The Induction of Bone Formation by the recombinant human transforming growth Factor-β3 : From preclinical studies in Papio ursinus to translational research in Homo sapiens
DOI:
https://doi.org/10.17159/2519-0105/2022/v77no3a1Keywords:
Bone induction, bone morphogenetic proteins, transforming growth factors-β proteins, transforming growth factors-β3 , redundancy, primates, human osteoinduction, inhibitors, translational clinical researchAbstract
Skeletal bone defects of the axial or the craniomaxillofacial skeletons still present formidable challenges to skeletal reconstructionists, tissue biologists and modern medicine. In systematic research experiments in the Chacma baboon Papio ursinus our laboratories have shown the previously unreported osteoinductive activity of the three mammalian transforming growth factor-β (TGF-β) isoforms. This review discusses the induction of bone formation by the mammalian TGF-βs with particular reference to the substantial and
rapid induction of bone by the recombinant hTGF-β3 from the laboratory benches, to pre-clinical studies in heterotopic and orthotopic mandibular sites of Papio ursinus to clinical translation in human patients. Design and MethodsA series of systematic research experiments in Papio ursinus using the hTGF-β3 together with earlier experiments using the -β1 and β2 isoforms are reviewed and re-analyzed molecularly nd morphologically to provide the basic research data for the reported clinical translation in human patients.
Results The three mammalian hTGF-β isoforms and notably hTGF-β3 induce rapid and substantial induction of heterotopic bone
in intramuscular sites of Papio ursinus. Relatively low doses of hTGF-β1or hTGF-β3 in binary application with hBMP-7 synergize to induce massive corticalized ossicles in the rectus abdominis muscle. In orthotopic mandibular sites, 125 and250 µg doses of hTGF-β3 induce bone formation across large mandibular defects in Papio ursinus with corticalized buccal and lingual plates by day 30, with modeling and maintenance of corticalized bone by 9 to 12 months after implantation of the 250 µg dose in 3 cm mandibular defects Papio ursinus. Discussion hTGF-β3 significantly up-regulates RUNX-2 and Osteocalcin expression on day 15 controlling the differentiation of progenitor stem cells into the osteoblastic lineage. The induction of bone by the hTGF-β3 is via the bone morphogenetic proteins pathway; hTGF-β3 controls theinduction of bone by regulating the expression of BMPs gene and gene products via Noggin expression, eliciting bone induction by up-regulating exogenous BMPs.
Downloads
References
Ripamonti U, Klar RM. Regenerative frontiers in craniofacial reconstruction: grand challenges and opportunities for the mammalian transforming growth factor-β proteins. Front Physiol. 2010;1:143. Published 2010 Nov 11. doi:10.3389/fphys.2010.00143.
Ferretti C, Ripamonti U. The Conundrum of human osteoinduction: Is the bone induction principle failing the clinical translation? J Craniofac Surg. 2021;32(4):1287-89.
The power of one. Introduction. Cell 2014; 157:3
Ripamonti U. Osteogenic proteins of the transforming growth factor-ß superfamily. In: HL Henry and AW Norman (Eds.), Encyclopedia of Hormones. Academic Press, Elsevier Inc., 2003; pp 80-86.
Wang EA, Rosen V, Cordes P, et al: Purification and characterization of other distinct bone-inducing factors. Proc Natl Acad Sci U S A 1988;85(24):9484
Luyten FP, Cunningham NS, Ma S, et al. Purification and partial amino acid sequence of osteogenin, a protein initiating bone differentiation.J Biol Chem. 1989;264(23):13377-13380.
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; 242:1528-34.
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 cad Sci U S A. 1990 Dec;87(24):9843-7. doi: 10.1073/
pnas.87.24.9843.
Özkaynak E, Rueger DC, Drier EA, Corbett C, Ridge RJ, Sampath TK, Oppermann H. OP-1 cDNA encodes an osteogenic protein in the TGF-beta family. EMBO J 1990; Jul;9(7):2085-93.
Reddi AH. Morphogenesis and tissue engineering of bone and cartilage: Inductive signals, stem cells, and biomimetic biomaterials. Tissue Eng. 2000; 6(4): 351-359.
Ripamonti U. Soluble osteogenic molecular signals and the induction of bone formation. Biomaterials. 2006 Feb;27(6):807-22. doi:10.1016/j.biomaterials.2005.09.021
Cook JD, Wolfe MW, Salkeld JL, Rueger DC. Effects of recombinant human osteogenic protein-1 on healing of segmental defects in non-human primates. J Bone Joint Surg. 1995;77A: 734-750.
Ripamonti U, van den Heever B, Sampath TK, Tucker MM, Rueger DC, Reddi AH. Complete regeneration of bone in the baboon by recombinant human osteogenic protein-1 (hOP-1, bone morphogenetic protein-7). Growth Factors. 1996;13(3-4). doi:10.3109/08977199609003228
Ripamonti U, van den Heever B, Crooks J, Tucker MM, Sampath TK, Rueger DC, Reddi AH. Long-term evaluation of bone formation by osteogenic protein-1 in the baboon and relative efficiency of bone-derived morphogenetic proteins delivered by irradiated xenogeneic collagenous matrices. J Bone Miner Res. 2000; 15(9):1798-09. doi: 10.1359/jbmr.2000.15.9.1798.
Ripamonti U. Bone induction by recombinant human osteogenic protein-1 (hOP-1, hBMP-7) in the primate Papio ursinus with expression of mRNA of gene products of the TGF-β superfamily. J Cell Mol Med. 2005;9:911-28.
Ripamonti U, Ramoshebi LN, Matsaba T, Tasker J, Crooks J, Teare J. Bone induction by BMPs/OPs and related family members. The critical role of deliverey systems. J Bone Joint Surg Am. 2001;83-A Suppl1 (Pt2):S116-27.PMID.
Ripamonti U, Duarte R, Ferretti C. Re-evaluating the induction of bone formation in primates. Biomaterials. 2014 Nov;35(35):9407-22. doi: 10.1016/j. biomaterials.2014.07.053. Epub 2014 Aug 23.
Urist MR. Bone: formation by autoinduction. Science. 1965;150(3698):893-899. doi:10.1126/science.150.3698.893
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.
Sampath TK, Raska KE, Doctor JS, Tucker RF, Hoffmann FM. Drosophila transforming growth factor beta superfamily proteins induce endochondral bone formation in mammals. Proc Natl Acad Sci USA, 1993; 90(13): 6004-08. https://doi: 10.1073/pnas.90.13.6004.
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. 2021; in press.
Ripamonti U. Recapitulating development: a template for periodontal tissue engineering. Tissue Eng. 2007 Jan;13(1):51-71. doi: 10.1089/ten.2006.0167. PMID: 17518581.
Ripamonti U. Biomimetism, biomimetic matrices 132 > RESEARCH www.sada.co.za / SADJ Vol. 77 No. 3and the induction of bone formation. J Cell Mol Med. 2009;13(9B):2953-2972. doi:10.1111/j.1582-4934.2008.00562.x
Ripamonti, U. Induction of Bone Formation in Primates. The Transforming Growth Factor beta 3, CRC Press, Taylor & Francis Group, Boca Raton, USA, 2016.
Ripamonti U, Ferretti C, Teare J, Blann L. Transforming growth factor-beta isoforms and the induction of bone formation: implications for reconstructive craniofacial surgery. J Craniofac Surg. 2009;20(5):1544-1555. doi:10.1097/SCS.0b013e3181b09ca6
Ripamonti U, Duneas N, van den Heever B, Bosch C, Crooks J. Recombinant transforming growth factorbeta1 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(10):1584-1595. doi:10.1359/jbmr.1997.12.10.1584
Ripamonti U, Crooks J, Matsaba T, Tasker J. Induction of endochondral bone formation by recombinant human transforming growth factor-β2 in the baboon (Papio ursinus). Growth Factors. 2000;17(4):269-285. doi:10.3109/08977190009028971
Ripamonti U, Ferretti C, Heliotis M. Soluble and insoluble signals and the induction of bone formation: molecular therapeutics recapitulating development. J Anat. 2006;209(4):447-68. doi: 10.1111/j.1469-7580.2006.00635.x.
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(4):575-vii. doi:10.1016/j.coms.2007.07.006
Ripamonti U, Teare J, Ferretti C. A Macroporous Bioreactor Super Activated by the Recombinant Human Transforming Growth Factor-β(3). Front Physiol. 2012;3:172. Published 2012 Jun 7. doi:10.3389/fphys.2012.00172
Seeherman HJ, Berasi SP, Brown CT, et al. A BMP/activin A chimera is superior to native BMPs and induces bone repair in nonhuman primates when delivered in a composite matrix. Sci Transl Med. 2019;11(489):eaar4953. doi:10.1126/scitranslmed.aar4953
Langer R, Vacanti JP. Tissue engineering. Science. 1993;260(5110):920-926. doi:10.1126/science.8493529
Williams D. F. Tissue engineering: the multidisciplinary epitome of hope and despair, in Studies in Multidisciplinarity eds Paton R., McNamara L. (Amsterdam: Elsevier BV; ) 2006, 483–524.
Martin I. Engineered tissues as customized organ germs. Tissue Eng Part A. 2014;20(7-8):1132-1133. doi:10.1089/ten.tea.2013.0772
Klar RM, Duarte R, Dix-Peek T, Ripamonti U. The induction of bone formation by the recombinant human transforming growth factor-β3. Biomaterials. 2014;35(9):2773-2788. doi:10.1016/j.biomaterials.2013.12.062
Ripamonti U, Dix-Peek T, Parak R, Milner B, Duarte . Profiling bone morphogenetic proteins and transforming growth factor-βs by hTGF-β3 pre-treated coral-derived macroporous bioreactors: the power of one. Biomaterials. 2015;49:90-102. doi:10.1016/j.
biomaterials.2015.01.058
37 Ripamonti U, Parak R, Klar RM, Dickens C, DixPeek T, Duarte R. The synergistic induction of bone formation by the osteogenic proteins of the TGF-βsupergene family. Biomaterials. 2016;104:279-296. doi:10.1016/j.biomaterials.2016.07.018
Ferretti C, Ripamonti U, Tsiridis E, Kerawala CJ, Mantalaris A, Heliotis M. Osteoinduction: translating preclinical promise into clinical reality. Br J Oral Maxillofac Surg. 2010;48(7):536-539. doi:10.1016/j.bjoms.2009.08.043.
Ferretti C, Teare J, Renton L, Ripamonti U. Mandibular reconstruction with TGF-ß superfamily proteins: Preclinical and clinical results. 7th International Conference on Bone Morphogenetic Proteins, Lake Tahoe, USA, July 2008.
Ripamonti U, Ferretti C. The induction of bone formation by bone morphogenetic proteins in non-human and human primates. 8th International Conference on Bone Morphogenetic Proteins, Leuven, Belgium, September 2010.
Ripamonti U. BMPs/TGF-β superfamily: Challenges for clinical translation. 9th International Conference on Bone Morphogenetic Proteins, Lake Tahoe, USA, June 19-23, 2012.
Ripamonti U, Klar RM, Renton LF, Ferretti C. Synergistic induction of bone formation by hOP-1, hTGF-beta3 and inhibition by zoledronate in macroporous coral-derived hydroxyapatites. Biomaterials. 2010;31(25):6400-6410. doi:10.1016/j.biomaterials.2010.04.037
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. SADJ. 2021; 76(6):331-356.
Ripamonti U, Ferretti C. Regeneration of Mandibular Defects in non-Human Primates by the Transforming Growth Factor-β3 and Translational Research in Clinical Contexts. In: Ripamonti U (ed.) CRC Press Taylor & Francis, Boca Raton USA, Induction of Bone Formation in Primates. The Transforming Growth Factor-beta3; 2016, Chapter 5, 105-121.
Ferretti C, Ripamonti U. Long Term Follow-Up of Pediatric Mandibular Reconstruction With Human Transforming Growth Factor-β3
. J Craniofac Surg. 2020;31(5):1424-1429. doi:10.1097/SCS.0000000000006568
Ripamonti U, Feretti C. Grand challenges for craniomandibulofacial reconstruction by human recombinant transforming growth factor-β3. In: Tuan RS, Guilak F, Atala A, editors, Keystone Symposia on regenerative tissue engineering, Breckenridge CO, USA;
http//:www.keystonesymposia.org.
Ripamonti U, Roden LC, Renton LF. Osteoinductive hydroxyapatite-coated titanium implants. Biomaterials. 2012;33(15):3813-3823. doi:10.1016/j.biomaterials.2012.01.050
Urist MR. The reality of a nebulous, enigmatic myth. Clin Orthop Rel Res. 1968; 59:3-6.
Urist MR, Silverman BF, Büring K, Dubuc FL, Rosenberg JM. The bone induction principle. Clin Orthop Relat Res.
;53:243-283.
Ripamonti U, Richter PW, Nilen RW, Renton L. The induction of bone formation by smart biphasic hydroxyapatite tricalcium phosphate biomimetic matrices in the non-human primate Papio ursinus. J Cell Mol Med. 2008;12(6B):2609-2621. doi:10.1111/j.1582-4934.2008.00312.x
Ripamonti U. Biomimetic functionalized surfaces and the Induction of bone formation. Tissue Eng Part A. 2017;23(21-
:1197-1209. doi:10.1089/ten.tea.2017.0321.RESEARCH < 133
Ripamonti U, Crooks J, Kirkbride AN. Sintered porous hydroxyapatites with intrinsic osteoinductive activity: geometric induction of bone formation. S Afr J Sci 1999;95:335-343.
Ripamonti U. Soluble, insoluble and geometric signals sculpt the architecture of mineralized tissues. J Cell Mol Med. 2004;8(2):169-180. doi:10.1111/j.1582-4934.2004.tb00272.x
Ripamonti U. The concavity: The “Shape of Life” and the control of bone differentiation. 2012 Feature Paper – Science in Africa, May 2012.
Ripamonti U. Functionalized surface geometries induce: "Bone: Formation by Autoinduction". Front Physiol. 2018;8:1084. Published 2018 Feb 6. doi:10.3389/fphys.2017.01084
Fujibayashi S, Neo M, Kim HM, Kokubo T, Nakamura T. Osteoinduction of porous bioactive titanium metal. Biomaterials. 2004;25(3):443-450. doi:10.1016/s0142-9612(03)00551-9
Fujibayashi S, Nakamura T, Nishiguchi S, Tamura J, Uchida M, Kim H-M, Kobuko T. Bioactive titanium prepared by alkali and heat treatment. J Biomed Mat Res. 2001; 56(4):562-570.
Kobuko T, Miyaji F, Kim H-M. Spontaneous formation of apatite layer on chemically treated titanium metals. J Am Ceram Soc. 1996; 79(4): 1127-1129.
Nishiguchi S, Kat H, Fujita H, Kim H-M, Miyaji F, Kobuko T, Nakamura T. Enhancement of bone-bonding strengths of titanium alloyimplants by alkali and heat treatments. J Biomed Mater Res (Appl Biomater), 1999;48(5):689-699.
Uchida M, Kim H-M, Kobuko T, Fujibayashi S, Nakamura T. Effect of water treatment on the apatite-forming activity of NaOH-treated titanium metal. J Biomed Mater Res (Appl Biomater), 2002;63(5):522-530.
Takemoto M, Fujibayashi S, Neo M, Suzuki J, Matsushita T, Kobuko T, Nakamura T. osteoinductive porous titanium implants: Effects of sodium removal by dilute HCl treatment. Biomaterials. 2006;27(13):2682-2691.
Kawai T, Takemoto M, Fujibayashi S, Akiyama H, Tanaka M, Yamaguchi S, Pattanayak DK, Doi K, Matsushita T, Nakamura T, Kobuko T, Matsuba. Osteoinduction on acid and heat treated porous Ti metal samples in canine muscle. PLos One. 2014; 10;9(2):e88366. Doi: 10.1371/journal.pne.0088366. eCollection 2014.PMID: 24520375.
Brubaker DK, Lauffenburger DA. Translating preclinical models to humans. Science. 2020;367(6479):742-743. doi:10.1126/science.aay8086
Roberts AB, Sporn MB, Assoian RK, Smith JM,Roche NS, Wakefield LM et al. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986;83(12):4167-4171. doi:10.1073/pnas.83.12.4167
Armstrong JPK, Keane TJ, Roques AC, Patrick PS, Mooney CM, Kuan W-L, Pisupati V, Oreffo ROC et al. Sci Transl Med 2020;12,eaaz2253.
Trueta J. The role of the vessels
Downloads
Published
Issue
Section
License
Copyright (c) 2022 Carlo Ferretti, Jakobus Hoffman, Ugo Ripamonti
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
.png){kind=spacer}