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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 6  |  Issue : 2  |  Page : 74-77

Bone morphogenetic proteins in periodontal tissue regeneration


1 Department of Periodontology, Kamineni Institute of Dental Sciences, Nalgonda, Telangana, India
2 Department of Periodontology, MNR Dental College, Sangareddy, Telangana, India

Date of Web Publication6-Dec-2017

Correspondence Address:
Dr. Suryakanth Malgikar
Department of Periodontology, Kamineni Institute of Dental Sciences, Narketpally, Nalgonda - 508 254, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jdas.jdas_50_16

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  Abstract 


Progress in understanding the role of bone morphogenetic proteins (BMPs) in craniofacial and tooth development, the demonstration of stem cells in dental pulp, and accumulating knowledge on biomaterial scaffolds have set the stage for tissue engineering and regenerative therapy of the craniofacial complex. Furthermore, the recent approval by the US Food and Drug Administration (FDA; Rockville, MD, USA) of recombinant human BMPs for accelerating bone fusion in slow-healing fractures indicates that this protein family may prove useful in designing regenerative treatments in dental applications. In the near term, these advances are likely to be applied to endodontics and periodontal surgery; ultimately, they may facilitate approaches to regenerating whole teeth for use in tooth replacement. Early on, scientists focused on creating a suitable environment that favored the innate potential for regeneration. However, complex clinical protocols and extended treatments, in addition to inconsistent results, often brought treatment protocols out of favor. Predictable outcomes and minimally invasive protocols have become fundamental to clinicians and patients. Thus, novel regenerative concepts with improved or superior outcomes, predictability, and minimally invasive protocols are being developed and considered.

Keywords: Bone morphogenetic proteins, bone regeneration, growth factors


How to cite this article:
Malgikar S, Akula U. Bone morphogenetic proteins in periodontal tissue regeneration. J Dent Allied Sci 2017;6:74-7

How to cite this URL:
Malgikar S, Akula U. Bone morphogenetic proteins in periodontal tissue regeneration. J Dent Allied Sci [serial online] 2017 [cited 2022 May 21];6:74-7. Available from: https://www.jdas.in/text.asp?2017/6/2/74/219981




  Introduction Top


The regeneration of the tooth-supporting structures which have been lost as a consequence of periodontal disease progression has been an elusive goal in the field of periodontics. Although bone has been known to have a remarkable potential for repair and regeneration, the periodontal regeneration is recognized as a possible objective for several periodontal therapeutic modalities. Outcomes of such modalities are not always predictable, despite conclusive evidence that some regeneration may occur following regenerative procedures.[1] Tissue engineering, defined as the science of fabrication of new tissues for replacement and the regeneration of lost or destroyed tissues, has learned and is still learning, the secrets of its principles from bone repair and regeneration, and it is likely that more secrets still remain to be learned from the principles of bone tissue engineering.[2] The complex tissue morphologies of the periodontal tissues are a superb example of design architecture and engineering. The supportive alveolar bone consists of cortical or compact bone and cancellous or trabecular bone. The periodontal ligament system, epitomized by inserting Sharpey's fibers into the cementum, provides a gomphosis that uniquely articulates the tooth to the alveolar bone and permits mechanical function and adaptation to changing mechanical environments and signals additionally modulated by the avascular mineralized root cementum.[3],[4]

Events and processes required for periodontal regeneration:

  1. Regeneration depends on availability of appropriate cell types and signals that activate the cells
  2. Wrong cell types may have to be excluded
  3. Local environment plays a major role in the recruitment of the right cells and preventing the wrong cells. Local environment includes cementum matrix and cementodentinal junction
  4. Substances in the local environment affect cell migration, adhesion, proliferation, and differentiation
  5. The effect may be cell specific and/or nonspecific.


Successful tissue engineering requires an interplay among three components, the implanted and cultured cells that will create the new tissue, biomaterial to act as a scaffold or matrix to hold the cells, and biological signaling molecules that instruct the cells to form the desired tissue type.


  Bone Morphogenetic Proteins Top


Several decades ago, Dr. Marshal Urist, an orthopedic surgeon, discovered a group of proteins sequestered in bone and aptly named them bone morphogenetic proteins (BMPs).[5],[6] He observed that bone matrix preparations contained BMPs that induced cartilage, bone, and marrow formation when implanted intramuscularly in rodent models. Following purification and subsequent molecular cloning, the responsible proteins were identified.[7] Most BMPs comprise three portions: signal peptide, propeptide, and mature region. The propeptide and mature region contains seven conserved cysteine residues characteristic of the transforming growth factor-β (TGF-β) superfamily.

BMPs belong to a group of proteins called TGF-β gene superfamily that share common structural features. Currently, there are 43 members of this gene family. BMPs are synthesized as large precursors consisting of a prodomain and carboxy-terminal region of 100–125 amino acids. Most of the BMPs as well as TGF-β share a conserved pattern of seven cysteine residues in the mature domain. Each mature active BMP consists of dimers whose chains are connected by disulfide bonds, and the dimerization is a prerequisite for bone induction. BMPs are active both as homodimers (two identical chains) and heterodimers (two different chains) molecules.[8]

The BMP family can be divided into four distinct subfamilies:[9]

  1. BMP-2 and BMP-4
  2. BMP-3 and BMP-3B, the latter also known as growth/differentiation factor 10 (GDF10)
  3. BMPs 5, 6, 7, and 8
  4. GDFs 5, 6, and 7, also known as cartilage-derived morphogenetic proteins 1, 2, and 3.


BMP-1 is not a member of the BMP family but rather is a procollagen C-proteinase involved in the proteolytic processing of soluble procollagen, leading to the self-assembly of insoluble collagen fibers in the extracellular matrix.

Bone morphogenetic protein carriers[10]

As BMP is soluble in extracellular solution, it must have a carrier, without which it is phagocytized within 10 days. One of the major obstacles to the clinical use of BMPs is the challenge to define the optimal delivery system. Although a matrix carrier is not essential to promote bone formation, there are a number of advantages to an appropriate carrier including localization and retention of BMP to the site, providing a 3D extracellular matrix scaffold for mesenchymal cell infiltration, a shape that may help and define the resulting new bone, and providing a substrate for cell growth and differentiation. The carrier material can be in the form of blocks, granules, paste, and solution or as self-setting cement.

Classification of carriers[10]

Most cell-seeding scaffolds are fabricated from two classes of biomaterials, derived from either synthetic or natural products. In addition, they may be constructed from either resorbable or nonresorbable materials. Examples of cell delivery devices and scaffolds in periodontics are:

  • Nonresorbable: Expanded polytetrafluoroethylene, ceramic, and titanium mesh
  • Resorbable: Alpha-hydroxy acids, polyglycolic acid, polylactic acid, copolymers of poly (lactic, glycolic acid), amino acid-based polymers, collagen-like proteins, and elastin-like proteins
  • Natural products: Collagen, hyaluronan, chitosan, gelatin, fibrin, and alginate
  • Synthetic hydrogels: Polyethylene glycol, polyethylene oxide, matrix extracts, and Matrigel.


The regenerative potential of GDFs is dependent on a carrier material that serves as a delivery system and as a scaffold for cellular ingrowth. The ideal carrier, which should be able to provide space for bone regeneration, allow cell ingrowth, and provide controlled release of bioactive molecules, has not yet been discovered. Research should address the questions regarding the clinically effective doses required, the properties of an ideal carrier material, and the optimal release kinetics for the clinical applications of growth factors.

Production of recombinant human bone morphogenetic protein-2[11]

Recombinant proteins are produced from one of several cellular expression systems of bacteria, insect cells, or mammalian cells. Recombinant human (rhBMP-2) is produced using a mammalian cell expression system. To produce an rhBMP-2 expressing cell line, the BMP-2 coding sequence or c-c DNA is linked to a strong promoter and a selectable marker. This construct is transfected into the host cell, and the cells that contain the coding sequence are chosen using the selectable marker. A series of cell lines are created and one is chosen that expresses high levels of protein. The cell line goes through a series of validation steps, including a check of the fidelity of the BMP-2 coding sequence. For pharmaceutical production of recombinant proteins, the rhBMP-2 cell line is expanded and frozen in multiple aliquots so that the identical starting cells can be used for decades to come. Medium is harvested, the cells are removed by filtration, and rhBMP-2 is purified from the medium by a series of column chromatography steps to >98% purity. Final liquid rhBMP-2 is sterilized by ultrafiltration before placement in vials. A third method of obtaining bone GDFs entails gene therapy and direct delivery of a genetic growth factor to the site of interest to encode for certain desired factors.

Gene therapy as a method of growth factor delivery

Gene therapy involves the transfer of genetic information to cells. When a gene is properly transferred to a target cell, the cell synthesizes the protein encoded by the gene. Therefore, with gene therapy, the genetic message is delivered to a particular cell, which then synthesizes the protein. In general, the duration of protein synthesis after gene therapy depends on the techniques used to deliver the gene to the cell. Several gene therapy options are currently under investigation.

Delivery methods such as electroporation or sonoporation have been used to transfer the Gdf11 gene (which encodes BMP-11) to amputated dental pulp, stimulating the formation of reparative dentin. In a recent paper,[12] syngeneic dermal fibroblasts were transduced ex vivo with adenoviruses encoding BMP 7, subsequently seeded onto gelatin carriers and then transplanted into rats with large mandibular alveolar bone defects. The lesions treated with BMP 7 demonstrated rapid chrondrogenesis, with subsequent osteogenesis, cementogenesis, and predictable bridging of the periodontal bone defects.

A recent systematic review assessed the preclinical and human studies regarding the clinical, histological, and radiographic outcome of the use of growth factors for localized alveolar ridge augmentation. Different levels and quantity of evidence were available for the growth factors evaluated, revealing that BMP-2, BMP-7, GDF-5, platelet-derived growth factor, and parathyroid hormone may stimulate local bone augmentation to various degrees. It was therefore concluded that clinical data support the use of BMP-2 in the promotion of bone healing for socket preservation, sinus floor elevation, and horizontal ridge augmentation.[13]

Bone morphogenetic protein in periodontal regeneration

Effective and safe therapies for periodontal regeneration require preclinical evaluation to estimate their biologic potential, efficacy, and safety before clinical application and introduction. For these purposes, researchers developed and characterized critical-size supra-alveolar periodontal defect model[11],[14] and supra-alveolar peri-implant defect model; these models are considered as litmus test for candidate therapies for periodontal regeneration and later for alveolar reconstruction and dental implant osseointegration before clinical application [Figure 1].
Figure 1: Endochondral bone formation after implanting bone morphogenetic and osteogenic proteins

Click here to view


Since BMPs can now be isolated and purified using recombinant technology (rhBMP-2), it has been extensively studied in a variety of clinical models for the regeneration of periodontium. Animal studies show that a single dose of rhBMP-2 increases the rate of normal intramembranous bone formation and enhanced cementum formation during periodontal wound healing. However, the optimal effects of BMPs are modulated by a range of factors that need careful evaluation in clinical studies; these factors include BMP dose, influence of root conditioning, and occlusal load release characteristics of the carrier as well as suitability of the model. To evaluate the efficacy of BMPs, each of these factors may affect the rate of BMP-induced osteogenesis and cementogenesis and subsequent periodontal ligament formation.[15]


  Conclusion Top


Several preclinical studies have shown that rhBMP-2 induces normal physiological bone in clinically relevant defects in the craniofacial skeleton. Recombinant protein morphogens recently approved by the FDA, such as BMP-2 and BMP-7, could be applied in dentistry to facilitate the repair of craniofacial structures. Further, studies are needed for the development of carrier materials that have mechanical properties and surgical practicality appropriate for controlled release of BMPs.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
American academy of Periodontology. Position paper. Periodontal Regeneration. J Periodontol 2005;76:1601-22.  Back to cited text no. 1
    
2.
Reddi AH. Morphogenesis and tissue engineering of bone and cartilage: Inductive signals, stem cells, and biomimetic biomaterials. Tissue Eng 2000;6:351-9.  Back to cited text no. 2
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3.
Bartold PM, McCulloch CA, Narayanan AS, Pitaru S. Tissue engineering: A new paradigm for periodontal regeneration based on molecular and cell biology. Periodontol 2000 2000;24:253-69.  Back to cited text no. 3
    
4.
Ripamonti U, Reddi AH. Periodontal regeneration: Potential role of bone morphogenetic proteins. J Periodontal Res 1994;29:225-35.  Back to cited text no. 4
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5.
Urist MR. Bone: Formation by auto induction. Science 1965;150:893-9.  Back to cited text no. 5
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Urist MR, Strates BS. Bone morphogenetic protein. J Dent Res 1971;50:1392-406.  Back to cited text no. 6
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7.
Sampath TK, Maliakal JC, Hauschka PV, Jones WK, Sasak H, Tucker RF, et al. Recombinant human osteogenic protein-1 (hOP-1) induces new bone formation in vivo with a specific activity comparable with natural bovine osteogenic protein and stimulates osteoblast proliferation and differentiation in vitro. J Biol Chem 1992;267:20352-62.  Back to cited text no. 7
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8.
Granjeiro JM, Oliveira RC, Valenzuela JC, Sogayar MC, Taga R. Bone morphogenetic proteins: From structure to clinical use. Braz J Med Biol Res 2005;38:1463-73.  Back to cited text no. 8
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Nakashima M, Reddi AH. The application of bone morphogenetic proteins to dental tissue engineering. Nat Biotechnol 2003;21:1025-32.  Back to cited text no. 9
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Bartold PM, Xiao Y, Lyngstaadas SP, Paine ML, Snead ML. Principles and applications of cell delivery systems for periodontal regeneration. Periodontol 2000 2006;41:123-35.  Back to cited text no. 10
    
11.
Lynch SE, Genco RJ, Marx RE. Tissue Engineering, Applications in Maxillofacial Surgery and Periodontics. Chicago: Quintessence Books; 1996. p. 25-75.  Back to cited text no. 11
    
12.
Jin QM, Anusaksathien O, Webb SA, Rutherford RB, Giannobile WV. Gene therapy of bone morphogenetic protein for periodontal tissue engineering. J Periodontol 2003;74:202-13.  Back to cited text no. 12
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13.
Jung RE, Thoma DS, Hammerle CH. Assessment of the potential of growth factors for localized alveolar ridge augmentation: A systematic review. J Clin Periodontol 2008;35:255-81.  Back to cited text no. 13
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14.
Wikesjo UM, Susin C, Qahash M, Polimeni G, Leknes KN, Shanaman RH, et al. The critical-size supraalveolar peri-implant defect model: Characteristics and use. J Clin Periodontol 2006;33:846-54.  Back to cited text no. 14
    
15.
King GN, Cochran DL. Factors that modulate the effects of bone morphogenetic protein-induced periodontal regeneration: A critical review. J Periodontol 2002;73:925-36.  Back to cited text no. 15
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    Figures

  [Figure 1]


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