Bone morphogenetic proteins /certified fixed orthodontic courses by Indian dental academy

Bone morphogenetic proteins
and the induction of periodontal
tissue regeneration

INDIAN DENTAL ACADEMY
Leader in Continuing Dental Education

www.indiandentalacademy.com

Introduction:
 Tissue engineering defined as the science of
fabrication of new tissues for replacement and
the regeneration of lost or destroyed tissues.
 The three critical ingredients for optimal tissue
engineering are;
 Soluble molecular signals,
 Responding cells with associated cell-surface
receptors, and
 Assembly of the extracellular matrix
 This knowledge can now be applied not only to
bone regeneration but also to alveolar bone with
associated cementum and periodontal ligament
regeneration.

 Substantial knowledge has now been gained
about the molecular signals that determine the
emergence of the complex tissue morphologies
during regeneration of the periodontal tissues.
 The molecular mechanisms for such
regeneration are the osteogenic proteins of the
transforming growth factor-β superfamily of
which the bone morphogenetic and osteogenic
proteins (BMPs/OPs) are a class of powerful
inducers of endochondral bone differentiation.
 Lacroix in 1945 hypothesized that bone contains
substances which he named osteogenins, that
initiate bone growth and differentiation.

 Urist 1964 made the key discovery that Demineralized
bone matrix when implanted heterotopically in
intramuscular sites of allogenic rat recipients, induces de
novo endochondral bone formation by induction.

 BMP is the generic name for proteins which are
extracted from bone matrix with agents such as 4M
guanidine hydrochloride, 6M urea in 0.5M CaCl2 or
ethylene glycol in an aqueous/nonaqueous solvent
mixture.

 Reddi and Huggins showed that subcutaneous
implantation of Demineralized bone matrix results in de
novo local endochondral bone differentiation.

Endochondral bone formation in subcutaneous space ( rodent)
5–20µg of BMPs/OPs.


The sequential developmental cascade In
endochondral bone formation;
activation and migration of undifferentiated mesenchymal cells by
chemotaxis

anchorage dependent cell attachment to the matrix via fibronectin

mitosis and proliferation of responding mesenchymal cells

differentiation of chondroblasts and deposition of cartilage

mineralization of the cartilage

angiogenesis, vascular invasion and chondrolysis

differentiation of osteoblasts and bone matrix deposition

mineralization of the newly induced bone and
differentiation of hemopoietic marrow in the newly formed ossicles

 The dissociative extraction of the demineralized bone
matrix with agents (urea and guanidinium hydrochloride)
yielded an insoluble component mainly type I collagen
(insoluble collagenous bone matrix) and a soluble protein
extract containing the putative osteogenic proteins.
 The operational reconstitution of the inactive and
insoluble collagenous bone matrix with protein extracts
after a single step of gel-filtration chromatography
restored the biological activity yielding endochondral
bone differentiation by induction after recombining the
insoluble with the soluble signals.
 Endochondral bone induction is the result of the
combined action of BMPs/OPs and the complementary
substratum that delivers the osteogenic activity of the
soluble molecular signal.


BMPs/OPs induction of cementogenesis and PDL
regeneration:
 More than 40 related proteins with BMP/OP-like
sequences and activities have been sequenced and
cloned.
 each protein either purified to BMPs and the induction of
periodontal tissue regeneration homogeneity from
natural sources or cloned and expressed by recombinant
DNA technology induces endochondral bone formation,
by induction in heterotopic sites of a variety of animal
models including adult primates.
 In addition to bone induction, BMPs/OPs are expressed
during early development and organogenesis indicating
that BMPs/OPs are related members play critical roles
as soluble mediators of epithelial–mesenchymal
interactions and inductive events unrelated to bone
induction. (Hogan 1996; Nakashima 2003)

Bone induction in implantation of highly purified
bone-derived bovine (BMPs/OPs)


 The induction of bone by hOP-1 develops as a mosaic
structure with distinct spatial and temporal patterns of
gene expression of members of the transforming growth
factor-β superfamily that singly, synergistically initiate
and maintain tissue induction and morphogenesis.
 The expression of OP-1, type IV collagen, BMP-3 and
transforming growth factor-β1 mRNAs by Northern blot
analyses showed progressing stages of osteogenic
differentiation during the initiation of bone formation by
the hOP-1 osteogenic device. (Ripamonti 2005)
 The continuous high-expression patterns of type IV
collagen mRNA indicates the critical role of hOP-1 in the
induction of angiogenesis.


 BMPs/OPs are involved in tooth morphogenesis at different
stages of development. During the later developmental
stages of tooth morphogenesis, the induction of
cementogenesis, PDL and alveolar bone differentiation
which are regulated by the co-ordinated expression of
BMPs/OPs.

 A systematic analysis of the expression of six different
BMPs in tooth morphogenesis has shown that the
expression patterns of each BMP is different and there is
co-distribution between specific family members.

 Root morphogenesis is a classical example of epithelial–
mesenchymal interactions. The localization of BMP-3 and
OP-1 during morphogenesis of the mouse root suggests
that these proteins play a role during cementogenesis and
the assembly www.indiandentalacademy.com periodontal ligament
of a functionally oriented
fiber syste. (Thomadakis et al 1999)

Imuuno-localization of BMP- 3 & OP- 1:


 The localization of BMP-2 in alveolar bone only and
BMP-3 and OP-1 in all three components of the
periodontium, indicates that the morphogenesis of
periodontal tissues may involve a composite pattern of
co-ordinated expression of different signaling isoforms.
 The mosaicism of BMP/OP expression during root
morphogenesis indicates that optimal therapeutic
regeneration and tissue engineering may entail binary
combinations of osteogenic gene products based on
recapitulation of embryonic development.
 Amino acid sequence variations in the active C-terminal
domain of each morphogenetic protein confer
specialized activities to BMP/OP isoforms and this is the
molecular basis that determines the structure–activity
profile of single BMPs/OPs.


Periodontal tissue regeneration by naturally derived and
recombinant human BMPs/OPs in the nonhuman primate
 To induce the cascade of bone differentiation, the
soluble osteogenic molecular signals of the transforming
growth factor-β superfamily must be reconstituted with
an insoluble signal or substratum that triggers the bone
differentiation cascade.
 Different BMPs/OPs and combinations of these have
been implanted in furcation defects of the mandibular
first and second molars of adult baboons, which are
delivered by insoluble collagenous bone matrices as a
carrier.
 Naturally derived BMPs/Ops induced cementum,
periodontal ligament and alveolar bone regeneration in
surgically created class II furcation defects of mandibular
molars.

 The newly formed Sharpey’s fibers were inserted
perpendicularly into the newly formed cementum
covered by a thin layer of cementoid.

 The sources of responding cells that initiate
cementogenesis and periodontal ligament regeneration
are still not well understood. Recent studies have
indicated that the periodontal ligament system contains
stem cells that have the potential to regenerate
cementum and periodontal ligament in vivo (Seo et al
2004).


 Synchronous but spatially distinct OP-1 and BMP-2
expression during murine root formation points to
specific functions of OP-1 and BMP-2 in periodontal
tissue morphogenesis and thus regeneration in postnatal
life.

 The co-localization findings of OP-1 and BMP-2 during
tooth morphogenesis has suggested that co-
administration of OP-1 and BMP-2 in recombinant form
would result in synergistic tissue morphogenesis as a
recapitulation of memory of developmental events in the
embryo.

 hBMP-2 was found to be more osteogenic than
cementogenic in both beagle dogs and baboons.

 hOP-1 clearly modulates the expression of the
cementogenic phenotype and the induction of
cementogenesis in both animal models, and also on root
surfaces exposed by disease (Ripamonti 2002).

 hBMP-6 has also been investigated in a periodontal
fenestration defect model in rodents. The study indicated
that hBMP-6 induced significantly more new cementum
formation as compared to control fenestration defects
(Huang et al 2005).

 hBMP-12 has also become the focus of attention for
periodontal regenerative studies. (Wikesjo¨ et al. 2004)


Perspectives in periodontal tissue
engineering by BMPs:
 The capacity of mammalian BMPs/OPs to initiate a
programmed cellular cascade that results in the induction of
bone is a functionally conserved process utilized in
embryonic development, recapitulated in post-fetal
osteogenesis and can be re-exploited for the therapeutic
initiation of periodontal tissue regeneration.

 The presence of the structure–activity profile amongst
soluble osteogenic molecular signals indicates a therapeutic
significance in clinical contexts (Ripamonti 2006).

 A soluble osteogenic and recombinant molecular signals
when combined with an insoluble signal, triggers periodontal
tissue regeneration with the induction of cementogenesis
and insertion of Sharpey’s fibers. Therfore these signals are
essential ingredients to engineer periodontal tissue
regeneration (Ripamonti 2002 & 2006).

Bone morphogenetic proteins /certified fixed orthodontic courses by Indian dental academy

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