BMPs are proteins that are important for skeletal development and bone formation. They commit undifferentiated cells to differentiate into cartilage and bone forming cells. BMPs were first discovered when demineralized bone matrix implanted into rodents induced new bone formation. Since then, 13 BMP sequences have been cloned. BMPs are being researched for applications in bone healing, dental procedures like sinus lifting, and tissue engineering.

1. BONE MORPHOGENIC
PROTEINS
KISHORE B POOVATTIL
HOUSE SURGEON

2. INTRODUCTION
 The bone morphogenic proteins are a group of related proteins that are found in
the body and are important for skeletal development.
 Extracellular matrix(ECM) contains ‘morphogenetic factors’ apart from growth
factors which are capable of inducing de-novo bone formation.
 Inductive interactions between these morphogenetic proteins and target cell leads
to sequential biochemical and morphogenetic events resulting in differentiation of
endochondral bone.

3.  Bone Morphogenetic Proteins (BMPs) were acknowledged to the world when
Marshall Urist implanted demineralized bone matrix intra muscularly into the
rodents and observed new bone formation.
 Urist named them ‘bone morphogenetic proteins’ believing that they are capable
of determining morphogenesis of structures such as bone.
 Subsequently he was able to isolate the protein responsible for inducing new bone
formation.

4.  BMPs, composed of 400-525 amino acids, comprise one subset of the transforming
growth factor-B superfamily
 BMPs stimulate proliferation and migration of undifferentiated bone cell precursors
with little or no effect on mature osteoprogenitor cells
 Thus, the main action of BMPs is to commit undifferentiated puripotential cells to
differentiate in to cartilage and bone forming cells
 BMPs are abundant in bone and are produced by several cell types including
osteoblasts

5. HISTORICAL BACKGROUND
 In 1889 Senn first found that decalcified ox bone promoted healing of
osteomyelitic defects
 He proposed that there was something in decalcified bone that was responsible for
bone formation
 In 1938 Lavender implanted living bone fragments 1-1.5cm in length either
subcutaneously or intramuscularly

6.  These fragments were first treated by scraping away the periosteum, and in some
specimens, a superficial layer of bone was also removed
 Upon obtaining regenerated bone, he was able to show that it was neither the
periosteum nor the cells on the surface or within the graft was responsible for new
bone growth
 He proposed that there must be something which originated from the graft itself,
possibly a substance which was soluble in the lymph tissue

7.  In early 1960s several resarchers were investigating the process of calcification
 In a series of experiments designed to test the triphasic theory of calcification, Urist
et al discovered that control samples of untreated, decalcified bone implanted into
muscle pouches of rabbits and rats resulted in new cartilage and bone formation
by auto-induction

8.  The purification of BMPs was completed using the rat ectopic bone formation
assay
 This assay involves combining the sample containing the unknown protein to be
assayed with demineralized rat bone matrix, which has been treated with
dissociative agents such as guanidine and urea to remove all of the endogenous
BMP activity

9.  This combination is then implanted subcutaneously in rats, and after 1-2 weeks,
formation of new cartilage and bone is detected histologically
 Using this bioassay, BMPs were purified and sequenced
 Johnson et al in 1992 successfully purified human bone morphogenic proteins
 13 BMP sequences have been cloned so far

10. PROPERTIES OF BONE MORPHOGENIC
PROTEINS
 They act as mitogens on undifferentiated mesenchymal cells and osteoblast
precursors
 Structurally they are related members of TGF-B superfamily
 BMP 2-12 singly initiate de novo endochondral bone formation
 BMPs induce bone formation where as other growth factors such as TGF-B1 or
PDGF do not

11.  BMPs have an anabolic effect on periodontal tissues through stimulation of
osteoblastic differentiation in human periodontal ligament cells
 Bone allograft materials contain varying amount of BMPs, such as BMP-2,4 and -7 .
A deficiency of BMP like proteins retards bone cell differentiation and may account
for a failure of fracture to heal
 Recombinant BMP’s (rh BMP’s) have been shown to promote bone formation

12.  They induce the expression of osteoblast phenotype ( ie. Increase in alkaline
phosphatase activity in bone cells)
 Act as chemoattractants for mesenchymal cells and monocytes as well as binding
to extracellular matrix type IV collagen

13. Role of BMPs IN PERIODONTAL
REGENERATION
 BMPs have been used extensively by researchers to induce periodontal tissue
regeneration in a variety of animal models as well as in human studies with varying
degrees of success
 Researchers have proposed that BMPs possess a structure/activity profile with
BMP-2 exhibiting mainly osteogenic properties while oseteogenic protein-1 (OP-1),
also known as BMP-7, was mainly cementogenic in its activities

14.  Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been used to
investigate periodontal regeneration
 Researchers successfully achieved periodontal regeneration in dogs using
recombinant human bone morphogenetic protein-2(rhBMP-2) and a synthetic
carrier
 Clinical trials using rhBMP-2 in an absorbable collagen sponge carrier have yielded
encouraging results with the protein and carrier being well tolerated locally and
systemically.

15. STRUCTURE OF BMPs
 There are about 20 BMPs identified till now
 They belong to Transforming Growth Factor B superfamily except BMP1 which is a
metalloproteinase
 The basic structure of a BMP protein has:
Hydrophobic secretory leader sequence
Large propeptide region, and
Mature of domain

17.  BMPs are divided into 3 groups:
BMP-2 and BMP-4 has similar seven-cysteine domains but varies in amino terminal
regions- share 92% of homology
BMP-5, BMP-6, BMP-7, BMP-8 share sequence homology
BMP-7 is OP-1 osteoprotegrin 1 and BMP-8 is OP-1 osteoprotegrin 2
BMP-3(osteogenin), differs from these two subgroups, form a different entity

18.  Recombinant human BMP-2 (rhBMP-2) has been produced using a Chinese
hamster ovary (CHO) cell expression system
rhBMP-2 causes bone formation by intramembranous as well as the
endochondral method.
Other BMPs, including BMP-4, BMP-5, BMP-6 and BMP-7, also induce bone in a
similar manner although there could be variation in the amount and rate of bone and
cartilage formation

19. BMP ALTERNATE NAMES

20. BMP SIGNALLING SYSTEM
 BMPs signal through serine/threonine kinase receptors that are composed of type I
and type II subtypes
 Three type I receptors have been shown to bind BMP ligands, including type IA and
type IB BMP receptors [BMPR IA(ALK-3) and BMPR-IB(ALK-6)] and type IA activin
receptor (Act RIA or ALK-2)

21.  The type I BMP receptor substrates include the Smad proteins, which play a central role
in the relay of BMP signals from the receptor to target genes in the nucleus.
 Smad1, Smad5 and Smad8 are phosphorylated by BMP receptors in a ligand dependent
manner
 After release from the receptor, Smad proteins associate with the related protein
Smad4, which acts as a shared partner
 This complex translocates into the nucleus and participates in gene transcription with
other transcription factors

22. BRIEF DESCRIPTION OF SOME WELL
INVESTIGATED BMPs
 BMP1: Genes for BMP1 are located on chromosome 8
It does not belong to the TGF-B family of proteins
It is a metalloprotease that acts on procollagen I, II, III
It is involved in cartilage development
BMP2: It is a major inducer of osteoblast differentiation
The genes are located on chromosome 20

23.  BMP 3: Induces bone formation
The genes are located on chromosome 14
BMP 4: Regulates the formation of teeth, limbs and bone from mesoderm
It also plays a role in fracture repair
Genes are located on chromosome 14

24.  BMP 5 : Performs functions in cartilage development
Genes are located on chromosome 6
BMP 6: Plays a role in joint integrity in adults
Genes are located on chromosome 6
BMP 7: Plays a key role in osteoblast differentiation
It also induces the production of SMAD1
Also key in renal development and repair
Genes are located on chromosome 20
It is also known as osteogenic protein-1

25. ROLE OF BMPs in EMBRYO DEVELOPMENT
 The bone inducing property of BMPs in extra skeletal tissues gives clue regarding
their involvement in embryonic development and also in post natal bone
differentiation (RIPOMANTI 1992)
 BMP2 was localised in mouse embryo at condensing precartilagenous
mesenchyme, and in developing bones thus indicating it could also regulate
cartilage and bone formation

26.  Osteogenin was also observed in rat embryo
 BMP 2A was found localized in developing mouse hair follicles, limb buds, tooth
buds – including the dental papilla and the odontoblastic layer, and in the
mesenchyme of craniofacial region including Meckel’s and nasal cartilage and that
of the palatal shelves
 Thus BMPs are believed to regulate embryogenesis

27. CLINICAL APPLICATIONS
 BMPs are of tremendous interest as therapeutic agents for healing bone fractures,
including non union and in open tibial fracture
 Also used in spinal fusion and reported to prevent osteoporosis
 In dentistry, it is used for augmentation of maxillary sinus floor and alveolar ridge

28.  BMPs may provide a promising alternative to traditional grafting procedures
 Its scope further extends in treating periodontal bone defects and in implant placement
along with alloplastic materials, root coverage procedures and in periodontal
regeneration
 The combination of BMP2/ACS is commercially available as INFUSEVR bone graft
(Medtronic, Minneapolis, MN), is useful for sinus lifting and implant dentistry
 Potential of BMP-2 helps in regenerating bone in irradiated tissues seems promising in
rehabilitating patients who have undergone radiation therapy and need bone
reconstruction

29. BMPs in TISSUE ENGINEERING
 Tissue engineering aims to reconstruct lost tissues or organs and is considered as
the ultimate regenerative technique
 Using tissue engineering, unwanted reaction which arise due to grafts such as
tissue biocompatibility or rejection could be avoided
 With the help of tissue engineering, therapies such as the production of skin to
treat burns, bone grafts, arteries to treat atherosclerotic vascular disease and
cartilage for plastic and reconstructive surgeries have been achieved

30.  Tissue engineering is being applied in dentistry for the regeneration of
temporomandibular joint, periodontal ligament, dentin, enamel, pulp and
integrated tooth tissues
 Tissue engineering has three key features namely:
Cells
Scaffolds
Signaling molecules such as growth factors

31.  Cells synthesise the matrix essential for the new tissue
 Scaffolds provide the environment for the cells to synthesise matrix
 Growth factors facilitate and promote this action
 The growth factors that have been frequently applied to tissue engineering include
bone morphogenetic proteins(BMP), basic fibroblast growth factor, vascular
epithelial growth factor and transforming growth factor-B

32.  The BMP/TGF-b signalling pathway mediates osteoblastic differentiation and in
vivo bone formation; BMP-2 and -7 were reported to play a role in the
differentiation of periodontal ligament stem cells(PDLSC) and dental follicle stem
cells
 Reparative dentin formation was promoted by BMP-2 and -7.

33. BMPs in SOCKET AUGMENTATION
 BMPs when used in augmentation of socket and maxillary sinus wall were found to
:
promote soft tissue healing
minimize surgery time
reduce potential post surgical infection
accelerate cell migration
promotes early bone formation

34. BMPs in IMPLANTOLOGY
 Application of BMPs for the osseointegration of endosseous implant has been
evaluated by some authors
 Osseointegration is critical for endosseous implant in which there is complete
union of implant with bone
 Sometimes there would be insufficiency in quality or amount of bone, which is
addressed by using grafts or growth factors

35.  In human trial studies conducted by Howell in 1997 and Cochran et al in 2000
using recombinant human BMP-2 in collagen sponge carrier, bone formation at the
extracted site was observed, which helped in endosseous implant placement
 Boyne et al in 1997, observed bone formation in sinus lift procedure using the
same combination and this aided in implant placement (Boyne PJ)

36. LIMITATIONS
 Though BMPs are potential candidates for promotion of regeneration of
periodontium, limitations do exist
 Ankylosis of varying degrees has been observed in some studies
 Still there are difficulties in the method of delivering BMPs to the target site to
achieve a constant supply of BMPs
 Thus gene therapy and other modes of targeted delivery are being developed.
BMPs are also associated with some systemic toxicity

37. CONCLUSION
 BMPs apart from inducing new bone also seem applicable in multiple modes of
regeneration like being used along with implants
 Though the discovery and usage of BMPs are like the ‘light at the end of tunnel’
towards periodontal regeneration, more experimental studies and research are
needed to fully tap their potential for regeneration