Bone Morphogenetic Proteins (BMPs) in Periodontics

1. Introduction and Definition

• BMPs are a group of regulatory glycoproteins that are members of the transforming growth factor-beta (TGF-β) superfamily.
• They function primarily as differentiation factors, inducing mesenchymal stem cells to differentiate into chondroblasts and osteoblasts.
• The human genome encodes at least 20 BMPs (Reddi 1998).
• BMPs are multifunctional polypeptides with potent bone regenerative capacity. (Newman & Carranza 14th ed.; Lindhe 6th ed.; Periodontics Medicine Surgery Implants)

2. Historical Background / Discovery

• The osteoinductive potential of bone was first discovered by Marshall Urist (1965), who demonstrated the ability of BMPs to induce ectopic bone formation in muscle pouches.
• Using crude protein preparations derived from decalcified bone placed in muscle or subdermal pouches:
  • Cartilage formed after 12 days
  • Bone formed after 28 days
• This discovery of endochondral bone induction stimulated clinical interest in bone preparations as graft materials. (Periodontics Medicine Surgery Implants; Lindhe 6th ed.)
• Demineralization of bone in cold, diluted hydrochloric acid exposes components of the bone matrix closely associated with collagen fibrils - these were termed BMPs.
• BMP-3 (osteogenin) was identified as the key bone-inductive protein isolated from the extracellular matrix of human bone. (Carranza 10th ed.; Newman & Carranza 14th ed.)

3. Classification / Types Relevant to Periodontics

• Additionally, BMP-2, BMP-4, and BMP-6 promote differentiation of pre-osteoblasts and precursors of cementoblasts.
• BMP-3 is found selectively in root-lining cells and plays a role in cementoblast pathway differentiation. (Newman & Carranza 14th ed.; Orban's Oral Histology & Embryology)

4. Mechanism of Action / Signal Transduction Pathway

• BMPs bind to Type I and Type II receptors that function as serine-threonine kinases.
• The Type I receptor protein kinase phosphorylates intracellular signaling substrates called Smads (named from Sma gene in C. elegans and Mad gene in Drosophila).
• Phosphorylated BMP-signaling Smads enter the nucleus and initiate production of bone-related matrix proteins, leading to bone morphogenesis. (Lindhe 6th ed.)
• BMP-2 specific pathway:
  • Target genes include a wide cohort of transcription factors in the cell nucleus.
  • The osteogenic effects of BMP-2 are mediated by formation of Runx2-Smad complexes.
  • BMP-2 promotes osteoblast maturation by increasing expression of RUNX2, OSX, and DLX5 transcription factors.
  • These lead to expression of OSE2, the osteoblast marker gene responsible for osteoblast differentiation. (Newman & Carranza 14th ed.)
• Multiple signaling pathways involved in osteoblastogenesis via BMPs:
  • Smad pathway
  • Hedgehog pathway
  • TGF-β pathway
  • Cytokine-cytokine receptor interaction (Newman & Carranza 14th ed.)

5. Role in Periodontal Tissues (Histology/Embryology Perspective)

• Cementogenesis: BMPs 2, 4, and 7 promote differentiation of pre-osteoblasts and precursors of cementoblasts. BMP-3 plays a role in cementum formation, found selectively in root lining cells and directing follicle cells along the cementoblast pathway. (Orban's Oral Histology & Embryology)
• Alveolar bone formation: BMP-2, BMP-4, and BMP-6 direct pluripotent cells to commit to an osteoblastic pathway; BMPs can also upregulate cbfa1/RUNX2 under certain conditions; IGF-1 along with BMP-2 acts synergistically on osterix expression. (Orban's Oral Histology & Embryology)
• BMPs during tooth development and periodontal repair including alveolar bone have been demonstrated in multiple studies. (Lindhe 6th ed.)
• Intramembranous ossification involves BMPs and activation of transcription factor cbfa1. (Orban's Oral Histology & Embryology)

6. BMPs in Bone Graft Materials (FDBA and DFDBA)

• BMPs are present in both FDBA and DFDBA, but in very low concentrations.
• Approximately 10 kg of bovine bone yields only 2 μg of BMP - making natural extraction clinically impractical. (Newman & Carranza 14th ed.; Periodontics Medicine Surgery Implants)
• DFDBA is considered osteoinductive because demineralization exposes BMPs within the donor matrix.
• However, controversy exists: some studies suggest DFDBA may not contain sufficient BMPs to induce bone formation - variations depend on:
  • Source of bone donor (young donor bone retains significantly greater BMP quantities than older donor bone)
  • Processing methods (Carranza 10th ed.)

7. Recombinant Human BMPs (rhBMPs) - Production

• Because natural BMP extraction is inefficient, recombinant DNA technology was used to produce recombinant human BMPs (rhBMPs) in clinically usable quantities.
• This has made BMPs available for clinical use. (Newman & Carranza 14th ed.; Periodontics Medicine Surgery Implants)

8. Clinical Applications in Periodontics

A. Periodontal Regeneration

• Early studies using crude preparations of BMP-2 and BMP-3 applied in surgically induced furcation defects appeared to stimulate periodontal regeneration.
• More recent studies with rhBMP-2 indicate that periodontal regeneration is associated with areas of ankylosis - this has been a major concern.
• BMP-7 augmentation resulted in significant increase in periodontal regeneration without ankylosis (in contrast to BMP-2). (Newman & Carranza 14th ed.; Periodontics Medicine Surgery Implants)
• When rhBMP-2 was used in horizontal periodontal bony defects:
  • Gains in bone: 3.5 mm vs. 0.8 mm for controls
  • Gains in cementum: 1.6 mm vs. 0.4 mm for controls
  • Histological analysis revealed periodontal regeneration with areas of ankylosis. (Periodontics Medicine Surgery Implants)
• Research using rhBMPs has involved correction of:
  • Intrabony defects
  • Supra-alveolar defects
  • Furcation defects
  • Fenestration defects (Newman & Carranza 14th ed.)

B. Ridge Augmentation and Implant Site Preparation

• Because of the ankylosis concern in periodontal sites, most research shifted to implant site preparation where ankylosis is not a concern.
• rhBMP-2 (INFUSE) soaked onto an absorbable collagen sponge (ACS) is FDA approved for:
  • Ridge augmentation
  • Sinus floor augmentation (Newman & Carranza 14th ed.)
• Clinical trial (Fiorellini et al. 2005): In a human buccal wall defect model following tooth extraction, significant bone formation occurred with rhBMP-2 on ACS compared to ACS alone. (Lindhe 6th ed.; Lindhe 6th ed. - Tissue Regeneration section)
• BMP-7 (OP-1) stimulates bone regeneration around:
  • Teeth
  • Endosseous dental implants
  • In maxillary sinus floor augmentation procedures (Lindhe 6th ed.)
• In critical-sized defects, rhBMP-2 impregnated in a polymer carrier placed with or without barrier membrane demonstrated bony union in treated sites but not controls. (Carranza 10th ed.)

C. Peri-implantitis Defects

• rhBMP-2 has been studied for bone formation and re-osseointegration in peri-implantitis defects following surgical implantation. (Newman & Carranza 14th ed. - reference cited)

D. BMP-7 and Tissue Engineering

• More recently, BMP-7 has been utilized in animal models to improve bone formation by incorporating it into a patterned scaffold for:
  • Formation of PDL-like tissue
  • Overall integrity of the bone-PDL interface
• Future translational and human studies are still needed. (Newman & Carranza 14th ed.)

9. FDA Approval Status

• rhBMP-2 (INFUSE - Medtronic) on an absorbable collagen sponge is FDA-approved for:
  • Ridge augmentation
  • Sinus augmentation (has been used by the orthopedic community for fracture healing)
• rhBMP-2 and rhBMP-7 for periodontal regeneration per se are NOT FDA-approved - they have undergone clinical trials but remain without approval for periodontal indications. (Newman & Carranza 14th ed.)
• FDA-approved biologics for surgical use in periodontics are:
  1. Enamel matrix proteins (Emdogain)
  2. Recombinant human PDGF-BB (GEM 21S)
  3. rhBMP-2 (INFUSE) - for ridge/sinus augmentation only (Newman & Carranza 14th ed.)

10. Delivery System / Carrier

• Absorbable collagen sponge (ACS) is the primary carrier for rhBMP-2 (INFUSE).
• The carrier system is critical because growth factors once delivered suffer from:
  • Proteolytic breakdown
  • Receptor-mediated endocytosis
  • Solubility and quick dilution
• Atelocollagen scaffolds (both constructs of atelocollagen) were found effective in supporting rhBMP-induced bone formation.
• BMPs can also be delivered from synthetic materials such as poly(ethylene glycol) hydrogels.
• Patterned scaffolds are being explored for BMP-7 delivery for PDL regeneration. (Newman & Carranza 14th ed.; Lindhe 6th ed.; Orban's Oral Histology & Embryology)

11. Tissue Engineering Context

• In the tissue engineering framework, BMPs serve as signaling molecules - one of the three key elements (along with scaffolds and cells).
• BMP along with PDGF represent key signaling molecules used to enhance regeneration of tissue/organs. (Newman & Carranza 14th ed.)
• Gene therapy approaches using viral vectors (e.g., adenovirus expressing BMP-7) to achieve sustained local delivery of BMPs have been investigated, overcoming the short biological half-life of delivered growth factors. (Lindhe 6th ed.)

12. Adverse Effects / Complications

• Osteolysis
• Seroma / hematoma
• Infection
• Arachnoiditis (mainly with spine use)
• Dysphagia
• Increased neurological deficits
• Cancer (oncological concern)

13. Limitations of BMP Use in Periodontics

• Ankylosis risk with rhBMP-2 in periodontal regeneration - limits use around natural teeth.
• Short biological half-life - growth factors are subject to proteolytic breakdown and receptor binding issues after delivery.
• Carrier stability - depends on the stability and characteristics of the carrier system.
• Low concentrations in natural bone graft materials (FDBA/DFDBA).
• High cost of recombinant production.
• Results from animal studies still need translation to human clinical trials (especially for BMP-7 and patterned scaffolds). (Newman & Carranza 14th ed.; Lindhe 6th ed.; Periodontics Medicine Surgery Implants)

14. Comparison: BMP-2 vs. BMP-7 in Periodontal Healing

15. Summary Points for Quick Revision

1. BMPs are TGF-β superfamily members; at least 20 in human genome.
2. Key periodontal BMPs: BMP-2 (OP-2), BMP-3 (osteogenin), BMP-7 (OP-1).
3. Mechanism: Bind Type I/II serine-threonine kinase receptors → Smad phosphorylation → nucleus → bone morphogenesis.
4. BMP-2 pathway: Runx2-Smad complexes → RUNX2, OSX, DLX5 → OSE2 expression → osteoblast differentiation.
5. Natural source: 10 kg bovine bone = 2 μg BMP - insufficient for clinical use.
6. Solution: recombinant DNA technology → rhBMPs.
7. rhBMP-2 in periodontal defects: gains bone (3.5 mm) and cementum (1.6 mm) but causes ankylosis.
8. BMP-7: regeneration without ankylosis - preferred around natural teeth.
9. FDA-approved use: rhBMP-2 (INFUSE) on absorbable collagen sponge for ridge/sinus augmentation only.
10. Role in cementogenesis: BMP-3 found in root-lining cells; BMPs 2, 4, 7 differentiate cementoblast precursors.
11. DFDBA osteoinductive potential related to BMP content; young donor bone > older donor bone.
12. Adverse effects: osteolysis, seroma, infection, cancer risk.
13. Future: BMP-7 in patterned scaffolds for PDL regeneration - human studies pending.

• Newman & Carranza 14th ed. - Most comprehensive: BMP classification, molecular mechanisms (Runx2-Smad, RUNX2/OSX/DLX5/OSE2), clinical applications in intrabony/furcation/fenestration/supra-alveolar defects, INFUSE FDA approval, BMP-7 in patterned scaffolds, adverse effects, tissue engineering framework.
• Carranza 10th ed. - BMP-3/osteogenin identification, DFDBA-BMP relationship, rhBMP-2 in critical-sized defects with barrier membranes, donor age effect on BMP content.
• Lindhe 6th ed. - Receptor-Smad signal transduction details, BMP-2 clinical trial (Fiorellini 2005 buccal wall defect model), BMP-7 (OP-1) in implants and sinus augmentation, gene therapy (adenoviral BMP-7), growth factor delivery challenges.
• Orban's Oral Histology - Role of BMPs (2, 3, 4, 7) in cementoblast differentiation, BMP-3 in root-lining cells, BMP delivery from absorbable collagen sponge for bone defect healing, intramembranous ossification via BMPs and cbfa1.
• Periodontics Medicine Surgery Implants - Quantitative data on rhBMP-2 in horizontal defects (3.5 mm bone, 1.6 mm cementum gain), ankylosis concern, BMP-7 advantage over BMP-2, osteoinductive mechanism (ectopic bone formation), gene therapy rationale for overcoming short BMP half-life.