament regeneration by recombinant human transforming growth factor-ß3in Matrigel with rectus abdominis responding cells. J Periodont Res. 2009; 44: 141-152.
63. Ripamonti U, Ma S, Cunningham N, Yeates L, Reddi AH. Initiation of bone regeneration in adult baboons by osteogenin, a bone morphogenetic protein. Matrix 1992; 12: 369-380.
64. Coura GS, Garcez RC, Mendes de Agular CBN, Alvarez-Silva M, Magini RS, Trentin AG. Human periodontal ligament: a niche of neuronal crest stem cells. J Periodont Res 2008; 43: 331-36.
65. Han J, Menicanin D, Gronthos S, Bartold PM. Stem cells, tissue engineering and periodontal regeneration. Aust Dent J 2014; 59 Suppl 1:117-30. doi: 10.1111/adj.12100. Epub 2013 Sep 23.
66. Teare JA, Petit J-C, Ripamonti U. Synergistic induction of periodontal tissue regeneration by binary application of hTGF-β3 and hOP-1 in Class II furcation defects of Papio ursinus. J Periodont Res. 2011
Dec 6. doi: 10.1111/j.1600-0765.2011.01438.x. [Epub ahead of print]; 2012; 47: 336-344.
67. Ripamonti U, Klar RM, Renton LF, Ferretti C. Synergistic induction of bone formation by hOP- 1, hTGF-β3and inhibition by zoledronate in macroporous coral-derived hydroxyapatites. Biomaterials 2010; 31: 6400-6410.
68. Duneas N, Crooks J, Ripamonti U. Transforming growth factor-ß1: 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 1998; 15: 259-277.
69. Ripamonti U, Parak R, Klar RM, Dickens C, Dix-Peek T, Duarte R. The synergistic induction of bone formation by the osteogenic proteins of the TGF-β supergene family. Biomaterials 2016; 104: 279-296. Doi: 10.1016/j.biomaterials.2016.07.018.
70. Ripamonti U, Teare J, Ferretti C. A macroscopic bioreactor super activated by the Recombinnat human transforming growth factor-β3. Frontiers in Physiology www.frontiersin.org 2012;3:1-18.
71. Ripamonti U, Duarte R, Ferretti C. Re-evaluating the induction of bone formation in primates. Biomaterials 2014; 35: 9407-9422.
72. Ramoshebi LN, Ripamonti U. Osteogenic protein-1, a bone morphogenetic protein, induces angiogenesis in the chick chorioallantoic membrane and synergize with basic fi broblast growth factor and transforming growth factor-�1. Anat Rec. 2000; 259: 97-107.
73. Kleinman HK, McGarvey ML, Hassell JR, Star VL, Cannon FB, Laurie GW, Martin GR. Basement membrane complexes with biological activities. Biochemistry 1986; 25(2): 312-318 DOI: 10.1021/bi00350a005
74. Ripamonti U, van den Heever B, Heliotis M, Dal Mas I, Hahnle U, Biscardi A. Local delivery of bone morphogenetic proteins using a reconstituted basement membrane gel: Tissue engineering with Matrigel. S Afr J Sci. 2002; 98: 429-433.
75. Vukicevic S, Luyten FP, Kleinman HK, Reddi AH. Differentiation of canalicular cell processes in bone cells by basement membrane matrix components: Regulation by discrete domains of laminin. Cell 1990, 63, 437-445.
76. Paralkar VM, Nandedkar AK, Pointer RH, Kleinman HK, Reddi AH. Interaction of osteogenin, a heparin binding bone morphogenetic protein, with type IV collagen. J Biol Chem. 1990 5;265(28):17281-4.
77. Vukicevic S, Latin V, Chen P, Batorsky R, Reddi AH, Sampath TK. Localization of osteogenic protein-1 (bone morphogenetic protein-7) during human embryonic development: high affi nity binding to basement membranes. Biochem Biophys Res Commun. 1994; 198(2):693-700. doi:10.1006/bbrc.1994.1100.
78. Paralkar VM, Vukicevic S, Reddi AH. Transforming growth factor beta type 1 binds to collagen IV of basement membrane matrix: implications for development. Dev Biol. 1991;143(2):303-8. doi: 10.1016/0012-1606(91)90081-d.
79. Folkman J, Klagsburn M, Sasse J, Wadzinsky M, Ingber D, Vlodavsky I. A heparinbinding protein – basic fi broblast growth factor – is stored within basement membrane. Am J Path. 1988; 130(2), 393-400 -ncbi.nim.nih.gov
80. Buxboim A, Discher DE. Stem Cells Feel the Difference. Nature Methods 2010, 7 (5), 695-697.
81. Discher DE, Janmey P, Wang Y-L. Tissue Cells Feel and Respond to the Stiffness of Their Substrate. Science 2005, 310, 1139-43.
82. Fu J. Wang, Y-K, Yang MT. Desai RA, Yu X, Liu Z, Chen CS, Mechanical Regulation of Cell Function with Geometrically Modulated Elastomeric Substrates. Nature Methods 2010, doi:10.1033/NMETH.1487.
83. Engler AJ, Sen S, Sweeney L, Discher DE. Matrix Elasticity Directs Stem Cell Lineage Specifi cation. Cell 2006; 126: 677–89. doi10.1016/j.cell.2006.06.044.
84. Ripamonti U. Biomimetism, biomimetic matrices and the induction of bone formation. J Cell Mol Med. 2009; 13 9B: 2953-2972.
85. Luan X, Walker C, Dangaria S, Iti Y, Druzinsky R, Jarosius K, Lesot H, Rieppel O. The mosasaur tooth attachment apparatus as paradigm for the evolution of the gnathostome periodontium. Evol & Develop 2009; https://doi.org/10.1111/j.1525-142X.2009.00327.x
86. Jiménez-Durán K, López-Letay S, Zeichner-David M, Higinio Arzate H. Cloning, expression and biological activity of cementogenin (CMGN): A novel protein from human cementum. Manuscript ID: 1009419, 2022, www.frontiersin.org
87. Klar M R, Duarte R, Dix-Peek T, Ripamonti U. The induction of bone formation by the recombinant human transforming growth factor-β3. Biomaterials 2014; 35: 2773-2788 http://dx.doi.org/10.1016/ j.biomaterials.2013.12.062
88. Ripamonti U, Dix-Peek T, Parak R, Milner B, Duarte R. Profi ling bone morphogenetic Proteins and transforming growth factor-βs by hTGF-β3 pre-treated coral-derived macroporous constructs: The power of one. Biomaterials 2015; 49: 90-102.
89. Research Article Summary, Tissue Morphogenesis, Editorial Science 382, 902, 2023.
90. Yang S. Palmquist KH, Nathan L, Pfeifer CR, Schultheiss PJ, Sharma A, Kam LC, Miller PW, Shyer AE, Rodrigues AR. Morphogens enable interacting supracellular phases that generate organ architecture. Science 2023; 382, 902. https://doi: 10.1126/science.adg5579
91. Ripamonti U. Global morphogenesis regulating tissue architecture and organogenesis. Biomaterials Advances 2025; 172 214262, https://doi.org/10.1016/j.bioadv.2025.214262
92. Ripamonti U, Tsiridis E, Ferretti C, Kerawala CJ, Mantalaris A, Heliotis M. Perspectives in regenerative medicine and tissue engineering of bone. J Oral Maxillofac Surg. 2010; doi:10.1016/j.bjoms.
93. Ferretti C, Ripamonti U. Special Editorial: The conundrum of human osteoinduction: Is the bone induction principle failing clinical translation? J Craniofac Surg. 2021; 32:
1287-1289; doi:10.1097/ SCS0000000000007429.
94. Ramasamy SK, Kusumbe AP, Adams RH. Regulation of tissue morphogenesis byendothelial cell-derived signals. Trends in Cell Biol. 2015; 25(3): 148-57. https:/doi:
10.1016/j.tcb.2014.11.007.Epub 2014 Dec 17.
95. Gomez-Salinero JM, Rafi i S. Endothelial cell adaptation in regeneration. Science 2018;362(419): 1116-11.https://doi: 10.1126/science.aar4800.
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