Lecture 16; Post Natal Growth 2 Flashcards
What is the process of bone growth known as?
Endochondral ossification
What do bones start from in endochondral ossification?
Cartilaginous structures
Describe endochondral ossification;
- Cartilaginous bone
- Periosteal bone collar
- Primary center of ossification forms
- Growth plate forms between formed diaphysis and secondary center of ossification
- Secondary center gives rise to epiphysis
- Growth plate forms on the metpahysis
Describe the structure of the growth plate at the metaphysis;
- Well these are initially chondrocytes in the cartilage structure
- Resting Zone; Chondrocytes
- Proliferating zone; Chondrocytes is proliferating
- Hypertrophic zone; Chrondrocytes are becoming hypertrophic (cells in columns)
Chondrocytes = stem cells??
What happens to the growth plate?
Bone invade the hypertrophic chondrocytes and the columns give rise to the bone architecture.
Cartilage deposition vs bone absorption rates will determine epiphyseal closure
Describe the growth plate morphology in terms of cell types;
Secondary center of ossification Proliferating Chondrocytes Pre-hypertrophic chondrocytes Hypertrophic chondrocytes Primary center of ossification
LONG BONE FORMS FROM THE ENDS TOWARDS THE MIDDLE (I.E EPIHYSIS TO DIAPHYSIS)
What explains the pathology in bone malformation;
Looking at the signalling
What sort of signalling disruptions can lead to bone pathology in growth;
GH = Essential for chond. prolif. (via IGF1)
FGF = Tonic inhibition
T3,T4 are key integrating factors of chon. hypertrophy. (can double inhibit PThrP to cause Hyp. i.e they inhibit PThrP which would normally inhibit hyp.)
What hormones promote blood vessel invasion of the bone and effect the balance of osteoclast:osteoblasts?
BV invasion; VEGF,
BMPs; Osteoblast
RANKL; Osteoclast
How does GH generate proliferation?
GH appears to stimulate growth by a combination of direct effects and effects mediated by IGFs.
How does GH stimulate IGF?
– It stimulates the production of endocrine (hepatic!) IGF-1 and its major binding protein (IGFBP-3).
What does GH do in bone growth?
– Directly induces the clonal expansion and differentiation of target stem cells (such as prechondrocytes)
How do chondrocytes respond to GH?
– Differentiating cells (chondrocytes) then respond to GH by forming IGF-1 and IGF-1 receptors, which makes them responsive to the growth-promoting effect of both endocrine IGF-1 and IGFs secreted locally (autocrine and paracrine IGFs).
What does IGF and GH receptor KO in rats tell us?
GH has a direct effect on growth
IGF and GH have a much larger effect together than either alone
Where does IGF 1 come from and act on?
• Major post-natal growth promoting factor.
- Majority bound to binding proteins (BP-3).
- Principally produced in liver (endocrine) and bone (paracrine, autocrine). Acts on wide range of tissues.
What is IGF-1 function?
- Insulin-like (promoting glucose, lipid and amino acid uptake).
- Cell proliferation & differentiation.
What does defects in IGF-1 action lead to?
Defects in IGF-1 synthesis or action lead to growth failure in humans and laboratory animals.
What may the effects of IGF-1 depend on?
• The effects of IGF-1 may depend on the tissue of origin.
– Local production of IGF-1GH-induced somatic growth
– circulating IGF-1, mainly from the liver, may not be essential for growth, but provides negative feedback for the GH axis.
What portion of circulating IGF-1 is active?
• The free (unbound) IGF-1 is thought to be the biologically active fraction of circulating IGF-1
What is IGF-1 regulated by?
• IGF-1 is primarily regulated by GH when nutrition is normal.
What is IGF-2 regulated by?
• IGF-2 is produced by cells independently of GH and IGF-1
– Essential for normal fetal growth
– Effects largely through IGF-1 receptor: more severe defects from receptor knockout than loss of either IGF
What do chondrocytes secrete that is essential for their proliferation?
IHH (indian Hedgehog)
• Secreted by chondrocytes transitioning from proliferation to hypertrophy