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INDIAN DENTAL ACADEMY
Leader in continuing dental education
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Growth factors
This collective term originally referred to
substances that promote cell growth.
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Growth factors
Introduction
 Growth factors are proteins that bind to
receptors on the cell surface, with the
primary result of activating cellular
proliferation and/or differentiation. Many
growth factors are quite versatile,
stimulating cellular division in numerous
different cell types; while others are
specific to a particular cell-type.
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Growth factors comprises of molecules
that function as growth stimulators but also
as growth inhibitors (sometimes referred to
as negative growth factors ), factors that
stimulate cell migration or as chemotactic
agents or inhibit cell migration or invasion
of tumor cells, factors that modulate
differentiated functions of cells, factors
involved in apoptosis , factors involved in
angiogenesis , or factors that promote
survival of cells without influencing growth
and differentiation.
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Growth factors are polypeptides that
belongs to a number of families.
Cell surface receptors capture them.
Upon capturing receptor interacts with
membrane and cytoplasmic bound
components to bring about alteration in
gene expression of a cell.
Thus a growth factor is an inductive agent.
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A growth factor produced by one cell and
acting on another is described as
paracrine regulation.
Whereas the process of a cell that
recaptures its own product is known as
autocrine regulation.
Few growth factors act during
embryogenesis.
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By contrast, the retinoic acid family freely
enters a cell to complex with intracellular
receptors, which eventually affect gene
expression.
Both growth factors and the retinoids
regulate the expression of the homeobox
genes, which, in turn, regulate the
expression of growth factors(role of
regulatory loops in development).
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Epidermal Growth Factor (EGF)
Platelet-Derived Growth Factor (PDGF)
Fibroblast Growth Factors (FGFs)
Transforming Growth Factors-b (TGFs-b)
Transforming Growth Factor-a (TGF-a)
Erythropoietin (Epo)
Insulin-Like Growth Factor-I (IGF-I)
Insulin-Like Growth Factor-II (IGF-II)
Interleukin-1 (IL-1)
Interleukin-2 (IL-2)
Interleukin-6 (IL-6)
Interleukin-8 (IL-8)
Tumor Necrosis Factor-a (TNF-a)
Tumor Necrosis Factor-b (TNF-b)
Interferon-g (INF-g)
Colony Stimulating Factors (CSFs)www.indiandentalacademy.com
Osteoblasts synthesize and regulate the
deposition and mineralization of the
extracellular matrix of bone. Systemic and
locally active hormones, growth factors,
ions, lipid metabolites and steroids are
regulators of osteoblastic activity and/or
differentiation.
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Members of the transforming growth factor
beta (TGF-b) family, particularly TGF-b
and the bone morphogenetic proteins
(BMPs) are important to bone
homeostasis. These factors modulate
osteoblast proliferation and differentiation .
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Matrixmetalloproteinases
Extracellular matrix degrading metallo
enzymes are known collectively as
Matrixmetalloproteinases(MMPs).
Tissue inhibitors of
metalloproteinases(TIMPs).
Depend on Zn²+ and Ca²+ for activity.
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Matrixmetalloproteinases
Rather than being primarily involved in
matrix degradation MMPs have equally or
more important roles as efficient
processing enzymes of many bioactive
mediators such as cytokines, chemokines,
growth factors, their receptors and specific
matrix protein anchors for these
molecules.
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Cytokines
Includes a family of molecules which are
small proteins with either paracrine or
endocrine functions which are involved in
local inflammation or immunoregulation.
Within this definition growth factors could
be included.
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Cytokines.
Cytokines are a unique family of growth
factors.
Secreted primarily from
leukocytes, cytokines stimulate both the
humoral and cellular immune
responses, as well as the activation of
phagocytic cells.
Lymphokines
Monokines.
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Cytokines
A large family of cytokines are
produced by various cells of the body.
Many of the lymphokines are also
known as interleukins (ILs), since they
are not only secreted by leukocytes but
also able to affect the cellular
responses of leukocytes.
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Cytokines
Specifically, interleukins are growth
factors targeted to cells of
hematopoietic origin.
The list of identified interleukins grows
continuously with the total number of
individual activities now at 22.
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Factor Principal
Source
Primary
Activity
Comments
PDGF platelets,
endothelial cells,
placenta
promotes
proliferation
of connective
tissue, glial
and smooth
muscle cells
two
different
protein
chains form
3 distinct
dimer
forms; AA,
AB and BB
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Factor Principal
Source
Primary Activity
EGF submaxillary
gland, Brunners
gland
promotes proliferation
of mesenchymal, glial
and epithelial cells
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Factor Principal
Source
Primary
Activity
Comments
TGF-a common in
transformed
cells
may be
important
for normal
wound
healing
related to
EGF
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Factor Principal
Source
Primary Activity Comments
FGF wide range
of cells;
protein is
associated
with the
ECM
promotes
proliferation of many
cells; inhibits some
stem cells; induces
mesoderm to form in
early embryos
at least 19
family
members, 4
distinct
receptors
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Factor Principal
Source
Primary Activity Comments
NGF promotes neurite
(axites &
dendrites)
outgrowth and
neural cell survival
several
related
proteins
first
identified as
proto-
oncogenes;
trkA
(trackA),
trkB, trkC
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Factor Principal
Source
Primary Activity Comments
Erythropoietin kidney promotes
proliferation and
differentiation of
erythrocytes
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Factor Principal
Source
Primary Activity Comments
TGF-b activated TH1
cells (T-helper)
and natural
killer (NK) cells
anti-inflammatory
(suppresses
cytokine
production and
class II MHC
expression),
promotes wound
healing, inhibits
macrophage and
lymphocyte
proliferation
at least 100
different
family
members
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Factor Principal Source Primary
Activity
Comments
IGF-I primarily liver promotes
proliferation
of many cell
types
related to
IGF-II and
proinsulin,
also called
Somatomedin
C
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Factor Principal
Source
Primary
Activity
Comments
IGF-II variety of cells promotes
proliferation
of many cell
types
primarily of
fetal origin
related to
IGF-I and
proinsulin
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Factors modulating growth, chemotactic behavior and/or
functional activities of smooth muscle cells include
Activin A , Adrenomedullin , aFGF, ANF , Angiogenin ,
Angiotensin-2 , Betacellulin , bFGF , CLAF , ECDGF
(endothelial cell-derived growth factor ), ET (Endothelins
), Factor X , Factor Xa , HB-EGF , Heart derived inhibitor
of vascular cell proliferation , IFN-gamma , IL1 , LDGF
(Leiomyoma-derived growth factor ), MDGF
(macrophage-derived growth factor , monocyte-derived
growth factor ), Oncostatin M , PD-ECGF , PDGF ,
Prolactin , Protein S , SDGF (smooth muscle cell-derived
growth factor ), SDMF (Smooth muscle cell-derived
migration factor ), Tachykinins , TGF-beta ,
Thrombospondin .
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Factors modulating growth, chemotactic
behavior and/or functional activities of vascular
endothelial cells include AcSDKP , aFGF , ANF
, Angiogenin , angiomodulin , Angiotropin
, AtT20-ECGF , B61 , bFGF , bFGF inducing
activity , CAM-RF , ChDI , CLAF , ECGF , ECI
, EDMF , EGF , EMAP-2 , Neurothelin
, Endostatin , Endothelial cell growth inhibitor
, Endothelial cell-viability maintaining factor
, Epo , FGF-5 , IGF-2 , HBNF , HGF , HUAF
, IFN-gamma , IL1 , K-FGF , LIF , MD-ECI
, MECIF , NPY , Oncostatin M , PD-ECGF
, PDGF , PF4 , PlGF , Prolactin , TNF-alpha
, TNF-beta , Transferrin , VEGF .
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A mind once
stretched by a
new idea, never
regains its
original
dimensions.
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Bone – enormous reservoir
1.PDGF
2.IGF – I
IGF – II
3.BMP (PART OF TGF-β FAMILY)
Binding proteins to keep these factors
within bone itself.
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Transforming Growth Factors-β
(TGFs- β)
ALTERNATIVE NAMES
CIF-B ( cartilage inducing factor B =TGF-
beta-2 )
DIF ( differentiation-inhibiting factor )
DSF ( decidual suppressor factor =TGF-
beta-2 )
EIF ( Epstein-Barr virus inducing factor )
EGI (epithelial growth inhibitor )
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MDGF ( milk-derived growth factor )
MGF ( milk growth factor )
MGF-a ( milk growth factor =TGF-beta-2 )
MGF-b ( milk growth factor =TGF-beta-1 )
TCGF ( transformed cell growth factor )
TGI ( tissue-derived growth inhibitor )
TIF-1 ( tumor inducing factor-1 ).
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Sources of TGFs- β
Found predominantly in spleen and bone tissues.
Platelets - milligrams of TGF-beta/ kg.
other tissues - microgram TGF/kg.
Human milk – MGF.
Synthesized also by - macrophages(TGF-beta-1
), lymphocytes(TGF-beta-1 ), endothelial cells(TGF-
beta-1 ), keratinocytes(TGF-beta-2 ), granulosa
cells(TGF-beta-2 ), chondrocytes (TGF-beta-1
), glioblastoma cells(TGF-beta-2 ), leukemia
cells(TGF-beta-1 ).
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Inducers of TGFs- β
secretion can be induced by a no. of
different stimuli including: steroids,
retinoids, EGF , NGF , activators of
lymphocytes, vitamin D3 , and IL1 .
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Inhibitors of TGFs- β
The synthesis of TGF-beta can be
inhibited by: EGF , FGF , dexamethasone,
calcium, retinoids and follicle stimulating
hormone .
TGF-beta also influences the expression
of its own gene and this may be important
in Wound healing .
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TGFs- β
With the extracellular matrix as a complex
with betaglycan and decorin.
Stored in a biologically inactive form.
The exact molecular mechanisms
underlying its release from these
reservoirs is unknown.
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PROTEIN CHARACTERISTICS
Five isoforms
TGF-beta-1 , TGF-beta-2 , TGF-beta-3
, TGF-beta-4 , TGF-beta-5 .
They are not related to TGF-alpha .
Their amino acid sequences display
homologies on the order of 70-80 percent.
TGF-beta-1 - prevalent form.
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PROTEIN CHARACTERISTICS
The biologically active forms of all
isoforms are disulfide-linked homodimers.
Sometimes hetrodimers.
The isoforms of TGF-beta arise by
proteolytic cleavage of longer precursors.
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PROTEIN CHARACTERISTICS
Isoforms isolated from different species
are evolutionarily closely conserved and
have sequence identities on the order of
98 percent.
Mature human, porcine, simian and bovine
TGF-beta-1 are identical and differ from
murine TGF-beta-1 in a single amino acid
position.
Carboxy terminal end and Amino terminal
end of precursor.
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Biosynthesis and processing of mature
TGF-beta (dark blue)
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L - TGF
Almost all forms of TGF-β are released as
biologically inactive forms that are known
also as L-TGF ( latent TGF ).
Latent forms are complexes of TGF-β, an
aminoterminal portion of the TGF-beta
precursor, designatedTGF-LAP ( TGF-
latency associated peptide ), and a
specific binding protein, known as LT-BP (
latent TGF binding protein).
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L-TGF
L-TGF - localized at the cell surface by
binding to the mannose-6-phosphate/IGF-
2 receptor.
Biologically active TGF-beta results after
dissociation from the LAP complex.
The nature of the activation mechanism of
L-TGF in vivo is unclear.
Direct cell-to-cell
contacts, proteases, specifically
plasmin, transglutaminases
Thrombospondin .www.indiandentalacademy.com
Alpha2M/TGF-beta complexes
The main fraction of the factor in the
serum is covalently attached to one of the
acute phase proteins , Alpha-2-
Macroglobulin (Alpha2M).
Alpha2M/TGF-beta complexes are
believed to represent TGF-beta molecules
released by platelets after tissue injuries
and destined to degradation.
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Mutant TGF- β
Mutant forms of TGF- β have been
created.
They form wild-type/mutant heterodimers
deficient in assembly or processing.
Such mutants behave as dominant
negative mutants and are useful in
investigation of the role of TGF- β in
normal and pathological conditions.
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GENE STRUCTURE
The different isoforms of TGF-β are
encoded by different genes.
All genes have a length of more than 100
kb and contain seven exons.
The genes map to different chromosomes.
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GENE STRUCTURE
The TGF-beta-1 gene maps to human chromosome
19q13.
The TGF-beta-2 gene maps to human chromosome
1q41.
The TGF-beta-3 gene maps to human chromosome
14q24.
These genes are expressed differentially.
The TGF-beta-3 gene is expressed strongly in
embryonic heart and lung tissues but only marginally
in liver, spleen, and kidney tissues. TGF-beta-1 is
expressed strongly in spleen tissues.
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RELATED FACTORS
TGF-beta is the prototype of a protein
family known as the TGF-beta
superfamily.
This family includes Inhibins , Activin A ,
MIS (Müllerian inhibiting substance ), BMP
(bone morphogenetic proteins ), dpp
(decapentaplegic ) and Vg-1 .
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RECEPTORS
An entire family of glycoprotein receptors
for TGF-beta has emerged.
Some of these proteins do not bind
TGFbeta-related factors belonging to the
TGF-beta family.
Type-1 receptors (hematopoietic
progenitor cells) and type-2 receptors.
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RECEPTOR AFFINITY
Individual TGF-b isotypes - varying
affinities.
E.g., TGF-beta-1 binds approximately
tenfold better than TGF-beta-2.
Expression of the TGF-beta receptors is
decreased by EGF (Receptor
transmodulation).
In endothelial cells the expression of the
TGF-beta receptor is decreased by bFGF .
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RECEPTORS
Almost all types of cells express, type-3
receptor.
This receptor type is not expressed in
primary epithelial, endothelial, and
lymphoid cells .
The type-3 receptor is a proteoglycan
(Betaglycan), binds TGF-beta-1 and TGF-
beta-2 equally well.
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BIOLOGICAL ACTIVITIES
Not species-specific.
TGF-beta-2 is the only variant that does
not inhibit the growth of endothelial cells.
Most pronounced differences in the TGF-
beta isoforms is their spatially and
temporally distinct expression of both the
mRNAs and proteins in developing
tissues, regenerating tissues, and in
pathologic responses.
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BIOLOGICAL ACTIVITIES
TGF-beta is the most potent known growth
inhibitor for normal and transformed
epithelial cells, endothelial cells,
fibroblasts, neuronal cells, lymphoid cells
and other hematopoietic cell types (CFU-S
), hepatocytes, and keratinocytes.
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BIOLOGICAL ACTIVITIES
Inhibits the proliferation of T-lymphocytes.
Inhibits the growth of natural killer cells in
vivo.
Deactivates macrophages.
Blocks the antitumor activity mediated in
vivo by IL2 and transferred lymphokine-
activated or tumor infiltrating lymphocytes .
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BIOLOGICAL ACTIVITIES
Inhibits the growth of immature
hematopoietic progenitor cells .
In particular growth of CFU-GEMM .
Inhibits megakaryocytopoiesis.
Antagonizes the biological activities of
EGF , PDGF , aFGF and bFGF .
Latent form of TGF-beta is a strong
inhibitor of erythroleukemia cell lines.
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BIOLOGICAL ACTIVITIES
The extent of growth inhibition induced by
TGF-beta depends on the cell type, on the
concentration of TGF-beta, and on the
presence of other factors.
The growth-inhibitory activities of TGF-
beta can be abolished by HGF
(hepatocyte growth factor ).
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BIOLOGICAL ACTIVITIES
At concentrations of 1-2 fg/cell - growth inhibition
for smooth muscle cells, fibroblasts, and
chondrocytes.
At higher concentrations - stimulation.
This bimodal activity is mediated in part by
PDGF .
Low concentrations of TGF-beta - synthesis and
secretion of PDGF.
Higher concentrations – lower expression of the
PDGF receptors and hence diminish the
biological effects of PDGF .
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BIOLOGICAL ACTIVITIES
Overproduction of TGF-beta-1 by tumor
cells - neovascularization and may help
promote tumor development in vivo.
TGF-beta is an autocrine growth
modulator for malignant gliomas.
It stimulates the growth of fibroblasts and
osteoblasts in vivo and in vitro.
TGF-beta induces the synthesis of bone
matrix proteins in osteoblasts.
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BIOLOGICAL ACTIVITIES
Factors that promote bone resorption (IL1
, vitamin D3 , parathormone) induce the
synthesis of TGF-beta in bone cells.
While calcitonin, an inhibitor of bone
resorption, reduces the synthesis of TGF-
beta.
It suppresses the expression of class II
MHC antigens .
Microglial cells.
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BIOLOGICAL ACTIVITIES
TGF-beta stimulates the synthesis of the
major matrix proteins including collagen,
proteoglycans , glycosaminoglycans,
fibronectin , integrins, Thrombospondin ,
osteonectin, osteopontin .
It inhibits degradation mainly by inhibiting
the synthesis of neutral metalloproteinases
and by increasing the synthesis of
proteinase inhibitors.
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BIOLOGICAL ACTIVITIES
Involved in metastatic processes.
It is responsible for the transformation of
epithelial cells into mesenchymal cells.
Suppressive effects on the immune
system .
TGF-beta-1 is the most potent known
chemoattractant for neutrophils .
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CLINICAL USE AND
SIGNIFICANCE
It may be a potent regulator of Wound
healing and of bone fracture healing.
Local application of TGF-beta has been
shown to accelerate wound repair.
In combination with bone morphogenetic
protein-2 it causes development of
ossification of the posterior longitudinal
ligament of the cervical spine.
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CLINICAL USE AND
SIGNIFICANCE
The factor may be helpful in the treatment
of traumatic tissue injuries.
Treatment of osteoporosis.
Reverses age- or glucocorticoid-impaired
Wound healing even if given 24 hours
before wounding.
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Bone morphogenetic protein (BMP)
Responsible for osteoinductive activity in
bone matrix.
Non-collagenous.
Water soluble.
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Bone morphogenetic protein (BMP)
The cellular and molecular events
governing bone formation in the embryo,
healing of a fractured bone, and induced
bone fusion follow a similar pattern.
Bone is unique of all the tissues.
When injured, it heals by formation of new
bone.
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BMP-Introduction
The molecular and cellular processes that
lead to the development of the skeletal
structures within the embryo are very
similar to the cascades that occur in the
healing process in an injured bone.
Thus, there is a common theme in the
development of bone from primitive
mesenchymal tissues to a well-structured,
well-organized mature bone.
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BMP-Introduction
The ongoing remodeling process in an
adult organism, which is exposed to
external physical and hormonal
influences, is also modulated through a
similar molecular mechanism.
Intracartilaginous process.
Intramembranous process.
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BMP-Introduction
Postfracture healing - intracartilaginous
ossification process.
Very high concentration of BMP -
intramembranous route may be taken.
It is unclear what factor(s) direct(s) one
process as opposed to the other in the
embryonic phase or during fracture
healing.
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Stages of bone healing and remodeling
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GF and cytokines involved in
generation of new bone
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History
Senn(1889)-Decalcified ox bone promotes
healing of osteomyelitic defects.
Lexer(1908)-Necrotic bone tissue released
stimulating factors that affect osteoblasts.
Polettini(1922)-Substance released from
graft tissue resulted in differentiation of
fibroblasts into bone and cartilage forming
cells.
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History
Leriche(1928)-Ca materials contained in
the graft tissue were the agents inducing
new bone formation.
Levander(1934)-crude alcohol extracts of
bone induce bone formation in muscle.
Sharrard and Collin(1961)-EDTA
decalcified allograft induced spinal fusion
in children.
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History
Urist(1965)-acid-decalcified bone induced
ectopic bone in rat model. He coined the
term "bone morphogenetic protein" or
"osteogenic protein" .
Reddi and Sampath(1983)-crude but
reproducible bioassay for BMP; bone
matrix when dissociated from BMP
ineffective in bone induction; reconstituted
matrix effective.
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History
Johnson(1992)-first clinical study; purified
human BMP successful clinically.
Creative biomolecules and genetic
institute(1990s)-simultaneous gene sequencing
for various BMP’s and related patent dispute.
Stryker Corp., Medtronic Sofamor Danek(2002)-
FDA approval of OP-1 (BMP-7) for long bone
defects and BMP-2 in a collagen carrier within a
cage for anterior lumbar interbody fusions.
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Classification of BMP
Bone morphogenic proteins are members of
TGF superfamily.
The BMP subfamily comprises more than 10
proteins, and newer ones are being discovered.
Several structural homologies between BMPs
and TGF growth factors.
The amino acid sequence of BMPs is
considered to be as old as 600 million years.
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Classification
Because of this conservation, human
recombinant BMPs are highly effective in
lower life forms, including fruit flies.
BMPs are synthesized as precursor
proteins.
The mature portion of the protein is
located at the carboxy terminal of the
precursor molecule.
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BMP
It is the only morphogen of all known growth
factors that has the ability to transform
connective tissue cell into osteoprogenitor cells.
Thus, it is not only a mitogen but can be a
morphogen as well.
All other growth factors such as TGF, insulin-like
growth factor, fibroblast growth factor, PDGF,
and vascular endothelial growth factor all induce
multiplication of cells but do not transform one
cell type into the other.
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Signaling Mechanism of BMP
BMP receptors - Type I and Type II
serine/threonine kinase proteins.
The binding of the ligand to the Types I
and II serine/threonine kinase
transmembrane receptors results in the
activation of the signaling cascade.
Type II receptor kinase phosphorylates the
Type I receptor.
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Signaling Mechanism of BMP
Type I receptor phosphorylates the
intracytoplasmic signaling molecules
Smads 1, 5, and 8.
Smads 1, 5, and 8 bind to Smad 4.
Translocate into the cell nucleus.
Activation of transcriptional factors for the
early BMP response genes.
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Dosage
Normal bone contains approximately
0.002 mg of BMP per kilogram of
pulverized bone.
At a fracture site, presumably the BMP is
released at a higher concentration.
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Dosage
The concentration required for ideal
induced bone bridging in osseous defects
depends on several factors.
- state of the organism in the evolutionary
scale.
- type of defect.
Bone induced under the influence of BMP
matures faster than natural healing of the
bone.
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Other uses
Brain protective agent.
kidneys are their primary source in the
human adult. In chronic renal disease
levels of BMP are lower. systemic
administration of BMP may restore some
of the renal functions.
Local application for dialysis patient in
osteodystrophy.
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BMP
Named because of their osteoinductive
ability.
Role in embryonic and post embryonic
development.
Signaling molecules in no. of tissues.
Implicated in mesodermal
patterning, neurogenesis and
organogenesis.
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BMP
BMP signaling pathways ↔ other growth
factors ↔ hormonal signaling pathways.
Cross talk between them must be
evaluated to avoid side effects of BMP
based therapies.
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BMP
Mutations perturbing functions of BMP
genes:
BMP-5 gene mutation – short ear –
abnormal growth & patterning of skeletal
structures and diminished repair of bone
fracture.
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BMP
GDF-5 gene mutation – brachypod
phenotype in mice & in autosomal
recessive syndromes Hunter – Thompson
chondrodysplasia in humans – shortening
of appendicular skeleton and loss or
abnormal development of some joints.
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BMP
BMP-2 & BMP-4 knock out mice die early
in embryonic development, long before
development of skeleton, because of
defects in gastrulation.
BMP-7 knock out – eye and kidney
defects, only mild skeletal defects.
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BMP
Several extracellular proteins regulate
activities of BMP.
Noggin (BMP-4 & BMP-2)
Follistatin (BMP-4 & BMP-7)
Protein chordin
Astacin family of metalloproteases –
cleaves chordin.
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Platelet-Derived Growth Factor
(PDGF)
ALTERNATIVE NAMES
MDGF ( monocyte-derived growth factor )
ODGF ( osteosarcoma-derived growth factor )
SOURCES
megakaryocytes
stored in the alpha granules of platelets(PDGF-
BB/AB)
released after cell activation of platelets for
example by thrombin .
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Sources
Unstimulated cells of osteoblastic lineage
– PDGF-AA.
Other cells - macrophages, endothelial
cells, fibroblasts, glial cells, astrocytes,
myoblasts, smooth muscle cells, and a
number of tumor cell lines.
Synthesis of PDGF can be induced by IL1
, IL6 , TNF-alpha , TGF-beta and EGF .
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Platelet-Derived Growth Factor
(PDGF)
PDGF is composed of two distinct
polypeptide chains, A and B, that form
homodimers (AA or BB) or heterodimers
(AB).
3 isoforms.
PDGF receptors have intrinsic tyrosine
kinase activity.
www.indiandentalacademy.com
PDGF
PDGF-BB – binds to receptor – activates
extracellular signal regulated kinase 1&2 –
cellular proliferation by accelerating cell recycle
& inducing quiescent cells into the proliferation
portion of the cell cycle.
This effect is mediated by protein kinase B, a
serine-threonine protein kinase.
TGFb1 – inhibits receptor autophosphorylation –
neutralizes mitogenic effect of PDGF.
www.indiandentalacademy.com
PDGF
Proliferative responses to PDGF action
are exerted on many mesenchymal cell
types.
Two related receptors, called PDGFR
alpha or PDGFR beta.
PDGF is not released into the circulation.
The biological half-life is less than two
minutes after intravenous administration.
www.indiandentalacademy.com
PDGF
In the adult organism PDGF is involved in
Wound healing processes.
The dimeric form of PDGF is mainly
mitogenic for cells of mesenchymal origin
while monomeric forms of PDGF are
mainly chemotactic.
Disruption of PDGF signaling – perinatal
lethality > 50%.
www.indiandentalacademy.com
PDGF
At low concentrations PDGF is a
chemoattractant for fibroblasts.
PDGF is also chemotactic and activating
for monocytes and neutrophils.
PDGF (alone and in combination) may be
useful in promoting bone formation.
Promotes fracture healing.
Doesn’t provides entire osteogenic
properties itself.
www.indiandentalacademy.com
PDGF
Osteoblasts can specifically bind and
proliferate in response to PDGF.
Enhanced proliferation of both osteoblasts
and osteoclasts.
In tissue culture, PDGF alone has not yet
been proved to be osteoinductive in vivo.
In osteosarcoma – positive feedback loop.
Platelet gel.
www.indiandentalacademy.com
PDGF
PDGF is chemotactic for both alkaline
phosphatase positive and negative cells.
It may so contribute to recruitment of bone
cells during remodeling and repair.
Used in implants and periodontal
therapies.
With or without IGF-I.
www.indiandentalacademy.com
Fibroblast Growth Factors
(FGFs)
19 distinct members
FGF1 (acidic-FGF, aFGF) and FGF2
(basic-FGF, bFGF).
Studies of human disorders & gene knock-
out studies in mice show the prominent
role for FGFs is in the development of the
skeletal system in mammals.
www.indiandentalacademy.com
aFGF
SOURCE
Best sources of aFGF is brain tissue.
The mechanism underlying the release of
aFGF is unknown.
www.indiandentalacademy.com
bFGF
SOURCES
Almost all tissues of mesodermal and
neuroectodermal origin.
Also in tumors derived from these tissues.
Endothelial cells.
www.indiandentalacademy.com
FGF
potent inducers of mesodermal
differentiation in early embryos.
Specific cell-surface receptors.
4 distinct receptor types identified as
FGFR1 - FGFR4.
Receptors has intrinsic tyrosine kinase
activity .
autophosphorylation of the receptor is the
immediate response to FGF binding.
www.indiandentalacademy.com
FGF
FGFs also bind to cell-surface heparan-sulfated
proteoglycans with low affinity
The FGF receptors are widely expressed in
developing bone.
Mutations in the FGFR genes-autosomal
dominant disorders of bone growth e.g.
achondroplasia(FGFR3).
FGFR3 is predominantly expressed in quiescent
chondrocytes & it restricts chondrocyte
proliferation and differentiation.
www.indiandentalacademy.com
FGF
bFGF stimulates the growth of
fibroblasts, myoblasts, osteoblasts, endoth
elial cells, chondrocytes, and many other
cell types.
bFGF is not only a mitogen for
chondrocytes but also inhibits their
terminal differentiation.
www.indiandentalacademy.com
FGF
Animals experiments with bFGF -
promotes endosteal, but not periosteal,
bone formation.
bFGF may thus be a potential agent for
treatment of osteoporosis which may
increase bone mass without causing
outward deformation of the skeletal bones.
www.indiandentalacademy.com
FGF
Craniosynostosis syndromes have been
shown to result from mutations in
FGFR1, FGFR2 and FGFR3.
Sometimes the same mutation can cause
two or more different craniosynostosis
syndromes.
www.indiandentalacademy.com
Affected
Receptor
Syndrome Phenotypes
FGFR1 Pfeiffer broad first digits,
hypertelorism
FGFR2 Apert mid-face hypoplasia,
fusion of digits
FGFR2 Beare-
Stevenson
mid-face hypoplasia,
corrugated skin
www.indiandentalacademy.com
Affected
Receptor
Syndrome Phenotypes
FGFR2 Crouzon mid-face hypoplasia
FGFR2 Jackson-
Weiss
mid-face hypoplasia,
foot anamolies
FGFR2 Pfeiffer same as for FGFR1
mutations
www.indiandentalacademy.com
Affected
Receptor
Syndrome Phenotypes
FGFR3 Crouzon mid-face hypoplasia,
acanthosis nigricans
FGFR3 Non-syndromatic
craniosynostosis
digit defects, hearing
loss.
www.indiandentalacademy.com
Insulin-Like Growth Factor
IGFs are single chain peptides.
2 isoforms (IGF-I and IGF-II).
40-50% homology with insulin. Still all 3
have unique binding site to their receptors.
IGF also has general activity (metabolic &
growth promoting) in many tissue types.
www.indiandentalacademy.com
IGF-I
SOURCE
Mainly liver.
IGF – responsible for fetal and
postnatal growth and development in
general.
www.indiandentalacademy.com
IGF-I
IGF-I receptor gene – deleted mice died at birth
putatively due to poor muscular development.
IGF-I: pre + postnatal development.
IGF-II: prenatal stages only.
IGF-I/ IGF-II ratio increases with age in many
tissues.
Role in skeletal development and skeletal mass
maintenance and development of teeth.
www.indiandentalacademy.com
Insulin-Like Growth Factor-I
(IGF-I)
Called somatomedin C(considered as
circulating mediator of growth
hormone).
Primary protein involved in responses of
cells to growth hormone (GH)
IGF-I is produced in response to GH and
then induces subsequent cellular activities,
particularly on bone growth.
www.indiandentalacademy.com
IGF-I
IGF-I has autocrine and paracrine activities in
addition to endocrine activities on bone.
Family of transmembrane IGF-I(tyrosine
kinase), IGF-II(mannose-6-phosphate receptor)
& insulin receptor.
Receptor has intrinsic tyrosine kinase activity.
Plays role in general growth and maintenance of
body skeleton.
www.indiandentalacademy.com
Insulin-Like Growth Factor-II
(IGF-II)
Exclusively expressed in embryonic and
neonatal tissues.
Following birth, the level of detectable
IGF-II protein falls significantly.
The IGF-II receptor is identical to the
mannose-6-phosphate receptor.
www.indiandentalacademy.com
IGF
Osteoblast aging is associated with
impaired production of the stimulatory
components of the IGF-system, that may
contribute to age-related decline in
osteoblast functions.
Of all IFG binding proteins, IGFBP-5 is
abundant in bone matrix.
www.indiandentalacademy.com
IGF
IGF-I & II are potent survival factors for
fibroblasts, hematopoetic cells, cardiac
muscle cells & pancreatic beta cell.
IGF-I has anti apoptotic activity in these
cell types and in certain tumors.
Autocrine loop – tumor promoting effect.
IGF-I has chemotactic effect on
osteoblasts in a dose dependent manner.
IGF-II effects only at lowest conc.
www.indiandentalacademy.com
IGF
It promotes expression of bone specific
protein e.g. bone sialoprotein, and
osteopontin.
In vivo, systemic application of IGF-I –
rapidly activated bone turnover – increase
in serum osteocalcin, increased collagen
marker of bone formation, and an
increased urinary ratio of Ca/creatinine.
www.indiandentalacademy.com
IGF
In inflammatory tissue (e.g. fracture repair)
– IL1 increases IGF-I production.
IGF-I activity can be suppressed by
NSAIDs e.g. indomethacin.
www.indiandentalacademy.com
www.indiandentalacademy.com
Thank you
For more details please visit
www.indiandentalacademy.com

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Growth factors

  • 1. www.indiandentalacademy.com INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com
  • 2. Growth factors This collective term originally referred to substances that promote cell growth. www.indiandentalacademy.com
  • 3. Growth factors Introduction  Growth factors are proteins that bind to receptors on the cell surface, with the primary result of activating cellular proliferation and/or differentiation. Many growth factors are quite versatile, stimulating cellular division in numerous different cell types; while others are specific to a particular cell-type. www.indiandentalacademy.com
  • 4. Growth factors comprises of molecules that function as growth stimulators but also as growth inhibitors (sometimes referred to as negative growth factors ), factors that stimulate cell migration or as chemotactic agents or inhibit cell migration or invasion of tumor cells, factors that modulate differentiated functions of cells, factors involved in apoptosis , factors involved in angiogenesis , or factors that promote survival of cells without influencing growth and differentiation. www.indiandentalacademy.com
  • 5. Growth factors are polypeptides that belongs to a number of families. Cell surface receptors capture them. Upon capturing receptor interacts with membrane and cytoplasmic bound components to bring about alteration in gene expression of a cell. Thus a growth factor is an inductive agent. www.indiandentalacademy.com
  • 6. A growth factor produced by one cell and acting on another is described as paracrine regulation. Whereas the process of a cell that recaptures its own product is known as autocrine regulation. Few growth factors act during embryogenesis. www.indiandentalacademy.com
  • 7. By contrast, the retinoic acid family freely enters a cell to complex with intracellular receptors, which eventually affect gene expression. Both growth factors and the retinoids regulate the expression of the homeobox genes, which, in turn, regulate the expression of growth factors(role of regulatory loops in development). www.indiandentalacademy.com
  • 8. Epidermal Growth Factor (EGF) Platelet-Derived Growth Factor (PDGF) Fibroblast Growth Factors (FGFs) Transforming Growth Factors-b (TGFs-b) Transforming Growth Factor-a (TGF-a) Erythropoietin (Epo) Insulin-Like Growth Factor-I (IGF-I) Insulin-Like Growth Factor-II (IGF-II) Interleukin-1 (IL-1) Interleukin-2 (IL-2) Interleukin-6 (IL-6) Interleukin-8 (IL-8) Tumor Necrosis Factor-a (TNF-a) Tumor Necrosis Factor-b (TNF-b) Interferon-g (INF-g) Colony Stimulating Factors (CSFs)www.indiandentalacademy.com
  • 9. Osteoblasts synthesize and regulate the deposition and mineralization of the extracellular matrix of bone. Systemic and locally active hormones, growth factors, ions, lipid metabolites and steroids are regulators of osteoblastic activity and/or differentiation. www.indiandentalacademy.com
  • 10. Members of the transforming growth factor beta (TGF-b) family, particularly TGF-b and the bone morphogenetic proteins (BMPs) are important to bone homeostasis. These factors modulate osteoblast proliferation and differentiation . www.indiandentalacademy.com
  • 11. Matrixmetalloproteinases Extracellular matrix degrading metallo enzymes are known collectively as Matrixmetalloproteinases(MMPs). Tissue inhibitors of metalloproteinases(TIMPs). Depend on Zn²+ and Ca²+ for activity. www.indiandentalacademy.com
  • 12. Matrixmetalloproteinases Rather than being primarily involved in matrix degradation MMPs have equally or more important roles as efficient processing enzymes of many bioactive mediators such as cytokines, chemokines, growth factors, their receptors and specific matrix protein anchors for these molecules. www.indiandentalacademy.com
  • 13. Cytokines Includes a family of molecules which are small proteins with either paracrine or endocrine functions which are involved in local inflammation or immunoregulation. Within this definition growth factors could be included. www.indiandentalacademy.com
  • 14. Cytokines. Cytokines are a unique family of growth factors. Secreted primarily from leukocytes, cytokines stimulate both the humoral and cellular immune responses, as well as the activation of phagocytic cells. Lymphokines Monokines. www.indiandentalacademy.com
  • 15. Cytokines A large family of cytokines are produced by various cells of the body. Many of the lymphokines are also known as interleukins (ILs), since they are not only secreted by leukocytes but also able to affect the cellular responses of leukocytes. www.indiandentalacademy.com
  • 16. Cytokines Specifically, interleukins are growth factors targeted to cells of hematopoietic origin. The list of identified interleukins grows continuously with the total number of individual activities now at 22. www.indiandentalacademy.com
  • 18. Factor Principal Source Primary Activity Comments PDGF platelets, endothelial cells, placenta promotes proliferation of connective tissue, glial and smooth muscle cells two different protein chains form 3 distinct dimer forms; AA, AB and BB www.indiandentalacademy.com
  • 19. Factor Principal Source Primary Activity EGF submaxillary gland, Brunners gland promotes proliferation of mesenchymal, glial and epithelial cells www.indiandentalacademy.com
  • 20. Factor Principal Source Primary Activity Comments TGF-a common in transformed cells may be important for normal wound healing related to EGF www.indiandentalacademy.com
  • 21. Factor Principal Source Primary Activity Comments FGF wide range of cells; protein is associated with the ECM promotes proliferation of many cells; inhibits some stem cells; induces mesoderm to form in early embryos at least 19 family members, 4 distinct receptors www.indiandentalacademy.com
  • 22. Factor Principal Source Primary Activity Comments NGF promotes neurite (axites & dendrites) outgrowth and neural cell survival several related proteins first identified as proto- oncogenes; trkA (trackA), trkB, trkC www.indiandentalacademy.com
  • 23. Factor Principal Source Primary Activity Comments Erythropoietin kidney promotes proliferation and differentiation of erythrocytes www.indiandentalacademy.com
  • 24. Factor Principal Source Primary Activity Comments TGF-b activated TH1 cells (T-helper) and natural killer (NK) cells anti-inflammatory (suppresses cytokine production and class II MHC expression), promotes wound healing, inhibits macrophage and lymphocyte proliferation at least 100 different family members www.indiandentalacademy.com
  • 25. Factor Principal Source Primary Activity Comments IGF-I primarily liver promotes proliferation of many cell types related to IGF-II and proinsulin, also called Somatomedin C www.indiandentalacademy.com
  • 26. Factor Principal Source Primary Activity Comments IGF-II variety of cells promotes proliferation of many cell types primarily of fetal origin related to IGF-I and proinsulin www.indiandentalacademy.com
  • 27. Factors modulating growth, chemotactic behavior and/or functional activities of smooth muscle cells include Activin A , Adrenomedullin , aFGF, ANF , Angiogenin , Angiotensin-2 , Betacellulin , bFGF , CLAF , ECDGF (endothelial cell-derived growth factor ), ET (Endothelins ), Factor X , Factor Xa , HB-EGF , Heart derived inhibitor of vascular cell proliferation , IFN-gamma , IL1 , LDGF (Leiomyoma-derived growth factor ), MDGF (macrophage-derived growth factor , monocyte-derived growth factor ), Oncostatin M , PD-ECGF , PDGF , Prolactin , Protein S , SDGF (smooth muscle cell-derived growth factor ), SDMF (Smooth muscle cell-derived migration factor ), Tachykinins , TGF-beta , Thrombospondin . www.indiandentalacademy.com
  • 28. Factors modulating growth, chemotactic behavior and/or functional activities of vascular endothelial cells include AcSDKP , aFGF , ANF , Angiogenin , angiomodulin , Angiotropin , AtT20-ECGF , B61 , bFGF , bFGF inducing activity , CAM-RF , ChDI , CLAF , ECGF , ECI , EDMF , EGF , EMAP-2 , Neurothelin , Endostatin , Endothelial cell growth inhibitor , Endothelial cell-viability maintaining factor , Epo , FGF-5 , IGF-2 , HBNF , HGF , HUAF , IFN-gamma , IL1 , K-FGF , LIF , MD-ECI , MECIF , NPY , Oncostatin M , PD-ECGF , PDGF , PF4 , PlGF , Prolactin , TNF-alpha , TNF-beta , Transferrin , VEGF . www.indiandentalacademy.com
  • 29. A mind once stretched by a new idea, never regains its original dimensions. www.indiandentalacademy.com
  • 30. Bone – enormous reservoir 1.PDGF 2.IGF – I IGF – II 3.BMP (PART OF TGF-β FAMILY) Binding proteins to keep these factors within bone itself. www.indiandentalacademy.com
  • 31. Transforming Growth Factors-β (TGFs- β) ALTERNATIVE NAMES CIF-B ( cartilage inducing factor B =TGF- beta-2 ) DIF ( differentiation-inhibiting factor ) DSF ( decidual suppressor factor =TGF- beta-2 ) EIF ( Epstein-Barr virus inducing factor ) EGI (epithelial growth inhibitor ) www.indiandentalacademy.com
  • 32. MDGF ( milk-derived growth factor ) MGF ( milk growth factor ) MGF-a ( milk growth factor =TGF-beta-2 ) MGF-b ( milk growth factor =TGF-beta-1 ) TCGF ( transformed cell growth factor ) TGI ( tissue-derived growth inhibitor ) TIF-1 ( tumor inducing factor-1 ). www.indiandentalacademy.com
  • 33. Sources of TGFs- β Found predominantly in spleen and bone tissues. Platelets - milligrams of TGF-beta/ kg. other tissues - microgram TGF/kg. Human milk – MGF. Synthesized also by - macrophages(TGF-beta-1 ), lymphocytes(TGF-beta-1 ), endothelial cells(TGF- beta-1 ), keratinocytes(TGF-beta-2 ), granulosa cells(TGF-beta-2 ), chondrocytes (TGF-beta-1 ), glioblastoma cells(TGF-beta-2 ), leukemia cells(TGF-beta-1 ). www.indiandentalacademy.com
  • 34. Inducers of TGFs- β secretion can be induced by a no. of different stimuli including: steroids, retinoids, EGF , NGF , activators of lymphocytes, vitamin D3 , and IL1 . www.indiandentalacademy.com
  • 35. Inhibitors of TGFs- β The synthesis of TGF-beta can be inhibited by: EGF , FGF , dexamethasone, calcium, retinoids and follicle stimulating hormone . TGF-beta also influences the expression of its own gene and this may be important in Wound healing . www.indiandentalacademy.com
  • 36. TGFs- β With the extracellular matrix as a complex with betaglycan and decorin. Stored in a biologically inactive form. The exact molecular mechanisms underlying its release from these reservoirs is unknown. www.indiandentalacademy.com
  • 37. PROTEIN CHARACTERISTICS Five isoforms TGF-beta-1 , TGF-beta-2 , TGF-beta-3 , TGF-beta-4 , TGF-beta-5 . They are not related to TGF-alpha . Their amino acid sequences display homologies on the order of 70-80 percent. TGF-beta-1 - prevalent form. www.indiandentalacademy.com
  • 38. PROTEIN CHARACTERISTICS The biologically active forms of all isoforms are disulfide-linked homodimers. Sometimes hetrodimers. The isoforms of TGF-beta arise by proteolytic cleavage of longer precursors. www.indiandentalacademy.com
  • 39. PROTEIN CHARACTERISTICS Isoforms isolated from different species are evolutionarily closely conserved and have sequence identities on the order of 98 percent. Mature human, porcine, simian and bovine TGF-beta-1 are identical and differ from murine TGF-beta-1 in a single amino acid position. Carboxy terminal end and Amino terminal end of precursor. www.indiandentalacademy.com
  • 40. Biosynthesis and processing of mature TGF-beta (dark blue) www.indiandentalacademy.com
  • 41. L - TGF Almost all forms of TGF-β are released as biologically inactive forms that are known also as L-TGF ( latent TGF ). Latent forms are complexes of TGF-β, an aminoterminal portion of the TGF-beta precursor, designatedTGF-LAP ( TGF- latency associated peptide ), and a specific binding protein, known as LT-BP ( latent TGF binding protein). www.indiandentalacademy.com
  • 42. L-TGF L-TGF - localized at the cell surface by binding to the mannose-6-phosphate/IGF- 2 receptor. Biologically active TGF-beta results after dissociation from the LAP complex. The nature of the activation mechanism of L-TGF in vivo is unclear. Direct cell-to-cell contacts, proteases, specifically plasmin, transglutaminases Thrombospondin .www.indiandentalacademy.com
  • 43. Alpha2M/TGF-beta complexes The main fraction of the factor in the serum is covalently attached to one of the acute phase proteins , Alpha-2- Macroglobulin (Alpha2M). Alpha2M/TGF-beta complexes are believed to represent TGF-beta molecules released by platelets after tissue injuries and destined to degradation. www.indiandentalacademy.com
  • 44. Mutant TGF- β Mutant forms of TGF- β have been created. They form wild-type/mutant heterodimers deficient in assembly or processing. Such mutants behave as dominant negative mutants and are useful in investigation of the role of TGF- β in normal and pathological conditions. www.indiandentalacademy.com
  • 45. GENE STRUCTURE The different isoforms of TGF-β are encoded by different genes. All genes have a length of more than 100 kb and contain seven exons. The genes map to different chromosomes. www.indiandentalacademy.com
  • 46. GENE STRUCTURE The TGF-beta-1 gene maps to human chromosome 19q13. The TGF-beta-2 gene maps to human chromosome 1q41. The TGF-beta-3 gene maps to human chromosome 14q24. These genes are expressed differentially. The TGF-beta-3 gene is expressed strongly in embryonic heart and lung tissues but only marginally in liver, spleen, and kidney tissues. TGF-beta-1 is expressed strongly in spleen tissues. www.indiandentalacademy.com
  • 47. RELATED FACTORS TGF-beta is the prototype of a protein family known as the TGF-beta superfamily. This family includes Inhibins , Activin A , MIS (Müllerian inhibiting substance ), BMP (bone morphogenetic proteins ), dpp (decapentaplegic ) and Vg-1 . www.indiandentalacademy.com
  • 48. RECEPTORS An entire family of glycoprotein receptors for TGF-beta has emerged. Some of these proteins do not bind TGFbeta-related factors belonging to the TGF-beta family. Type-1 receptors (hematopoietic progenitor cells) and type-2 receptors. www.indiandentalacademy.com
  • 49. RECEPTOR AFFINITY Individual TGF-b isotypes - varying affinities. E.g., TGF-beta-1 binds approximately tenfold better than TGF-beta-2. Expression of the TGF-beta receptors is decreased by EGF (Receptor transmodulation). In endothelial cells the expression of the TGF-beta receptor is decreased by bFGF . www.indiandentalacademy.com
  • 50. RECEPTORS Almost all types of cells express, type-3 receptor. This receptor type is not expressed in primary epithelial, endothelial, and lymphoid cells . The type-3 receptor is a proteoglycan (Betaglycan), binds TGF-beta-1 and TGF- beta-2 equally well. www.indiandentalacademy.com
  • 51. BIOLOGICAL ACTIVITIES Not species-specific. TGF-beta-2 is the only variant that does not inhibit the growth of endothelial cells. Most pronounced differences in the TGF- beta isoforms is their spatially and temporally distinct expression of both the mRNAs and proteins in developing tissues, regenerating tissues, and in pathologic responses. www.indiandentalacademy.com
  • 52. BIOLOGICAL ACTIVITIES TGF-beta is the most potent known growth inhibitor for normal and transformed epithelial cells, endothelial cells, fibroblasts, neuronal cells, lymphoid cells and other hematopoietic cell types (CFU-S ), hepatocytes, and keratinocytes. www.indiandentalacademy.com
  • 53. BIOLOGICAL ACTIVITIES Inhibits the proliferation of T-lymphocytes. Inhibits the growth of natural killer cells in vivo. Deactivates macrophages. Blocks the antitumor activity mediated in vivo by IL2 and transferred lymphokine- activated or tumor infiltrating lymphocytes . www.indiandentalacademy.com
  • 54. BIOLOGICAL ACTIVITIES Inhibits the growth of immature hematopoietic progenitor cells . In particular growth of CFU-GEMM . Inhibits megakaryocytopoiesis. Antagonizes the biological activities of EGF , PDGF , aFGF and bFGF . Latent form of TGF-beta is a strong inhibitor of erythroleukemia cell lines. www.indiandentalacademy.com
  • 55. BIOLOGICAL ACTIVITIES The extent of growth inhibition induced by TGF-beta depends on the cell type, on the concentration of TGF-beta, and on the presence of other factors. The growth-inhibitory activities of TGF- beta can be abolished by HGF (hepatocyte growth factor ). www.indiandentalacademy.com
  • 56. BIOLOGICAL ACTIVITIES At concentrations of 1-2 fg/cell - growth inhibition for smooth muscle cells, fibroblasts, and chondrocytes. At higher concentrations - stimulation. This bimodal activity is mediated in part by PDGF . Low concentrations of TGF-beta - synthesis and secretion of PDGF. Higher concentrations – lower expression of the PDGF receptors and hence diminish the biological effects of PDGF . www.indiandentalacademy.com
  • 57. BIOLOGICAL ACTIVITIES Overproduction of TGF-beta-1 by tumor cells - neovascularization and may help promote tumor development in vivo. TGF-beta is an autocrine growth modulator for malignant gliomas. It stimulates the growth of fibroblasts and osteoblasts in vivo and in vitro. TGF-beta induces the synthesis of bone matrix proteins in osteoblasts. www.indiandentalacademy.com
  • 58. BIOLOGICAL ACTIVITIES Factors that promote bone resorption (IL1 , vitamin D3 , parathormone) induce the synthesis of TGF-beta in bone cells. While calcitonin, an inhibitor of bone resorption, reduces the synthesis of TGF- beta. It suppresses the expression of class II MHC antigens . Microglial cells. www.indiandentalacademy.com
  • 59. BIOLOGICAL ACTIVITIES TGF-beta stimulates the synthesis of the major matrix proteins including collagen, proteoglycans , glycosaminoglycans, fibronectin , integrins, Thrombospondin , osteonectin, osteopontin . It inhibits degradation mainly by inhibiting the synthesis of neutral metalloproteinases and by increasing the synthesis of proteinase inhibitors. www.indiandentalacademy.com
  • 60. BIOLOGICAL ACTIVITIES Involved in metastatic processes. It is responsible for the transformation of epithelial cells into mesenchymal cells. Suppressive effects on the immune system . TGF-beta-1 is the most potent known chemoattractant for neutrophils . www.indiandentalacademy.com
  • 61. CLINICAL USE AND SIGNIFICANCE It may be a potent regulator of Wound healing and of bone fracture healing. Local application of TGF-beta has been shown to accelerate wound repair. In combination with bone morphogenetic protein-2 it causes development of ossification of the posterior longitudinal ligament of the cervical spine. www.indiandentalacademy.com
  • 62. CLINICAL USE AND SIGNIFICANCE The factor may be helpful in the treatment of traumatic tissue injuries. Treatment of osteoporosis. Reverses age- or glucocorticoid-impaired Wound healing even if given 24 hours before wounding. www.indiandentalacademy.com
  • 63. Bone morphogenetic protein (BMP) Responsible for osteoinductive activity in bone matrix. Non-collagenous. Water soluble. www.indiandentalacademy.com
  • 64. Bone morphogenetic protein (BMP) The cellular and molecular events governing bone formation in the embryo, healing of a fractured bone, and induced bone fusion follow a similar pattern. Bone is unique of all the tissues. When injured, it heals by formation of new bone. www.indiandentalacademy.com
  • 65. BMP-Introduction The molecular and cellular processes that lead to the development of the skeletal structures within the embryo are very similar to the cascades that occur in the healing process in an injured bone. Thus, there is a common theme in the development of bone from primitive mesenchymal tissues to a well-structured, well-organized mature bone. www.indiandentalacademy.com
  • 66. BMP-Introduction The ongoing remodeling process in an adult organism, which is exposed to external physical and hormonal influences, is also modulated through a similar molecular mechanism. Intracartilaginous process. Intramembranous process. www.indiandentalacademy.com
  • 67. BMP-Introduction Postfracture healing - intracartilaginous ossification process. Very high concentration of BMP - intramembranous route may be taken. It is unclear what factor(s) direct(s) one process as opposed to the other in the embryonic phase or during fracture healing. www.indiandentalacademy.com
  • 68. Stages of bone healing and remodeling www.indiandentalacademy.com
  • 69. GF and cytokines involved in generation of new bone www.indiandentalacademy.com
  • 70. History Senn(1889)-Decalcified ox bone promotes healing of osteomyelitic defects. Lexer(1908)-Necrotic bone tissue released stimulating factors that affect osteoblasts. Polettini(1922)-Substance released from graft tissue resulted in differentiation of fibroblasts into bone and cartilage forming cells. www.indiandentalacademy.com
  • 71. History Leriche(1928)-Ca materials contained in the graft tissue were the agents inducing new bone formation. Levander(1934)-crude alcohol extracts of bone induce bone formation in muscle. Sharrard and Collin(1961)-EDTA decalcified allograft induced spinal fusion in children. www.indiandentalacademy.com
  • 72. History Urist(1965)-acid-decalcified bone induced ectopic bone in rat model. He coined the term "bone morphogenetic protein" or "osteogenic protein" . Reddi and Sampath(1983)-crude but reproducible bioassay for BMP; bone matrix when dissociated from BMP ineffective in bone induction; reconstituted matrix effective. www.indiandentalacademy.com
  • 73. History Johnson(1992)-first clinical study; purified human BMP successful clinically. Creative biomolecules and genetic institute(1990s)-simultaneous gene sequencing for various BMP’s and related patent dispute. Stryker Corp., Medtronic Sofamor Danek(2002)- FDA approval of OP-1 (BMP-7) for long bone defects and BMP-2 in a collagen carrier within a cage for anterior lumbar interbody fusions. www.indiandentalacademy.com
  • 74. Classification of BMP Bone morphogenic proteins are members of TGF superfamily. The BMP subfamily comprises more than 10 proteins, and newer ones are being discovered. Several structural homologies between BMPs and TGF growth factors. The amino acid sequence of BMPs is considered to be as old as 600 million years. www.indiandentalacademy.com
  • 75. Classification Because of this conservation, human recombinant BMPs are highly effective in lower life forms, including fruit flies. BMPs are synthesized as precursor proteins. The mature portion of the protein is located at the carboxy terminal of the precursor molecule. www.indiandentalacademy.com
  • 77. BMP It is the only morphogen of all known growth factors that has the ability to transform connective tissue cell into osteoprogenitor cells. Thus, it is not only a mitogen but can be a morphogen as well. All other growth factors such as TGF, insulin-like growth factor, fibroblast growth factor, PDGF, and vascular endothelial growth factor all induce multiplication of cells but do not transform one cell type into the other. www.indiandentalacademy.com
  • 78. Signaling Mechanism of BMP BMP receptors - Type I and Type II serine/threonine kinase proteins. The binding of the ligand to the Types I and II serine/threonine kinase transmembrane receptors results in the activation of the signaling cascade. Type II receptor kinase phosphorylates the Type I receptor. www.indiandentalacademy.com
  • 79. Signaling Mechanism of BMP Type I receptor phosphorylates the intracytoplasmic signaling molecules Smads 1, 5, and 8. Smads 1, 5, and 8 bind to Smad 4. Translocate into the cell nucleus. Activation of transcriptional factors for the early BMP response genes. www.indiandentalacademy.com
  • 80. Dosage Normal bone contains approximately 0.002 mg of BMP per kilogram of pulverized bone. At a fracture site, presumably the BMP is released at a higher concentration. www.indiandentalacademy.com
  • 81. Dosage The concentration required for ideal induced bone bridging in osseous defects depends on several factors. - state of the organism in the evolutionary scale. - type of defect. Bone induced under the influence of BMP matures faster than natural healing of the bone. www.indiandentalacademy.com
  • 82. Other uses Brain protective agent. kidneys are their primary source in the human adult. In chronic renal disease levels of BMP are lower. systemic administration of BMP may restore some of the renal functions. Local application for dialysis patient in osteodystrophy. www.indiandentalacademy.com
  • 83. BMP Named because of their osteoinductive ability. Role in embryonic and post embryonic development. Signaling molecules in no. of tissues. Implicated in mesodermal patterning, neurogenesis and organogenesis. www.indiandentalacademy.com
  • 84. BMP BMP signaling pathways ↔ other growth factors ↔ hormonal signaling pathways. Cross talk between them must be evaluated to avoid side effects of BMP based therapies. www.indiandentalacademy.com
  • 85. BMP Mutations perturbing functions of BMP genes: BMP-5 gene mutation – short ear – abnormal growth & patterning of skeletal structures and diminished repair of bone fracture. www.indiandentalacademy.com
  • 86. BMP GDF-5 gene mutation – brachypod phenotype in mice & in autosomal recessive syndromes Hunter – Thompson chondrodysplasia in humans – shortening of appendicular skeleton and loss or abnormal development of some joints. www.indiandentalacademy.com
  • 87. BMP BMP-2 & BMP-4 knock out mice die early in embryonic development, long before development of skeleton, because of defects in gastrulation. BMP-7 knock out – eye and kidney defects, only mild skeletal defects. www.indiandentalacademy.com
  • 88. BMP Several extracellular proteins regulate activities of BMP. Noggin (BMP-4 & BMP-2) Follistatin (BMP-4 & BMP-7) Protein chordin Astacin family of metalloproteases – cleaves chordin. www.indiandentalacademy.com
  • 89. Platelet-Derived Growth Factor (PDGF) ALTERNATIVE NAMES MDGF ( monocyte-derived growth factor ) ODGF ( osteosarcoma-derived growth factor ) SOURCES megakaryocytes stored in the alpha granules of platelets(PDGF- BB/AB) released after cell activation of platelets for example by thrombin . www.indiandentalacademy.com
  • 90. Sources Unstimulated cells of osteoblastic lineage – PDGF-AA. Other cells - macrophages, endothelial cells, fibroblasts, glial cells, astrocytes, myoblasts, smooth muscle cells, and a number of tumor cell lines. Synthesis of PDGF can be induced by IL1 , IL6 , TNF-alpha , TGF-beta and EGF . www.indiandentalacademy.com
  • 91. Platelet-Derived Growth Factor (PDGF) PDGF is composed of two distinct polypeptide chains, A and B, that form homodimers (AA or BB) or heterodimers (AB). 3 isoforms. PDGF receptors have intrinsic tyrosine kinase activity. www.indiandentalacademy.com
  • 92. PDGF PDGF-BB – binds to receptor – activates extracellular signal regulated kinase 1&2 – cellular proliferation by accelerating cell recycle & inducing quiescent cells into the proliferation portion of the cell cycle. This effect is mediated by protein kinase B, a serine-threonine protein kinase. TGFb1 – inhibits receptor autophosphorylation – neutralizes mitogenic effect of PDGF. www.indiandentalacademy.com
  • 93. PDGF Proliferative responses to PDGF action are exerted on many mesenchymal cell types. Two related receptors, called PDGFR alpha or PDGFR beta. PDGF is not released into the circulation. The biological half-life is less than two minutes after intravenous administration. www.indiandentalacademy.com
  • 94. PDGF In the adult organism PDGF is involved in Wound healing processes. The dimeric form of PDGF is mainly mitogenic for cells of mesenchymal origin while monomeric forms of PDGF are mainly chemotactic. Disruption of PDGF signaling – perinatal lethality > 50%. www.indiandentalacademy.com
  • 95. PDGF At low concentrations PDGF is a chemoattractant for fibroblasts. PDGF is also chemotactic and activating for monocytes and neutrophils. PDGF (alone and in combination) may be useful in promoting bone formation. Promotes fracture healing. Doesn’t provides entire osteogenic properties itself. www.indiandentalacademy.com
  • 96. PDGF Osteoblasts can specifically bind and proliferate in response to PDGF. Enhanced proliferation of both osteoblasts and osteoclasts. In tissue culture, PDGF alone has not yet been proved to be osteoinductive in vivo. In osteosarcoma – positive feedback loop. Platelet gel. www.indiandentalacademy.com
  • 97. PDGF PDGF is chemotactic for both alkaline phosphatase positive and negative cells. It may so contribute to recruitment of bone cells during remodeling and repair. Used in implants and periodontal therapies. With or without IGF-I. www.indiandentalacademy.com
  • 98. Fibroblast Growth Factors (FGFs) 19 distinct members FGF1 (acidic-FGF, aFGF) and FGF2 (basic-FGF, bFGF). Studies of human disorders & gene knock- out studies in mice show the prominent role for FGFs is in the development of the skeletal system in mammals. www.indiandentalacademy.com
  • 99. aFGF SOURCE Best sources of aFGF is brain tissue. The mechanism underlying the release of aFGF is unknown. www.indiandentalacademy.com
  • 100. bFGF SOURCES Almost all tissues of mesodermal and neuroectodermal origin. Also in tumors derived from these tissues. Endothelial cells. www.indiandentalacademy.com
  • 101. FGF potent inducers of mesodermal differentiation in early embryos. Specific cell-surface receptors. 4 distinct receptor types identified as FGFR1 - FGFR4. Receptors has intrinsic tyrosine kinase activity . autophosphorylation of the receptor is the immediate response to FGF binding. www.indiandentalacademy.com
  • 102. FGF FGFs also bind to cell-surface heparan-sulfated proteoglycans with low affinity The FGF receptors are widely expressed in developing bone. Mutations in the FGFR genes-autosomal dominant disorders of bone growth e.g. achondroplasia(FGFR3). FGFR3 is predominantly expressed in quiescent chondrocytes & it restricts chondrocyte proliferation and differentiation. www.indiandentalacademy.com
  • 103. FGF bFGF stimulates the growth of fibroblasts, myoblasts, osteoblasts, endoth elial cells, chondrocytes, and many other cell types. bFGF is not only a mitogen for chondrocytes but also inhibits their terminal differentiation. www.indiandentalacademy.com
  • 104. FGF Animals experiments with bFGF - promotes endosteal, but not periosteal, bone formation. bFGF may thus be a potential agent for treatment of osteoporosis which may increase bone mass without causing outward deformation of the skeletal bones. www.indiandentalacademy.com
  • 105. FGF Craniosynostosis syndromes have been shown to result from mutations in FGFR1, FGFR2 and FGFR3. Sometimes the same mutation can cause two or more different craniosynostosis syndromes. www.indiandentalacademy.com
  • 106. Affected Receptor Syndrome Phenotypes FGFR1 Pfeiffer broad first digits, hypertelorism FGFR2 Apert mid-face hypoplasia, fusion of digits FGFR2 Beare- Stevenson mid-face hypoplasia, corrugated skin www.indiandentalacademy.com
  • 107. Affected Receptor Syndrome Phenotypes FGFR2 Crouzon mid-face hypoplasia FGFR2 Jackson- Weiss mid-face hypoplasia, foot anamolies FGFR2 Pfeiffer same as for FGFR1 mutations www.indiandentalacademy.com
  • 108. Affected Receptor Syndrome Phenotypes FGFR3 Crouzon mid-face hypoplasia, acanthosis nigricans FGFR3 Non-syndromatic craniosynostosis digit defects, hearing loss. www.indiandentalacademy.com
  • 109. Insulin-Like Growth Factor IGFs are single chain peptides. 2 isoforms (IGF-I and IGF-II). 40-50% homology with insulin. Still all 3 have unique binding site to their receptors. IGF also has general activity (metabolic & growth promoting) in many tissue types. www.indiandentalacademy.com
  • 110. IGF-I SOURCE Mainly liver. IGF – responsible for fetal and postnatal growth and development in general. www.indiandentalacademy.com
  • 111. IGF-I IGF-I receptor gene – deleted mice died at birth putatively due to poor muscular development. IGF-I: pre + postnatal development. IGF-II: prenatal stages only. IGF-I/ IGF-II ratio increases with age in many tissues. Role in skeletal development and skeletal mass maintenance and development of teeth. www.indiandentalacademy.com
  • 112. Insulin-Like Growth Factor-I (IGF-I) Called somatomedin C(considered as circulating mediator of growth hormone). Primary protein involved in responses of cells to growth hormone (GH) IGF-I is produced in response to GH and then induces subsequent cellular activities, particularly on bone growth. www.indiandentalacademy.com
  • 113. IGF-I IGF-I has autocrine and paracrine activities in addition to endocrine activities on bone. Family of transmembrane IGF-I(tyrosine kinase), IGF-II(mannose-6-phosphate receptor) & insulin receptor. Receptor has intrinsic tyrosine kinase activity. Plays role in general growth and maintenance of body skeleton. www.indiandentalacademy.com
  • 114. Insulin-Like Growth Factor-II (IGF-II) Exclusively expressed in embryonic and neonatal tissues. Following birth, the level of detectable IGF-II protein falls significantly. The IGF-II receptor is identical to the mannose-6-phosphate receptor. www.indiandentalacademy.com
  • 115. IGF Osteoblast aging is associated with impaired production of the stimulatory components of the IGF-system, that may contribute to age-related decline in osteoblast functions. Of all IFG binding proteins, IGFBP-5 is abundant in bone matrix. www.indiandentalacademy.com
  • 116. IGF IGF-I & II are potent survival factors for fibroblasts, hematopoetic cells, cardiac muscle cells & pancreatic beta cell. IGF-I has anti apoptotic activity in these cell types and in certain tumors. Autocrine loop – tumor promoting effect. IGF-I has chemotactic effect on osteoblasts in a dose dependent manner. IGF-II effects only at lowest conc. www.indiandentalacademy.com
  • 117. IGF It promotes expression of bone specific protein e.g. bone sialoprotein, and osteopontin. In vivo, systemic application of IGF-I – rapidly activated bone turnover – increase in serum osteocalcin, increased collagen marker of bone formation, and an increased urinary ratio of Ca/creatinine. www.indiandentalacademy.com
  • 118. IGF In inflammatory tissue (e.g. fracture repair) – IL1 increases IGF-I production. IGF-I activity can be suppressed by NSAIDs e.g. indomethacin. www.indiandentalacademy.com
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