chondrogenesis Flashcards
what is the origin of axial skeleton?
paraxial mesoderm —-> somites ——-> axial skeleton
which genes dictate the transition from cervical to thoracic vertebrae
boundary between hoxc5 and hoxc6
how do hox genes dictate the positional identity of vertebrae?
- dictates transitions in type of vertebrae e.g. from cervival to thoracic
- dictates amount of proliferation in a given tissue
what is a chondroblast
- 1st cartilage cell type
Pax1 or Pax9 is required for __________________________
medial sclerotome development
where is Pax1 more strongly expressed in the somite?
medial sclerotome
where is Pax9 more strongly expressed in the somite?
lateral sclerotome
what are the extrinsic signals controlling sclerotome formation?
- 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
what are the 2 main modes of ossification?
- intramembranous ossification
- endochondral ossification
what is intramembranous ossification and where does it occur?
mesenchymal cells condense and then directly differentiate into osteoblasts
occurs in the skull
what is the growth plate
cartilage separating the epiphysis from the diaphysis
involved in the growth of bone post-natally
describe the process of endochondrial ossification
- chondrogenesis –> cartilaginous model of bone formed
- maturation of chondrocytes to form hypertrophic chondrocytes
- hypertrophic chondrocytes die by apoptosis
- blood vessels enter the space and carry osteoclasts and osteoblasts into the space
- osteoclasts degrade collagen matrix and allow differentiation of osteoblasts into bone - osteoblasts deposit in bone matrix (replacing disappearing cartilage) = primary ossification centre
- blood vessels enter the epiphyses = secondary ossification centres
- epiphysis’ and diaphysis is ossified
what is the role of Desert Hedgehog?
development of genital organs
Campomelic dysplasia
sox9 mutation
defects in bone + cartilage formation and defects in intramembranous ossification
Cleidocranial dysplasia
Runx2 mutation
defects in bone formation + defects in forming hypertrophic chondrocytes
proliferating chondrocytes not capable of maturing
what does the axial skeleton consist of?
vertebral column (vertebral bodies and intervertebral discs), sternum and scapula
what would be observed in a pax1 KO?
mice = viable
slight abnormalities in axial skeleton
what would be observed in a pax9 KO?
normal development of axial skeleton
abnormal skull, visceral + limb skeleton development
mice die shortly after birth
where are the neural arches derived from?
dorsal sclerotome
where are the proximal ribs derived from?
lateral sclerotome
how are chondroblasts formed from sclerotome cells
- mesenchymal cells = sclerotome
- sclerotomal cells migrate around notochord & downregulate pax1/9 expression
- upregulate production of ECM proteins specific to cartilage - aids condensation around the notochord
- chondroblasts formed + formation of structure around the notochord looking like vertebrae
what is the role of sox9 in chondrogenesis?
induces transcription of cartilage matrix = collagen 2, collagen 4, collagen 11
how are chondrocytes formed from chondroblasts?
BMP2, BMP4 and BMP5 induce proliferation of chondrocytes
sox9 produces cartilage matrix
chondrocyte formed
what is the perichondrium?
fibrous layer surrounding the cartilage
what is endochondrial ossification and where does it take place
- after mesenchymal condensation, formation of cartilage which is replaced by bone
occurs in somites and limb
what would be observed if sox9 KO immediately after mesenchymal condensation?
complete absence of cartilage and bone
sox9 needed for mesenchymal condensation to form sclerotome
what would be observed if sox9 KO once chondrocytes formed
inhibit maturation of chondrocytes into hypertrophic chondrocytes
what does Osterix do?
expressed in osteoblasts and osteoclasts
controls bone formation
requires runx2 for its transcription
what are the layers of the growth plate?
- proliferative chondroblasts
- differentiated chondrocytes
- pre-hypertrophic chondrocytes
- hypertrophic chondrocytes
- zone of ossification
what is the function of PTHrP in the growth of bones?
prevents differentiation of chondroblasts into chondrocytes then hypertrophic chondrocytes in growth plate
what is the function of FGFR3 in the growth of bones?
promotes proliferation of chondroblasts in growth plate
describe the negative feedback loop in the growth of bones
- pre-hypertrophic chondrocytes release Ihh
- Ihh causes perichondrium to release PTHrH
- pTHrH diffuses into chondroblast and prevents it from differentiating into chondrocytes then hypertrophic chondrocytes
= negative feedback loop to maintain progenitors - FGFR3 inhibits Ihh
how can dwarfism occur
- GOF FGFR3 mutation –> excess of progenitors (chondrocytes) that will never differentiate
- LOF pTHrH —> chondrocytes differentiate too quickly - prevents maintenance of progenitor pool
