Section 12 mineralized tissues
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Section 12: Mineralized Tissues. 3. Ion exchange Mineralization Fluoride. note: paper on mech of fluorosis: JDR 84 , 832-6, 2005. 3/3/06. Hydroxyapatite (HA): ion exchange. in biological HA, ions are continuously in motion, dissociating, associating, etc. (dynamic equilibrium)

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Section 12: Mineralized Tissues

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Section 12 mineralized tissues

Section 12: Mineralized Tissues

3.

Ion exchangeMineralizationFluoride

note: paper on mech of fluorosis: JDR 84, 832-6, 2005

3/3/06


Hydroxyapatite ha ion exchange

Hydroxyapatite (HA): ion exchange

  • in biological HA, ions are continuously in motion, dissociating, associating, etc. (dynamic equilibrium)

  • even when there's no net precipitation or dissolution,exchange of ions is occurring

  • ion exchange rates depend on location:

crystalinterior

v slow

slow

surface

v fast

bulk solution

hydration shell

1


Ha ions substituted

HA: ions substituted

  • because bulk solutions in contact with HA vary in ion content, biological HA contains other ions:

    HA ionssubstitute ions

    Ca2+Mg2+, Sr2+, Pb2+, Fe2+

    PO43–CO32–HPO42–citrate3–

    OH–Cl–, F–, HCO3–

2


Ha ions substituted1

HA: ions substituted

  • because bulk solutions in contact with HA vary in ion content, biological HA contains other ions:

    HA ionssubstitute ions

    Ca2+Mg2+, Sr2+, Pb2+, Fe2+

    PO43–CO32–HPO42–citrate3–

    OH–Cl–, F–, HCO3–

  • most substitutions increase HA solubility

    • e.g., enamel solubility higher due to presence of 2–4% CO32– (1–2 CO32–/20 PO43– )

    • the term carbonated apatite sometimes used

    • F– exception: substitution with F–lowers solubility

2


Ion exchange in ha co 3 for po 4 3

Ion exchange in HA: CO3= for PO43–

trigonal

tetrahedral

3


Mineralization

Mineralization

  • if a solution of calcium & Pi with ion product, e.g.,1.5 mM2 (supersaturated relative to HA) is prepared,no HA forms

  • if crystal of HA added,it will grow until solution's ion product = K'sp

  • these experiments illustrate:

    • Ca-Pi solutions tend to stay supersaturated

    • precipitation on existing crystals (seed or nucleator)is much faster

  • stoichiometry of HA formation:

    10Ca2+ + 6HPO42– + 8OH–®Ca10(PO4)6(OH)2 + 6H2O

4


Mineralization in vitro

Mineralization in vitro

  • if above solution's ion product increased to >3 mM2,

    a different CaP salt forms:

    calcium hydrogen phosphate: CaHPO4.2H2OK'sp= 2.6mM2

    aka brushite, amorphous calcium phosphate (ACP)

    this illustrates:though more soluble, other simpler salts form faster than HA

  • stoichiometry of formation & dissolution of ACP:Ca2+ + HPO42– + 2 H2O ® CaHPO4.2H2O

  • How do the first crystals form in mineralizing tissues?i.e., how is mineralization initiated?

5


Initiation nucleation

Initiation (nucleation)

Ca

Pi

_ _

_ _

OH

+

+

_ –

_ –

+ +

+ +

+

+

+ +

+ +

+

+

+

+

+

+

heterogeneous nucleation (aka epitaxy):initiating template different from crystal components

  • first ions of crystal-to-be aligned by binding to surface of a protein

Model of part ofinitiator protein:surface complementaryin shape & chargeto HA unit cell

6

after first few ions have bound


Initiation nucleation1

Initiation (nucleation)

  • this first layer of ions then binds additional complementary ions to form a second layer, etc.

  • eventually, growth produces the final crystal

  • initiator proteins:phosphoryns,bone sialoprotein II

    • have numerous phosphorylatedser side chains:binding sites for Ca2+ of crystal-to-be

    • cationic side chainssupply + charges:binding sites forPO43– & OH–

_ _

+

_ –

+ +

+

+ +

+

+

+

7

HA unit cell


Crystal growth

Crystal Growth

  • matrix vesicles

    • phospholipid membrane-enclosed

    • contain bone sialoprotein II (osteoblasts) phosphoryns (odontoblasts)

    • produced by budding from osteoblasts/odontoblasts

    • contain transmembrane calcium pump (CaATPase)

      ATP hydrolysis drives Ca2+ transport

      ATP + H2O ®ADP + Pi

matrix vesicle

solid CaPi

facil-itateddiffusion

activetransport

Ca2+

Pi

Pi

Ca2+

CaATPase

8


Crystal growth1

Crystal Growth

matrix vesicle

  • growth of crystallites facilitated by concentrating calcium & Pi (maintains ion product > Ksp)

  • Pi also made by hydrolysis of

    • phosphoestersalkaline phosphatase

      ROPO3– + H2O ® ROH + Pi

    • pyrophosphate (PPi)pyrophosphatase

      PPi + H2O ® 2 Pi

  • membrane removed at some time after initiation of crystallization

solid CaPi

facil-itateddiffusion

activetransport

Ca2+

Pi

Pi

Ca2+

CaATPase

9


Mineralization in bone dentin

hole zone

Mineralizationin bone &dentin

tropocollagen

  • crystallitesinitially deposited inhole zones

  • eventually also deposited in spaces parallel to tropocollagen strands (pores)

pore

hst731du.gif

crystallites

pore

hole zone

hst731dl.gif

adapted fromTen Cate, 5thed., Fig. 5-6

10

surface hole


Mineralization of enamel

Mineralization of enamel

2

2

ameloblastmovement

3

1

2

3

  • matrix proteins

    • enamelins

      • nucleator ?

      • coat surface of mature HA crystallite

    • amelogenins

      • regulate HA crystallite growth

      • digested by proteases during maturation

  • stages of mineralization

    1. nucleation (at DEJ)initiator may be dentin-based

2. 2-D growth (ribbons)

3. 3-D growth (maturation)

dashed line indicates volume ofcrystal after maturation

11


Composition of mineralized tissues

Composition of mineralized tissues

bonedentin enamelnewmature

mineral,wt % 60 70 37 95

vol % 36 47 16 86

HA/total mineral 2/3 1 1

crystallite size, Ålength200 1400width, thickness 50 800

pores, % of enamel surface area 1-2

organic,vol % 36 33 20 2

main protein collagen amelogenins enamelins

H2O,vol % 28 21 64 12

12


Section 12 mineralized tissues fluoride

Section 12: Mineralized TissuesFluoride

3/3/06


Fluoride metabolism

Fluoride metabolism

  • definitions

    • [F–]: 1 ppm = 1 mg/L (1 mg/kg in solids) = 50 µM

    • daily dose ≈ 1 mg from drinking ~ 1 L H2O with 1 ppm F –

      (dose = mg/L F–x volume ingested)

  • absorption

    • stomach & small intestine

    • via simple diffusionin stomach as HF (pKa = 3.5)

    • rate = k [F–]

    • t½ ≈ 30 min

13


Fate of absorbed fluoride

Fate of absorbed fluoride

  • [F–] in plasma: ≈ 1µM for 1 mg daily dose

  • crosses placenta

  • present in breast milk

  • deposited in bone

    • via ion-exchange (non-enzymatic, at/near equilibrium)

    • adults: ~50% of dose

    • infants: 70-80%

  • rest excreted via kidneys

    • rate = k [F–] in plasma

    • t½ ≈ 4 hr (range: 2-9 hr)

14


Fluoride toxicity lethal

Fluoride toxicity: lethal

dentalfluorosis

acutelethal

chronicfluorosis

  • acute lethal:due to

    • F – inhibition of numerous enzymes

    • reaction of F – with Ca2+ in ECF (CaF2 precipitates) low [Ca2+] excites nerve & muscle cellshypocalcemic tetanylaryngospasm

10 g

1 mg

10

1 g

100 mg

daily fluoride dose (log scale)

15


Fluoride toxicity fluorosis

Fluoride toxicity: fluorosis

dentalfluorosis

acutelethal

chronicfluorosis

  • chronic fluorosis (aka skeletal fluorosis, osteofluorosis)

    • multi-year exposure

    • hypermineralization of bone

      resorption inhibited, formation increased*

    • ectopic mineralization of tendons, ligaments

10 g

1 mg

10

1 g

100 mg

daily fluoride dose (log scale)

*these effects are the basis for fluoride use in osteoporosis prevention/treatment

16


Fluoride toxicity fluorosis1

Fluoride toxicity: fluorosis

dentalfluorosis

acutelethal

chronicfluorosis

  • dental fluorosis: enamel hypomineralization

    • fluorotic enamel contains more protein, less mineral

    • due to exposure to high [F–] during enamel formation

    • pore size >2%

    • probable contributory factors

      • impaired apoptosis of ameloblasts

      • inhibition of amelogenin-digesting proteases duringenamel maturation

10 g

1 mg

10

1 g

100 mg

daily fluoride dose (log scale)

17


Effect of fluoride on caries dental fluorosis

Effect of fluoride on caries & dental fluorosis

10

4

1. v mild: small chalky areas < 25% of surface

2. mild: white opacities < 50% of surface

3. moderate: brown staining; some on all surfaces

4. severe: extensive discoloration & hypoplasia

2

decayed, missing, filled

5

fluorosis index

0

10

1

0.1

ppm fluoride

Fluorosis index (one version)

18


Anticaries effect of fluoride

Anticaries effect of fluoride

  • presence of fluoride during enamel formation and/or remineralization results in partial replacement of OH– with F– in HA

  • molecular rationale for anticaries effect

    • F– ion smaller & more symmetrical than OH–, allowing better packing of ions

      • within unit cell

      • between unit cells (shared ions)

    • interionic attractions greater, so solid state stabilized, therefore solubility (K'sp) lower

19


Ion exchange f for oh

Ion exchange: F– for OH–

hydroxyapatite unit cell,with 1 OH– replaced by 1 F–

for presenting

20


Anticaries effect of fluoride cont d

Anticaries effect of fluoride (cont’d)

  • HA crystals larger, have fewer defects (imperfections)

  • resulting enamel has less space between crystals (smaller pores)

  • stoichiometry of hydroxyapatite ↔ fluorapatite

    Ca10(PO4)6(OH)2 +2 F– ↔ Ca10(PO4)6F2 + 2 OH–

    (complete replacement of OH– by F– would yield 38,000 ppm F–)

  • maximum replacement <10% of this

  • 21


    Tooth surface proximity f concentration

    Tooth surface proximity & F– concentration

    • HA nearest enamel surface has highest [F–]

    • surface HA has lower solubilitydue to higher F– content

    • surface accumulationprobably due to F–incorporation duringcrown maturation

    • additionally, F– is added by long-term ion-exchange & demineralization/remineralization

    ppm in H2O

    1

    2000

    0.1

    ppm fluoride

    1000

    25

    50

    22

    microns from surface


    Fluoride incorporation over time

    Fluoride incorporation over time

    4000

    5 ppm in H2O

    • F – content of HA increases with age

    • dependent on [F–] in H2O

    • incorporation into HA by:remineralizationion exchange

    • F – presence in saliva inhibits net demineralization

    • topical F – application with high [F–] produces CaF2 deposit,providing slow-release of F–

    2000

    ppm F in surface enamel

    1000

    600

    1 ppm in H2O

    400

    30

    50

    tooth age, years

    23


    Anticaries effect of fluoride topical vs systemic

    Anticaries effect of fluoride:topical vs. systemic

    high systemic-F–

    thenlow topical-F–

    • people with enamel made in high-F– area who move to low-F– area have higher caries rate

    • people with enamel made in low-F– area who

      • move to high-F– area

      • use F– toothpastes

        have lower caries rate

    • people take on caries rate of region they move to

    • results suggest that F– presence during demineralization/ remineralization* is most important anticaries effect

    • i.e., topical exposure to F– more important than systemic exposure

      * acid challenges

    low systemic-F–

    thenhigh topical-F–

    (acid challenges)

    info from"Fluoride in Dentistry" chptr 19

    24


    Section 12 mineralized tissues

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    4. Saliva, pellicle, plaque

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