chondrogenesis

Question 1

what is the origin of axial skeleton?

Answer 1

paraxial mesoderm —-> somites ——-> axial skeleton

Question 2

which genes dictate the transition from cervical to thoracic vertebrae

Answer 2

boundary between hoxc5 and hoxc6

Question 3

how do hox genes dictate the positional identity of vertebrae?

Answer 3

• dictates transitions in type of vertebrae e.g. from cervival to thoracic
• dictates amount of proliferation in a given tissue

Question 4

what is a chondroblast

Answer 4

• 1st cartilage cell type

Question 5

Pax1 or Pax9 is required for __________________________

Answer 5

medial sclerotome development

Question 6

where is Pax1 more strongly expressed in the somite?

Answer 6

medial sclerotome

Question 7

where is Pax9 more strongly expressed in the somite?

Answer 7

lateral sclerotome

Question 8

what are the extrinsic signals controlling sclerotome formation?

Answer 8

• shh released from notochord —-> induces pax1/9 expression in ventral somite
• bmp4 released from lateral mesoderm —> stops pax1/9 expression domain from expanding by restricting pax1
  diffusion into lateral somite

Question 9

what are the 2 main modes of ossification?

Answer 9

• intramembranous ossification

- endochondral ossification

Question 10

what is intramembranous ossification and where does it occur?

Answer 10

mesenchymal cells condense and then directly differentiate into osteoblasts
occurs in the skull

Question 11

what is the growth plate

Answer 11

cartilage separating the epiphysis from the diaphysis

involved in the growth of bone post-natally

Question 12

describe the process of endochondrial ossification

Answer 12

1. chondrogenesis –> cartilaginous model of bone formed
2. maturation of chondrocytes to form hypertrophic chondrocytes
3. hypertrophic chondrocytes die by apoptosis
4. blood vessels enter the space and carry osteoclasts and osteoblasts into the space
   - osteoclasts degrade collagen matrix and allow differentiation of osteoblasts into bone
5. osteoblasts deposit in bone matrix (replacing disappearing cartilage) = primary ossification centre
6. blood vessels enter the epiphyses = secondary ossification centres
7. epiphysis’ and diaphysis is ossified

Question 13

what is the role of Desert Hedgehog?

Answer 13

development of genital organs

Question 14

Campomelic dysplasia

Answer 14

sox9 mutation

defects in bone + cartilage formation and defects in intramembranous ossification

Question 15

Cleidocranial dysplasia

Answer 15

Runx2 mutation
defects in bone formation + defects in forming hypertrophic chondrocytes
proliferating chondrocytes not capable of maturing

Question 16

what does the axial skeleton consist of?

Answer 16

vertebral column (vertebral bodies and intervertebral discs), sternum and scapula

Question 17

what would be observed in a pax1 KO?

Answer 17

mice = viable

slight abnormalities in axial skeleton

Question 18

what would be observed in a pax9 KO?

Answer 18

normal development of axial skeleton
abnormal skull, visceral + limb skeleton development
mice die shortly after birth

Question 19

where are the neural arches derived from?

Answer 19

dorsal sclerotome

Question 20

where are the proximal ribs derived from?

Answer 20

lateral sclerotome

Question 21

how are chondroblasts formed from sclerotome cells

Answer 21

1. mesenchymal cells = sclerotome
2. sclerotomal cells migrate around notochord & downregulate pax1/9 expression
3. upregulate production of ECM proteins specific to cartilage - aids condensation around the notochord
4. chondroblasts formed + formation of structure around the notochord looking like vertebrae

Question 22

what is the role of sox9 in chondrogenesis?

Answer 22

induces transcription of cartilage matrix = collagen 2, collagen 4, collagen 11

Question 23

how are chondrocytes formed from chondroblasts?

Answer 23

BMP2, BMP4 and BMP5 induce proliferation of chondrocytes
sox9 produces cartilage matrix
chondrocyte formed

Question 24

what is the perichondrium?

Answer 24

fibrous layer surrounding the cartilage

Question 25

what is endochondrial ossification and where does it take place

Answer 25

• after mesenchymal condensation, formation of cartilage which is replaced by bone
  occurs in somites and limb

Question 26

what would be observed if sox9 KO immediately after mesenchymal condensation?

Answer 26

complete absence of cartilage and bone

sox9 needed for mesenchymal condensation to form sclerotome

Question 27

what would be observed if sox9 KO once chondrocytes formed

Answer 27

inhibit maturation of chondrocytes into hypertrophic chondrocytes

Question 28

what does Osterix do?

Answer 28

expressed in osteoblasts and osteoclasts
controls bone formation
requires runx2 for its transcription

Question 29

what are the layers of the growth plate?

Answer 29

• proliferative chondroblasts
• differentiated chondrocytes
• pre-hypertrophic chondrocytes
• hypertrophic chondrocytes
• zone of ossification

Question 30

what is the function of PTHrP in the growth of bones?

Answer 30

prevents differentiation of chondroblasts into chondrocytes then hypertrophic chondrocytes in growth plate

Question 31

what is the function of FGFR3 in the growth of bones?

Answer 31

promotes proliferation of chondroblasts in growth plate

Question 32

describe the negative feedback loop in the growth of bones

Answer 32

1. pre-hypertrophic chondrocytes release Ihh
2. Ihh causes perichondrium to release PTHrH
3. pTHrH diffuses into chondroblast and prevents it from differentiating into chondrocytes then hypertrophic chondrocytes
   = negative feedback loop to maintain progenitors
4. FGFR3 inhibits Ihh

Question 33

how can dwarfism occur

Answer 33

• GOF FGFR3 mutation –> excess of progenitors (chondrocytes) that will never differentiate
• LOF pTHrH —> chondrocytes differentiate too quickly - prevents maintenance of progenitor pool