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3/9/2015 Bone Morphogenetic Proteins (BMP’s)
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Bone Morphogenetic Proteins (BMP’s)
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Introduction:
Bone morphogenetic proteins (BMP’s), composed of 400–525 amino acids, comprise one subset of
the transforming growth factor β superfamily. BMP’s stimulate proliferation and migration of
undifferentiated bone cell precursors with little to no effect on mature osteoprogenitor cells 1. Thus,
the main action of BMP’s is to commit undifferentiated puripotential cells to differentiate in to
cartilage and bone forming cells 24. BMP’s are abundant in bone and are produced by several cell
types including osteoblasts 56.
Properties of Bone morphogenetic proteins (BMP’s):
1. They act as mitogens on undifferentiated mesenchimal cells and osteoblast precursors.
2. Structurally they are related members of TGFβ superfamily.
3. BMP 212 singly initiate de novo endochondral bone formation 710.
4. BMP’s induce bone formation where as other growth factors such as TGFβ1 or PDGF do not.
5. BMPs have an anabolic effect on periodontal tissue through stimulation of osteoblastic
differentiation in human periodontal ligament cells 1112.
6. Bone allograft materials contain varying amount of BMP’s, such as BMP 2,4 and 7 13. A
deficiency of BMP like proteins retards bone cell differentiation and may account for a failure
of fracture to heal 14.
7. Recombinant BMP’s (rh BMP’s) have been shown to promote bone formation 1516.
8. They induce the expression of osteoblast phenotype (i.e. increase in alkaline phosphatise
activity in bone cells).
9. Act as chemoattractants for mesenchymal cells and monocytes as well as binding to
extracellular marix type IV collagen 17.
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.
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In 1938 Lavender 18 implanted living bone fragments 11.5 cm in length either subcutaneously or
intramuscularly. 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 that 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.
In early 1960’s several researchers 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 autoinduction 1920.
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. 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 21 in 1992 successfully purified human bone
morphogenetic proteins. 13 BMP sequences have been cloned so far. BMP1 which does not belong
to the TGFβ family of proteins, was identified as a type I procollagen carboxyterminal proteinase 22
23.
Recombinant human BMP2 through BMP 6 and osteogenic proteinl and 2 (OP1 and OP2, also
known as BMP7 and BMP8, respectively), in conjunction with the collagenous matrix, singly induce
de novo bone formation when implanted into extraskeletal sites of a variety of animal models 2426.
These recombinant BMPs have been produced using both a mammalian cell expression system and an
Escherichia coli expression system.
Structure of BMP’s:
The BMP’S are 30 to 38 kDa homodimers , glycosylated proteins. As individual BMP proteins are
synthesized by a cell, they dimerise and become glycosylated. They are synthesized as prepropeptides
of approximately 400–525 amino acids. The mature Cterminal region of 100–140 amino acid
residues is released from a propeptide region by cleavage at an ArgXXArg sequence. Cleavage
event occurs upon secretion that results in the formation of mature active protein, a dimer of carboxy
terminal region of the precursor peptide. Because of the dimeric nature of the BMP’s, it is possible
that both homodimeric and heterodimeric forms exist. The BMPs have been grouped into subsets
based on amino acid sequence homology. The groupings are suggested to be as follows:
A. BMP2 and BMP4,
B. BMP3 and BMP3b,
C. BMP5, BMP6, BMP7, and BMP8,
D. BMP9 and BMP10,
E. BMP12, BMP13, and BMP14, and
F. BMP11 and growth/differentiation factor 8 (GDF8).
Bone Morphogenetic Proteins (BMP’s) & their alternate names
BMP ALTERNATIVE NAME
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BMP2 BMP2a
BMP3 Osteogenin
BMP4 BMP2b
BMP5
BMP6 Vgr 1
BMP7 OP1
BMP8 OP2
BMP9 GDF2
BMP10
BMP11
BMP12 GDF11, CDMP3
BMP13 GDF6, CDMP2
BMP14 GDF5, CDMP2
BMP15 CDMP1
OP: Osteogenic proteinGDF: Growth and differentiation factorCDMP: Cartilage derived
morphogenetic proteinVgr: Vegetal related growth factor .
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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 IB
BMP receptors [BMPRIA (ALK3) and BMPRIB (ALK6)] and type IA activin receptor (ActRIA
or ALK2).
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 liganddependent 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.
Brief description of some well investigated BMP’s:
BMP1 : Genes for BMP 1 are located on chromosome 8. It does not belong to the TGFβ family of
proteins. It is a metalloprotease that acts on procollagen I, II and III. It is involved in cartilage
development.
BMP2 : It is a major inducer of osteoblast differentiation. The genes are located on chromosome 20.
BMP3 : Induces bone formation. The genes are located on chromosome 14.
BMP4 : Regulates the formation of teeth, limbs and bone from mesoderm. It also plays a role in
fracture repair. Genes are located on chromosome 14.
BMP5 : Performs functions in cartilage development. Genes are located on chromosome 6.
BMP6 : Plays a role in joint integrity in adults. Genes are located on chromosome 6.
BMP7 : 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 protein1.
Role of BMP’s in periodontal regeneration:
BMPs have been used extensively by researchers to induce periodontal tissue regeneration in a variety
of animal models 2731 as well as in human studies 3233 with varying degrees of success.
Researchers 34 have proposed that BMPs possess a structure/activity profile with BMP2 exhibiting
mainly osteogenic properties while osteogenic protein1 (OP1), also known as BMP7, was mainly
cementogenic in its activities.
Recombinant human bone morphogenetic protein2 (rhBMP2) has been used to investigate
periodontal regeneration. Researchers 32,35 successfully achieved periodontal regeneration in dogs
using recombinant human bone morphogenetic protein2 (rhBMP2) and a synthetic carrier.
Clinical trials using rhBMP2 in an absorbable collagen sponge carrier 3233 have yielded encouraging
results with the protein and carrier being well tolerated locally and systemically.
Challenges in clinical application of BMP’s:
The major challenges in clinical application of BMP’s are 3637:
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Need for high doses.
Nonspecific activity on different cell lineages in time and space.
Rapid loss of topically applied growth factors.
The greatest challenge of all in clinical application of BMP’s is the formulation of appropriate
delivery systems for BMPs suitable for periodontal regeneration. The operational reconstitution and
the implantation of the BMP’s with the collagenous matrix as carrier resulted in the induction of
cementogenesis and the morphogenesis of a functionally oriented periodontal ligament. An important
function for an osteogenic delivery system is the initiation of optimal osteoinductivity with relatively
low doses of recombinant BMPs.
Recent research:
As the expression of both BMP2 and BMP7 has been found during periodontal tissue
morphogenesis, it suggests that optimal therapeutic regeneration may require the combined use of the
two BMP’s. Recent research has been concentrated on the application of BMP’s in regenerative
periodontal therapy to aid in the healing of bone. In one study recombinant human (rh) osteogenic
protein1 (also referred to as BMP7) and BMP2 (rhBMP2) have been shown to be safe and
effective in improving and accelerating bone healing in orthotropic animal models and fibrous
nonunion fracture healing 38. To deliver BMP’s in an active form in a periodontal defect through a
carries is one of the most important step in its clinical application.
Application of CaPcoated porous titanium fiber mesh loaded with rhBMP2 in subcutaneous
implants using a rat model has been used to find out the osteoinductive property of recombinant
BMP 39. Ectopic bone formation with a cartilaginous phase was observed within 7–9 days, and bone
formation was observed to be similar to endochondral ossification. Another study done on rat bone
marrow stromal cell showed that rhBMP2 incorporated into CaP coatings had a greater potential to
stimulate alkaline phosphatase activity which is indicative of bone formation 40.
Summary of biological activities of BMP’s:
Embryo genesis
BMPs play an important role in early embryonic early development.
Apoptotic activity
BMPs appear to mediate programmed cell death at advanced stages of development.
Mitogenic for cells:
BMPs act as mitogens on undifferentiated mesenchymal cells and osteoblast precusors,
inducing the expression of osteoblast phenotype (e.g. increasing alkaline phosphatase activity in
bone cells). Also acts as chemoattractants for mesenchymal cells and osteocytes as well as
binding to extracellular matrix and collagen.
Periodontal regeneration
Many invivo studies have shown the ability of BMPs in inducing new bone and cementum
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3/9/2015 Bone Morphogenetic Proteins (BMP’s)
formation.
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