amelogenesis - semmelweis egyetem · the hydrophobic amelogenesis form globular aggregates...
TRANSCRIPT
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Amelogenesis
Dr. Gábor Varga
Department of Oral Biology
February, 2016
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Amelogenesis - introduction
• Amelogenesis as a part of tooth formation
• Secretory phase of amelogenesis
• Maturation phase of amelogenesis
• Proteins involved in amelogenesis
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Molar
longitudinal
section
the enamel
covers the dentin
Pulp Horn
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LAMINA BUD STAGE CAP STAGE BELL STAGE ERUPTION
Tooth development
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Gene activation during tooth development
Epithelium
Mesenchyme
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Tooth development – details 1
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Tooth development – details 2
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Section of tooth – enamel and dentin formation
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Formal and structural changes of ameloblasts
during enamel formation
1 2 3 4 5 6 7
1. morphogenetic, 2. inductive, 3. early secretory, 4 secretory,
5. maturation - ruffle-ended, 6. maturation – smooth-ended, 7. protective
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Amelogenesis
1st - Secretory phase
Secretion of proteins
Foundation of the mineral structure
2nd – Maturation phase
Reabsorption of proteins and water removal
Secretion of mineral ions
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The initiation of enamel formation on the surface of
the already formed, unstructured mantle-dentin
zománc=enamel .
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The arrangement of ameloblasts during enamel formation
Outer enamel epithelium
Stellate reticulum
Stratum intermedium
Ameloblasts
Enamel matrix
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Fully differentiated secretory ameloblasts
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Secretory ameloblasts and surrounding cells
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Ultrastucture
of secretory
ameloblasts
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Tomes process sorrounded by freshly produced enamel
SG – secretory granule, PZ – prismatic (rod) enamel, IPZ –
interprismatic (interrod) enamel
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Enamel
structure
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Proximal
Distal
PE
IPE
IPE
PE
PE
N
GA
SG
TP
Sh Sh
TP
N: Nucleus
GA: Golgo apparatus
SG: Secretory granule
TP: Tomes process
Sh: Sheath region
PE: Prismatic enamel
IPE: Interprismatic enamel
Secretory ameloblasts –
formation of prismatic enamel
(PE) and interprismatic enamel
(IPE)
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Three dimensional arrangement of crystal rods
(prismatic enamel) in the vincinity of Tomes processes
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Parallel running crystallites (Kr) in the early phase
of enamel development
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Amelogenesis
• 1st - Secretory phase
• 2nd – Maturation phase
2.a. reabsorption of proteins
and water removal
2.b. secretion of mineral ions
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Papillary layer (PL) cells between the capillaries
and the maturation ameloblasts (MA).
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Basement
membrane
Enamel
Dentin
Transitions Multiple
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Za & Zo
M
M
E
G
Maturation ameloblast phenotypes: ruffle-ended and smooth-ended
maturation ameloblasts cycle back and forth during the maturation
phase
Ruffle-ended and smooth-ended maturation ameloblasts cycle back and forth
during the maturation phase. Cycling of the two phenotypes involves extensive
remodeling of the distal cytoplasm and junctional complexes at both ends of
the cells. The Golgi complexes (G) and the lysosomal (L) apparatus are well
developed in both cell configurations. Zonula adherens (Za) and zonula
occludens (Zo) shift from distal position in the ruffle-ended ameloblasts to a
proximal position in the smooth-ended ameloblasts. Mitochondria (M) are
located primarily in the distal cytoplasm. Endosomes (E) containing enamel
matrix are present both in the ruffle-ended and smooth-ended ameloblasts. The
ruffle ended surface primarily supports electrolyte exchange while the smooth
ended form is for cell recovery and protein absorption.
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The two types of ameloblasts during the absorptive phase
Mineral secretion Protein and water absorption
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Ultrastructure
of ruffle-ended
maturation
ameloblasts
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CFTR
Na+
Basolateral
membrane
Apical
membrane
Tight junction
Na+
H+
Na+
2HCO3−
Na+
K+
2Cl−
H+
Na+
NHE1
NBCe1
(?) NKCC1
CaCC
NHE3 (?)
HCO3−
Cl−
CO2 + H2O (?)PMCA Ca
2+
AE2
~ 3Na+
2K+
Na-K-
ATPase K
+ (?) Maxi-K
K+
TASK2 (?)
CA 2HCO3−
Cl− PAT-1
Ameloblast transporters
CO2 CO2
H+
H+-ATPase ~
Ca2+/ K+
Na+
NCKX4
Ca2+
Na+
NCX
10 Ca2++ 6 HPO42-+ 2 H2O ↔ Ca10(PO4)6(OH)2+ 8 H+
Cl-(HCO3-)
(?)
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Na+
Basolateral
membrane
Apical
membrane
Tight junction
Na+
H+
Na+
2HCO3−
Na+
K+
2Cl−
H+
Na+
HCO3−
Cl−
CO2 + H2O PMCA Ca
2+
~ 3Na+
2K+
K+
K+
CA 2HCO3−
Cl−
Ameloblast calcium transport elements
CO2 CO2
H+
~
Ca2+/ K+
Na+
NCKX4
Ca2+
Na+
NCX
10 Ca2++ 6 HPO42-+ 2 H2O ↔ Ca10(PO4)6(OH)2+ 8 H+
Cl-(HCO3-)
(?)
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CFTR
Na+
Basolateral
membrane
Apical
membrane
Tight junction
Na+
H+
Na+
2HCO3−
Na+
K+
2Cl−
H+
Na+
NHE1
NBCe1
(?) NKCC1
CaCC
NHE3 (?)
HCO3−
Cl−
CO2 + H2O Ca
2+
AE2
~ 3Na+
2K+
Na-K-
ATPase K
+ (?) Maxi-K
K+
TASK2 (?)
CA 2HCO3−
Cl− PAT-1
Ameloblast bicarbonate transport elements
CO2 CO2
H+
H+-ATPase ~
Ca2+/ K+
Na+
Ca2+
Na+
10 Ca2++ 6 HPO42-+ 2 H2O ↔ Ca10(PO4)6(OH)2+ 8 H+
Cl-(HCO3-)
(?)
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Ameloblast bicarbonate transport elements
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Car 2
Car 9
2 HCO3- + 2 H+ 2 H2O
+ 2 CO2 Na+
Nbce
H+ HCO3-
H2O + CO2
Na+
Nhe1
Ae2 HCO3
-
Cl-
Cl-
Cl-
HCO3-
H+
PD Cftr
CO2
H2O
Apatite formation
Bicarbonate is generated by carbonic anhydrase 2
(Car2) and is exchanged by the pendrin (PD) anion
exchanger in the apical membrane for Cl-. Cl- is
imported basolaterally by Ae2 and conducted into
the enamel by CFTR.
Car 2 = carbonic anhydrase 2 (cytosolic),
Car 9 = carbonic anhydrase 9 (membrane-bound),
Cftr = cystic fibrosis transmembrane conductance regulator
Ae2 = anion exchanger 2,
Nbce1 = sodium bicarbonate exchanger 1,
Nhe1 = sodium hydrogen exchanger 1,
P D= pendrin: HCO3-/Cl- exchanger,
█ = tight junction
Basolateral
Apical
Hypothetic model for pH regulation by ruffle
ended ameloblasts to neutralize liberated H+
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Proposed pathway of enamel protein
reabsorption and digestion by ruffle-ended
ameloblasts
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B
1 2 3 4 5 6 7
A
Tj
M
M
End
G
End
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pH cycling in rodent incisior ameloblasts
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pH cycling in rodent incisior ameloblasts
Damkier at al. Bone, 60, 2014, 227 - 234
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Hypothesis on the dynamics of phosphate equilibrium in solution
and enamel crystal (A) and the effect of ameloblasts on phosphate
dynamics in the RA phase (B) and SA phase (C).
Damkier at al. Bone, 60, 2014, 227 - 234
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Rod enamel (prismatic enamel, PZ) in cross section
electron microscopy picture
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Cross sectional scanning electron microscopy
picture following acidic treatment
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Longitudinal sectional electron scanning microscopy
of the enamel – rods are well visible
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Amelogenesis - enamel proteins
• Amelogenin
• Enamelin
• Ameloblastin
• Amelotin (Ben Ganss, Toronto)
• Tuftelin
• Osterix (Ben Ganss, Toronto)
• Proteinases (enamelysin - MMP-20 kallikrein 4 – KLK4)
• Phosphatases
Proteins with know function are in bold
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Amelogenin
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1
2
3 4
5
Amelogenin
secretion
Assembly Hydrophylic
anionic terminals
exposed
Nanospheres act
as spacers
between
crystallites
Platelike crystallites
of hydroxyapatite
Proteinase- 1
(enamelysin)
removes hydrophylic
tails
Nanospheres
hydrophobic
Proteinase-2
degrades the
nanospheres
resorption
Crystals
grows in
thickness
Concept of the role of amelogenins in the
mineralization of enamel The hydrophobic amelogenesis form globular aggregates (nanospheres) on
secretion into the extracellular space. The nanospheres form lattices that
regulate the spacing and the orientation of the C-axis of the newly forming
enamel crystallites
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Disorder scores of amino
acid sequences of
proteins participating in
biomineralization
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Disorder frequency of amino acid chains of
proteins participating in various biological
functions
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Distribution of amelogenin and
ameloblastin in enamel matrix
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Defect of amelogenesis in ameloblastin-
null mice
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p75
Msx2 Amelogenin
Amelogenin
p21, p27 Regulation of cell cycle
Trks
?
Receptor?
Enamel crystal
Ameloblastin in the enamel matrix
Ameloblast
Role of ameloblastin in the regulation of
ameloblast function
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Amelogenesis imperfecta
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Amelogenesis imperfecta
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The human amelogenin gene
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Amelogenin mutation leading to hypoplasia
- loss of three amino acid and substitution of
another one
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56 66 48 42 45 435 160 56 66 48 42 45 435 160
1 2 3 4 5 6 7 1 2 3 4 5 6 7
Hypoplastic
Amelogenesis imperfecta
(X-linked)
Hypomineralization
Amelogenesis imperfecta
(X-linked)
Genomic
sequence
mRNA
Predicted
protein
Phenotype Thin enamel Poorly mineralized enamel
9 bp deletion 5 kb deletion
1 2 3 4 5 6 7 1 2 4 5 6 7 3
The bar segments represent the introns and the boxes (1 through 7)
correspond to the exons. The nucleotide numbers are indicated below the
exons. (Adapted from Simmer et al.)
Structure of the X-chromosomal copy of the
human amelogenin gene
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Two mutations of the amelogenin gene that
cause amelogenesis imperfecta
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Amelogenin (AMELX) mutations causing
X-linked amelogenesis imperfecta
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How are changes in the AMELX gene related
amelogenesis imperfecta? • One copy of the amelogenin gene is located on each of the sex chromosomes (the X and
Y chromosomes). The AMELX gene, which is located on the X chromosome, makes
almost all of the body's amelogenin. The copy of the amelogenin gene on the Y
chromosome, AMELY, makes very little amelogenin and is not needed for enamel
formation.
• At least 15 mutations in the AMELX gene have been identified in people with X-
linked forms of amelogenesis imperfecta. (X-linked disorders are caused by mutations
in genes on the X chromosome.) Some AMELX mutations lead to the production of an
abnormal version of the amelogenin protein that can interfere with the formation and
organization of enamel crystals. Other AMELX mutations prevent one copy of the gene
from producing any amelogenin protein at all. Enamel cannot form properly without an
adequate amount of amelogenin
• Males have a single copy of the X chromosome in each cell. Males who inherit a
defective copy of the AMELX gene have very little amelogenin and develop almost no
enamel to cover and protect their teeth. Females have two copies of the X chromosome
in each cell. Females who inherit one altered copy of the AMELX gene are less severely
affected because they have a normal copy of the gene on the other X chromosome to
produce amelogenin. Their tooth enamel may have structural defects such as a
distinctive pattern of vertical grooves. No symptoms other than abnormal enamel
development have been reported in people with AMELX mutations.
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Enamelin mutations causing autosomal
dominant amelogenesis imperfecta
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Enamelysin (MMP20) and kallikrein 4
(KLK4) mutations causing autosomal
recessive amelogenesis imperfecta
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Proteins of enamel involved in Amelogenesis Imperfecta
Amelogenin: (product of AMELX and AMELY genes located on the X and Y chromosomes) is the most
abundant protein in developing enamel [26, 27]. While its exact role in enamel formation is not fully
understood, it is thought to be crucial for regulating the size and shape of the mineralizing enamel
crystallites. Multiple human mutations in the AMELX gene are associated with different AI types. There are
no known AMELY mutations. A transgenic mouse lacking expression of this gene has only a very thin
covering of enamel that lacks a prismatic structure [28].
Ameloblastin: (product of AMBS gene located on chromosome 4) is another enamel associated protein that
appears to be the second most abundant enamel matrix protein [29]. The function of this protein is mónot
completely known but it may regulated ameloblast differentiation and formation. It is considered a likely
candidate for being associated with some AI types.
Enamelin: (product of ENAM gene located on chromosome 4) is secreted by amelobasts in relatively low
amounts. It is speculated that this protein could interact with amelogenin or other
enamel matrix proteins and be important in determining growth of the length of enamel crystallites.
Three different mutations ENAM gene mutations are associated with different AI types.
Enamelysin: (MMP20 gene located on chromosome 11) is a proteinase that cleaves amelogenin and is
thought to be the major proteinase involved in processing the enamel matrix proteins [32, 33]. The
enamelysin knockout mouse has a reduced enamel thickness and the enamel lacks a prismatic
structure.
Kalikrein 4: (KLK4 gene located on chromosome 19) is a proteinase that is secreted predominantly
during the maturation stage of enamel development [34]. This aggressive proteinase could be
responsible for processing any proteins not cleaved by enamelysin.
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Period of
amelogenesis in
the permanent
teeth of human
dentition.
Bars: from
beginning to
completion.
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Amelogenesis - summary
• Amelogenesis as a part of tooth formation
• Secretory phase of amelogenesis
• Maturation phase of amelogenesis
• Proteins involved in amelogenesis