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MSS > MSS26 Molecular Mechanism Of Bone Development > Flashcards

MSS26 Molecular Mechanism Of Bone Development Flashcards

1
Q

Forelimb development

A
  1. Lateral plate mesoderm
    - -> skeletal tissues of limbs
  2. Somites (Paraxial mesoderm):
    - -> nerves, blood vessels, muscles
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2
Q

Limb patterning

A
  1. Stylopod:
    - Humerus
  2. Zeugopod
    - Radius
    - Ulner
  3. Autopod
    - Carpals
    - Metacarpal
    - Phalanges
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3
Q

***Limb outgrowth

A

Proximal-distal: ***FGF signaling

  • **AER (apical ectodermal ridge) produce **FGF8
  • FGF8 diffuse from ***distal to proximal

Anterior-posterior: ***Hedgehog signaling

  • **ZPA (zone of polarising activity) produce **Shh (sonic hedgehog)
  • Shh diffuse from ***posterior to anterior
  • produce ***gradient of morphogen

Dorsal-ventral signaling: WNT signaling
- influence dorsal tissue

ALL these signals do not act alone

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4
Q

4 phases of skeletal morphogenesis

A
  1. Migration of mesenchymal cells
  2. Cell interaction: between epithelial cells and mesenchymal cells
  3. Condensation –> condensed mesenchymal cells
  4. Differentiation
    mesenchymal cells –> chondrocytes / osteoblasts
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5
Q

2 processes of bone formation

A
  1. Intramembranous
    Mesenchymal cells directly differentiate
    –> osteoblasts
    –> Clavicles, Craniofacial skeleton
2. Endochondral
Mesenchymal cells
--> cartilage cells
--> cartilage template of future bone
-->
- ***Cartilage replacement
- ***Blood vessel invasion
- ***Mineral deposition
- ***Bone synthesis
--> Axial and appendicular bones
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6
Q

Control of osteoblast differentiation

A
  • **RUNX2
  • a transcription factor (small family)
  • -> Gene activator
  • master gene for osteoblast differentiation
  • regulates osteoblast specific genes
  • RUNX2 deficient mice
  • -> normal cartilage skeleton develops
  • -> but NO bone tissue formed
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7
Q

Cleidocranial dysplasia (CCD)

A
  • Mutation in RUNX2 –> haploinsufficiency

Symptoms:

  1. Delayed closure of ***cranial suture and fontanelles
  2. Hypoplastic / aplastic ***clavicles
  3. ***Dental abnormalities
    - delayed eruption of deciduous and permanent teeth
    - supernumerary teeth of permanent dentition
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8
Q

Control of chondrocyte differentiation

A
  • **SOX9
  • a transcription factor (large family)
  • -> Gene activator
  • SRY-related (sex-determining region Y gene) HMG (high-mobility-group) box (DNA binding region)
  • required for expression of cartilage-specific ***ECM
  • -> Collagen II, IX, XI, Aggrecan
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9
Q

Campomelic dysplasia

A
  • Mutation in SOX9

Symptoms:

  1. Bowing and angulation of ***long bone
  2. ***Scapular and pelvic hypoplasia
  3. ***Vertebral column abnormalities
  4. Decreased no. of ribs
  5. Small cranium resulting from severe craniofacial anomalies
  6. XY sex reversal (male with normal female external genitalia)
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10
Q

***Transcriptional regulation of Osteochondroprogenitor

A

Mesenchymal cells
-(SOX9)-> Osteochondroprogenitor –>

  1. (RUNX2 on, SOX9 off) –> osteoblast –> functional osteoblast
  2. (SOX9 keeps on) –> chondrocyte –> hypertrophic chondrocyte
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11
Q

Developing limbs are formed in proximodistal sequence

A

FGF signaling

  • FGF8 produced by ***AER (apical ectodermal ridge)
  • FGF8 diffuse from ***distal to proximal

Cartilages are formed as continuous rods

  • -> Apoptosis
  • -> Bifurcations and segmentations
  • -> joints
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12
Q

Anterior-posterior patterning

A
  • ***Sonic hedgehog (Shh), Gli proteins
  • determine sequence of fingers

Absence of Gli protein

  • -> Greig cephalopolysyndactyly syndrome (fused fingers/toes, widely spaced eyes, macrocephaly)
  • -> polydactyly / abnormally wide thumb or big toe
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13
Q

Hedgehog processing and signaling

A
  • Hh sending cell
  • -> send signals to Hh receiving cell
  • -> with Ptc receptor, Smo receptor (controlled by Ptc)
  • -> Hh binds to Ptc receptor
  • -> Stop Ptc control on Smo
  • -> ***Gli complex stabilized
  • -> Gene activator

Overall: Hh —> Ptc —X—> Smo —> stabilise Gli complex —> gene activator

(No Hh signaling

  • -> Ptc inhibit Smo
  • -> Gli complex degraded
  • -> Gene repressor)

Shh-controlled processing (e.g. cleavage) regulates ***transcriptional activity of Gli3

Gene activator / repressor –> determine cell behaviour

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14
Q

Morphogens function as gradient

A

ZPA produce Shh from ***posterior to anterior

  • -> produce gradient of morphogen across different region
  • -> different regions have ***different positional values / threshold
  • -> different cell fates
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15
Q

Endochondral bone formation

A
  1. Cartilage model
  2. ***Chondrocyte proliferation then hypertrophy
  3. Cartilage mineralization
  4. Vascular invasion
  5. Cartilage replacement with bone
  6. Growth plate cartilage
  7. Linear growth of long bone
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16
Q

Balance between Proliferating cells and Hypertrophic cells

A

controlled by:

  • FGF and receptors
  • Ihh
  • PTH/PTHrP and receptors
17
Q

FGF and receptors

A
  • key roles in Chondrogenesis
  • Negative regulators of chondrocytes:
  • -> when FGF bind to FGFR3
  • -> ***Suppress proliferation (in contrast to usual role of FGF: ↑ cell proliferation)
  • Heparan sulphate proteoglycan (HSPG) required for FGF activity
  • > = 18 FGFs, 4 FGFR
  • FGFR: tyosine kinase receptor
Mechanism:
FGF bind to FGFR
--> dimerization of FGFR
--> phosphorylation of STAT1 to STAT1-P
--> transcription activation of p21
--> bind cdk4,2 complex
--> inhibit cyclin D, E dependent kinase activity
--> ***inhibit cell cycle progression from G1 (cell growth) to S (DNA synthesis)
--> ***block chondrocyte proliferation
--> retard bone growth
18
Q

Defects caused by mutations in FGF3 receptors

A

Too much FGF signaling

Osteochondrodysplasia:

  1. Achondroplasia
  2. Hypochondroplasia
  3. Thanatophoric dysplasia
19
Q

Proposed effects of FGFR3 mutation

A
  1. Mutations in **transmembrane domain
    - -> **    stabilization of dimer
    - -> too much phosphorylation
    - -> too much inhibition of cell cycle
  2. Formation of disulphide bonds between receptors
    - -> ***ligand independent activation of receptor
  3. Mutation in tyrosine kinase domain
    - -> ***ligand independent activation of receptor

ALL these are Gain-of-function mutations

20
Q

PTH, PTHrP and PTH1R

A

PTH1R: Receptor for PTH and PTHrP

PTHrP, PTH1R: major roles in normal endochondral bone formation and elongation

PTH and 1,25-dihydroxyvitamin D3
- regulators of Ca and PO4 homeostasis

PTHrP (PTH related protein):
–> tumour-associated humoral hypercalcemia

21
Q

Inactivation and Activation of PTHrP-R and PTHrP

A

PTHrP-R Inactivation: (齋differentiate唔proliferate)
No suppression of differentiation of proliferative chondrocyte into pre-hypertrophic chondrocyte
–> ↑ hypertrophic differentiation + ↓ proliferation

Differentiation speed faster than proliferation speed
–> Retard growth

PTHrP-R Activation: (齋proliferate唔differentiate)
↓ hypertrophic differentiation + ↑ proliferation
–> still Retard growth because hypertrophic differentiation essential for bone growth

Conclusion: must strike balance

22
Q

Indian hedgehog (Ihh)

A
  • Morphogen
  • Stimulate chondrocyte proliferation (form cartilage)
  • Prevent chondrocyte hypertrophy (form bone)

Mechanism:
- Ihh expressed in pre-hypertrophic cells (between proliferative and hypertrophic cells)

  • 2 effects:
    1. Short range effect: stimulate proliferating chondrocytes to proliferate
  1. Long range effect: diffuse to perichondrium
    - -> activate PTHrP
    - -> PTHrP diffuses back to pre-hypertrophic layer to bind to PTHrP-R
    - -> suppress differentiation of proliferative chondrocyte to pre-hypertrophic chondrocyte
    - -> ↓ no. of pre-hypertrophic chondrocyte
    - -> ↓ Ihh sent to PTHrP in perichondrium
    - -> -ve feedback to regulate proportion of proliferating and hypertrophic chondrocytes in growth plates
23
Q

***Summary

A 
RUNX2 mutation (唔夠direct differentiation into osteoblasts —> form唔到flat bone):
- Cleidocranial dysplasia (CCD)
SOX9 mutation (唔夠chondrocyte differentiation —> form唔到long bone):
- Campomelic dysplasia

Proximodistal sequence:
- FGF signaling

Anterior-posterior patterning:
- Sonic hedgehog (Shh), Gli proteins

Balance between proliferating vs hypertrophic chondrocyte controlled by:

  1. FGF and receptors (suppress proliferation)
  2. Ihh (stimulate proliferation, activate PTHrP)
  3. PTH/PTHrP and receptors (stimulate proliferation, suppress hypertrophy)

MSS (32 decks)

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