|Year : 2019 | Volume
| Issue : 1 | Page : 58-63
Bone morphogenetic proteins: Revivifying periodontium
Himani Sharma1, Anamika Sharma2
1 Department of Periodontology, School of Dental Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
2 Department of Dental Surgery, Lala Lajpat Rai Medical College and Hospital, Meerut, Uttar Pradesh, India
|Date of Web Publication||11-Oct-2019|
Dr. Himani Sharma
Department of Periodontology, School of Dental Sciences, Sharda University, Greater Noida - 201 306, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Bone morphogenetic proteins (BMPs), a family of signaling molecules, are considered to be a central factor present in the bone matrix. Originally discovered by Urist, they have been shown to affect a wide variety of cell types and processes beyond bone and osteogenesis. They are important morphogens in embryogenesis and development and also regulate the maintenance of adult tissue homeostasis. The loss of alveolar bone is a common consequence of periodontal disease. The regeneration of periodontal structures requires an environment consisting of cells, scaffold, and signaling molecules. The emergence of tissue engineering has enabled the mass production of BMPs, to be utilized refining the biomimetic scaffolds, thus facilitating an alternative to treatment approach in bone regeneration lost due to the disease process. This review discusses the critical data on the discovery of BMPs, its structure, mechanisms of action, and potential therapeutic application in periodontal regeneration.
Keywords: Bone; bone morphogenetic proteins; periodontal regeneration; periodontitis
|How to cite this article:|
Sharma H, Sharma A. Bone morphogenetic proteins: Revivifying periodontium. Indian J Multidiscip Dent 2019;9:58-63
| Introduction|| |
Regeneration of the lost periodontal structures constitutes a complex process. It is regulated by the interaction between cells, hormones, growth factors, and extracellular matrices. Periodontitis is an chronic inflammatory disease, caused by a group of specific microorganisms, resulting in progressive destruction of the periodontium, including periodontal ligament and alveolar bone, and ultimately, leading to tooth mobility and tooth loss.
Earlier introduced nonsurgical techniques were able to halt the disease progression; however; they were not able to regenerate the lost tissue completely. Therefore, it became necessary to establish a new treatment along with the conventional nonsurgical modality for suppressing the further progression of periodontitis and helping in regeneration and repair of the lost periodontal tissue. This leads the researchers to develop various techniques utilizing autogenous bone grafts, allografts, xenografts, and various alloplasts. However, these techniques also revealed limited success in periodontal regeneration. Therefore, various procedures were developed utilizing biological mediators and tissue engineering techniques. These techniques helped to isolate various growth factors including bone morphogenetic proteins (BMPs).
BMPs are a group of multifunctional growth factors, belonging to transforming growth factor-beta (TGF-β) superfamily. Dr. Marshall Urist first reported the activity of BMPs in the 1960s and considered them to be a central factor present in the bone matrix, responsible for de novo bone formation that could only be utilized after the 1980s when the purification and cloning techniques of human BMPs came into existence. BMPs have shown to play an important role in regulating the growth, differentiation, and apoptosis of various cell types, including osteoblasts, chondroblasts, neural cells, and epithelial cells, depending on the cellular microenvironment and the interaction with other regulatory factors. Hence, this review is an attempt to summarize the characteristics and various applications of BMPs in periodontoloy.
History and development of bone morphogenetic proteins
The idea of isolation of morphogens from adult bones is based on the finding of Hippocrates (460BC–370BC). Later in 1938, Levander demonstrated that the mesenchymal tissue surrounding the graft is responsible for the regeneration of bone. Lacroix in 1945 named this substance as osteogenin. Urist et al. in 1965, in the series of experiments, reported the formation of new bone and cartilage by autoinduction, into the ectopic sites, when the control samples of untreated decalcified bone were implanted, into the muscle pouches of rabbits and rats. This gave rise to a new hypothesis of bone formation by autoinduction, in which an inducing substance from within the inducer cell acts on an induced cell causing it to differentiate into either an osteoprogenitor cell or a chondroprogenitor cell. Urist named this bone inducing substance as, “BMP.”
Purification and isolation of bone morphogenetic proteins
The perplexity in the purification of BMPs was the insolubility of demineralized bone matrix. Sampath and Reddi overcame this impediment and invented a crude but successful, highly reproducible assay for the ectopic bone formation. Wang et al., in 1988, identified a group of proteins from bovine bone of 30 kD through sodium dodecyl sulfate-polyacrylamide gel electrophoresis, after which recombinant clones for each were isolated, and thus, recombinant human (rh) proteins BMP-1, BMP-2, BMP-2B (now called BMP-4), and BMP-3 (osteogenin) were obtained. This process also revealed the amino acid sequences along with the biological and biochemical characteristics of BMPs. Afterward, the isolation and characterization of other BMPs were carried out.
The DNA probes were used to obtain human complimentary DNA sequence which is then cloned and spliced into a viral expression vector to produce BMPs in large quantities. Thus, rhBMP (rh) came into existence. In 2001 and 2002, the Food and Drug Administration approved the use of rhBMP-2 and rhBMP-7. Hence, today, the human BMP is now produced using recombinant techniques, and the available protein is free from the risk of infection or allergic reaction.
Classification of bone morphogenetic proteins
Reddi stated that the amino acid sequences of these tryptic peptides revealed a homology to TGF-β1. Thus, BMPs and osteogenin were categorized as the members of TGF-β superfamily. Till date, only 20 different human BMPs have been discovered and classified into subfamilies, but including activin, inhibin, and growth differentiating factors (GDFs) there are nearly 30 members in BMP family.
BMPs are classified on the basis of their sequence similarities and functions into four subfamilies:
- Ist group – BMP-2 and BMP-4 – 80% homology – highly related molecules, differs mainly in amino-terminal region, where BMP-2 contains a heparin-binding domain
- IInd group – BMP-3 and BMP-3B (GDF10) – also called as osteogenin
- IIIrd group – BMP-5, BMP-6, BMP-7, BMP-8a, and BMP-8b – 78% homology
- IVth group – GDF5, GDF6, and GDF7 – cartilage-derived morphogenetic protein 1, 2, and 3.
BMP-1 however is not considered as a member of TGF-β superfamily, as it lacks the structure conserved in the TGF-β superfamily. In some studies, it has been reported as a procollagen C-proteinase, processing procollagen to collagen.
Structure of bone morphogenetic proteins
BMPs are dimeric molecules, constituting about 120 amino acids, and comprising seven conserved cysteine residues except BMP-8, which has eight cysteine residues. Of these six forms, a cystine-knot motif linked with three intramolecular disulfide bonds forming a critical core of the BMP monomer. This cysteine knot functions to define the trifold topology of monomer, allowing the structural variation to occur in the external loops, whereas the seventh one stabilizes the dimer by covalent disulfide bonds, forming an intermolecular cysteine bridge.,
BMPs are synthesized as precursor proteins having polypeptide chains ranging in size from 369 to 513 amino acids. Precursors are formed in the cytoplasm as dimeric pro-protein complexes, which are cleaved by pro-protein convertases and serine endoproteases to generate mature and active homodimers and heterodimers with N- and C-terminal fragments, during the process of dimerization, from the prodomain at Arg-X-X-Arg sequence [Figure 1].,
Receptors of bone morphogenetic proteins
BMP molecules exhibit their activity by binding to the specific cell surface receptors. There are two different types of serine-threonine kinase BMP receptors (BMPR) in humans:
- BMPR, Type 1
- BMPR, Type 2.
Both the serine/threonine kinase receptors are required for signal transduction.
Type II BMPR, Type II activin receptor (ActR-2A), and Type 2b ActRs are known as “dual-specificity kinases” because their cytoplasmic kinase domain has weak tyrosine kinase activity, but it binds strongly to serine/threonine kinase.
Both the BMPRs are composed of three parts [Figure 2]:
- A short extracellular domain with some conserved cysteine residues
- A single membrane-spanning domain
- An intracellular domain with active serine/threonine region.
Members of BMP family show different affinities to different combinations of Type I and Type II receptors. The 75 kDa Type II receptor acts as the primary binding site for BMP ligand. When a TGF-β superfamily ligand binds to the Type II receptor, it forms a heterotetrameric complex and activates Type I receptor (50–55 kDa) by phosphorylating at a glycine-serine-rich motif known as GS domain which is present at N-terminal to the serine-threonine kinase region. This results in the activation of the BMPR1 kinase and transduction of signals from BMPR1 serine-threonine kinase.
Signaling mechanism of bone morphogenetic proteins
The BMP signaling cascade is a complex process. They initiate the signal transduction cascade by binding to the cell surface receptors [Figure 3]. BMP can signal through both:
- Canonical pathways
- Noncanonical pathways.
In the canonical pathway, after the phosphorylation of the Type I receptor, the receptor signals are propagated to downstream substrates proteins known as the receptor-regulated Smads (R-Smads). Following phosphorylation, R-Smads 1, 5, and 8 translocate into the cell nucleus by binding to co-mediator Smad 4 (co-Smad). In the nucleus, they interact with the DNA-binding proteins, resulting in the activation of transcriptional factors for the early BMP response genes.
|Figure 3: Mechanism of activation of bone morphogenetic proteins (R-Smad – Receptor-regulated Smad, Co-Smad – Co-mediater Smad, BMRP – Bone morphogenetic protein receptor)|
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Various noncanonical pathways bringing out the BMP signaling have also been identified, such as mitogen-activated protein kinase (MAPK) pathway through which BMP-4 activates TAK-1 (a serine-threonine kinase of MAPK family). The specific pathway likely to be activated depends on the extracellular environment, other cellular activities, and crosstalk with other pathways.
Dosage of bone morphogenetic protein
According to Nelsen and Christian, the estimated amount of BMP per kilogram pulverized bone is 0.002 mg. However, at the site of bone fracture, more amount of BMP is seen because of increased secretion by osteoprogenitor cells and upregulation of BMP by the released cytokines. The amount of BMP required to induce bone bridging in osseous defects depends on:
- The state of organism in the evolutionary scale – Lower strata require less amount, for example, physiological dosage ranges from 0.01 mg/ml in small animal models, whereas higher evolved animals require more amount of BMP for the fusion of induced osseous defects, for example, dosage range is from 1.5 mg/ml in nonhuman primates
- Anatomic location of the site of application, depending on the degree of vascularization, defect size, and the number of resident responding cells
- Intrabony fusion due to sufficient vascularity, exposure, and supply of the bone marrow cells from the adjacent opposing osseous surface and <13 mm of bridging gap has a higher potential for fusion in comparison to intratransverse fusion and requires a smaller dosage of BMPs
- The type of defect – simple closed fractures splinted or internally stabilized do not require the introduction of BMP at the fracture site, while fractures with segmental defects in long bones require adjuvant autograft or BMP for adequate healing.
For the effectiveness of BMPs, a critical threshold concentration of rhBMP has to be maintained at the defect site for the necessary period of time. Haidar et al. reported that the recommended dose of rhBMP-7 implanted at the nonunion site is 7 mg; however, new delivery systems with optimized and controlled release profiles may alter concentrations of BMPs needed to a dose as low as 100 ng/ml. On the contrary, Setti reported that the super physiological dose approaching 3–3.5 mg of BMP is sufficient to induce bone formation and bridging the osseous defect in almost all cases, and additional doses of BMP do not provide any additional benefit in terms of rate of fusion and time taken for bone healing.
Carriers for bone morphogenetic protein
BMP is a water soluble relatively low-molecular weight protein that diffuses very easily in body fluids; thus, BMPs require a competent carrier to be contained and effective. The carrier provides an advantage by immobilizing the protein in the specific area along with the reduction in the amount of BMP required for being effective and controlling the rate of release of BMPs. However, it does not define the shape of the resulting bone. The ideal BMP carrier should be absorbed concurrent to bone healing, leaving no residue. It should be porous, with porosity equivalent to cancellous bone, noncollagenous, immunoginically inert, osteoconductive, and bioresorbable. The degradation of the carrier should not result in toxic residues. It should be able to support angiogenesis and subsequent vascularization.,
It has been reported that without a carrier <5% of the BMP dose remains at the application site, whereas about 15%–55% of retention was seen when BMPs were combined with gelatin foam or collagen. With the availability of recombinant BMPs, the significance of finding an ideal carrier becomes more important as they show the lack of heparin-binding domain, thus reducing their biological activity. These carriers can be broadly classified into inorganic salts, naturally occurring polymeric substances, synthetic polymers, and composites of synthetic and naturally occurring polymers and titanium.
Collagen, especially Type I collagen obtained from bovine bone, tendons, and ligaments, is the most commonly used carrier. Collagenous matrix used as a delivery measure because of its physiochemical properties together with the microenvironment they create plays an important role in the inductive outcome. However, collagen matrix is the natural carrier of BMPs, but potential problems associated with it like transmission of viral antigens, etc., makes it a bad choice for carrying BMPs. Calcium phosphate and calcium sulfate are the most commonly used inorganic salts.
Potential role of bone morphogenetic proteins in periodontal regeneration
Tissue engineering holds a great promise for revolutionizing many dental procedures. The discovery of BMPs has offered an alternative to treatment options in periodontal regeneration, bone healing, acceleration osseointegration, oral and maxillofacial reconstruction, bone pathology sequel repair, distraction osteogenesis as well as in endodontic procedures. The regeneration of periodontium requires the formation of new cementum on the denuded root surface, deposition of bone, insertion of functionally oriented new connective tissue fibers into new bone and cementum, and organization of a competent gingival unit. It also requires a functional reunion between connective and epithelial tissues with completely avascular and almost impermeable root surface. The research into the molecular initiators of bone differentiation has led to the identification of BMPs that are capable of regulating the bone and cartilage development thus can be helpful in the regeneration of periodontium.
BMPs have been implicated in the regulation of a variety of biological functions at a transcriptional level or higher by increasing the rate of transcription and/or stabilizing them RNA. A large number of BMPRs, which are about 2500/cell, and their variability allow the formation of heteromeric complexes with different signaling proteins, capable of inducing various responsive cascades when binding to the same ligand.
BMP-1, functions in collagen maturation as a procollagen C-proteinase, is reported to be able to induce bone and cartilage development. BMP-2 upregulates the inhibitor of differentiation gene expression and promotes specific phenotypic expression in the osteoblastic cells. Together with BMP-4, BMP-6, BMP-7, and BMP-9, BMP-2 demonstrates a potent bone-inducing activity and is referred to as the osteogenic BMPs. However, on the contrary, Bahamonde and Lyons demonstrated the inhibitory effect of BMP-3 on osteogenesis. BMP-3 is a negative regulator of bone density, and BMP-13 is a strong inhibitor of bone formation. A wide spectrum of cells are sensitive to BMPs including fibroblasts, mesenchymal connective tissue cells, muscle-derived connective tissue cells, osteoblast, chondroblasts, and many more. Thus, BMPs may be able to affect both the endochondral bone formation and intramembranous bone formation by affecting the proliferation of osteogenic and chondrogenic cells. It can also induce the differentiation of mesenchymal progenitor cells into osteoblasts and chondroblasts.
BMP-2 is considered to be the most important positive regulator of chondrocyte proliferation and differentiation during endochondral bone formation, whereas BMP-12 acts as a negative regulator of chondrogenesis. BMPs also play a part in the process of modeling and remodeling of the bone. BMPs along with other growth factors are produced in the forming bone matrix and get incorporated into the bone matrix, serving as a reservoir. During remodeling of the bone, the BMPs incorporated in bone matrix get liberated by the acidic environment created by the osteoclasts and affect the resorption of existing bone and deposition of new bone. Where certain BMPs such as BMP-7 play a superfluous role, other BMPs such as BMP-11, BMP-2, and BMP-3 play an important role in the regulation of bone remodeling.
Bowers et al. described the first successful use of BMP for periodontal regeneration. They reported about a bone-inductive protein, osteogenin, isolated from long bones of humans and suggested that osteogenin combined with a bone-derived matrix offers promise as a grafting material. Amelogenin-like factors and growth factors and BMPs demonstrate pleotrophic effects on the stimulation of several key events required for tissue regeneration, including DNA synthesis, chemotaxis, differentiation, and matrix synthesis. Several tests have been conducted, indicating the effectiveness of BMP-2 for correcting intra-bone, supra-alveolar, furcation, and fenestration defects.,, In these studies, increased height of alveolar bone regeneration amounted, corresponding values for bone area, and cementum regeneration in bone defects were observed. However, small amounts of root resorption and ankylosis of roots were also seen in some rhBMP-2-treated defects.
Apart from BMP-2, the inductive and stimulatory osteogenic capacity of BMP-3, BMP-4, BMP-5, and BMP-7 has also been reported., Although these analogs of BMPs show bone formation, the course of bone formation is significantly delayed, and also the amount required is approximately double of BMP-3, BMP-4, and BMP-5 in comparison to BMP-2. Rehabilitation therapy with BMPs produced by genetic engineering has also provided promising results around dental implants by inducing the bone formation at compromised sites which is reported in various in vivo and in vitro studies, thus promoting their osseointegration.,
Cochran et al., in their two different studies revealed that rhBMP 2 is well tolerated by patients and a significantly greater amount of bone deposition and bone-to-implant contact when implants are treated with rh-BMP-2 and bovine BMP, which was more significant after 4 and 12 weeks of healing. These results demonstrate that rhBMP-2 can be used to stimulate bone growth both around and onto the surface of endosseous dental implants. However, rehabilitation therapy of implants using BMPs also depends on chemical treatment of implant surface, material of implant, porosity of the implant surface, and proper oxygenation of BMP-producing cells.
| Conclusion|| |
Periodontal tissue engineering foremost entails the regeneration of alveolar bone, cementogenesis, and the genesis of Sharpey's fibers inserting into newly formed cementum. Several studies have highlighted that various morphogenetic factors including BMPs provide a framework for the regeneration of the various tissue components of the periodontium and in addition may play important physiological roles in repair, regeneration, and remodeling. However, despite a great deal of research effort, the ideal treatment modality using BMPs has yet to be established, and further basic research is required to elucidate the detailed mechanism of BMPR activation and signal transduction to the cell nucleus and the biological role of different BMPs and their clinical applications.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]